SAN ANTONIO BREAST CANCER SYMPOSIUM DECEMBER 2007
ANTHRACYCLINE THERAPY, BENEFITS HER2+ PATIENTS MORE THAN HER2- PATIENTS AND OTHER AGENTS SHOULD BE CONSIDERED FOR ADJUVANT TREATMENT IN EARLY STAGE BREAST CANCER
[13] Role of anthracycline-based therapy in the adjuvant treatment of breast cancer: efficacy analyses determined by molecular subtypes of the disease.
Slamon DJ, Mackey J, Robert N, Crown J, Martin M, Eiremann W, Pienkowski T, Bee V, Taupin H, Villalobos I, Lindsay M-A, Riva A, Hurvitz S, Glaspy J, Pauletti G, Sauter G, Press M. Cancer International Research Group (CIRG), Edmonton, AB, Canada
Background: The use of anthracycline-based therapies for the adjuvant treatment of high-risk breast cancer has now become a common standard part of clinical practice. The evidence supporting this approach was initially controversial but finally thought to be resolved when the Oxford overview demonstrated a 4-5 % survival advantage in favor of anthracycline-based therapies over those that did not contain an anthracycline.
Materials and Methods: We performed a systematic review of published data from randomized, controlled adjuvant chemotherapy trials reporting HER2 subtype, i.e. HER2 positive vs. HER2 normal breast cancers. In addition, the analysis of two recent and separately conducted adjuvant trials of HER2 positive and HER2 normal breast cancers respectively, that were further sub-classified by whether or not they contained co-amplification of the topoisomerase II alpha (topo IIa) gene were included.
Results: The published data demonstrate a remarkably consistent finding. Specifically, the incremental efficacy benefit attributed to anthracycline-based therapies is restricted to the HER2 positive subgroup. A recent analysis of the BCIRG 006 (HER2+) and 005 (HER2-) studies reveals that topo IIa amplification is confined to cancers that contain the HER2 amplicon. In >1,600 HER2 FISH negative samples there is not a single topo IIa amplified case. Conversely, deletion of topo IIa was found in 5% of HER2+ and 3% of HER2 tumors respectively. An analysis of the impact of topo IIa co-amplification demonstrates that the improved efficacy imparted by an anthracycline vs. a non anthracycline-based regimen is restricted to the HER2/topo IIa co-amplified cancers. These constitute 35% of the HER2+ cancers. In these cancers the efficacy resulting from an anthracycline-based regimen alone was similar in magnitude to the addition of trastuzumab to adjuvant therapy.
Conclusion: The use of anthracyclines in the adjuvant treatment of all breast cancer is not supported by the existing data. Given the known long-term cardiac and leukemogenic/MDS toxicities of anthracyclines and the lack of an incremental benefit in non HER2/topoIIa co-amplified cancers (which is 92% of the overall breast cancer population), other approaches to the adjuvant treatment of breast cancer should now be adopted.
ADRIAMYCIN IS SHOWN TO REDUCE RECURRENCE
[3077] Annual hazard rates of recurrence for early breast cancer. What has changed in the last 10 years? Results from the NORA study.
Cazzaniga ME, Mustacchi G, Pronzato P, De Matteis A, Di Costanzo F, Nardi M, Barberis G, D'Aprile M, Rulli E, Floriani I. Az Osp Treviglio-Caravaggio, Treviglio, Bergamo, Italy
BACKGROUND: 10 years ago, Saphner et Al (J Clin Oncol 14: 2738-2746, 1996) analyzed 3585 breast cancer (BC) patients (pts) in terms of annual hazard rates (HRs) of recurrence; 2661 (74.2%) were N+ve, 429 (11.9%) high-risk N-ve, 1965 (54.8%) were treated with CMF-based chemotherapy (CHT), 650 (18.1%) with anthracycline-based CHT, with or without tamoxifen (T) and 87 (2.4%) with T alone. The remaining pts were followed up. For the entire group, highest HRs of recurrence occurred during first and second year (13.30.7).
PURPOSE: to analyze in a cohort of early BC pts prospectively followed up for a median interval of 3.4 years whether the widespread of adjuvant therapy and the use of more active regimens, mainly 3-drug anthracycline-based, have induced modifications in the magnitude of recurrence peaks or in the appearance time.
METHODS: NORA is a cohort study aimed at investigating treatment modalities and clinical outcome in 3515 early BC pts radically resected in 71 oncological Italian centers. 56.5% of the pts were N-ve and 17.1% had >4 positive axillary nodes. Results concerning treatment details have been already published (Cazzaniga ME et Al, Ann Oncol 17: 1386-1392, 2006). Adjuvant medical treatment was delivered in 97.8% of the cases. Briefly, 1234 (35.1%) were treated with anthracycline-based CHT and 82 (2.3%) with taxanes, with or without T or aromatase inhibitors (AIs). CMF was delivered in 963 pts (27.3%). 3433 pts (97.7%), for whom full data concerning relapse are available, were analyzed in terms of annual HRs of recurrence, defined as the fraction of pts who recur during a 1-year interval.
RESULTS: for the entire group, the peak hazard of recurrence occurred in the interval from 3rd to 4th year (HR=3.4 0.5). The peak hazard of recurrence in all pts traditionally considered at high risk (N>10; T4) remained in the interval from 1st to 2nd year (18.2 3.6, 11.5 3.8, respectively), even if in some cases 2-3 fold reduced in comparison a decade ago. Details are listed in Table 1.
CONCLUSION: our results suggest that the widespread of adjuvant systemic therapy and the use of more active drugs, mainly anthracyclines, have delayed and reduced the peak hazard of recurrence in some groups of early BC pts. High risk pts showed a significant reduction of recurrence number but not a delay in the time of appearance.
CANCER TREATMENT RELATED BONE LOSS AND THE USE OF ZOLENDRIC ACID TO IMPROVE BONE MINERAL DENSITY
[27] The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up.
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group; Novartis Pharmaceuticals, East Hanover, NJ
Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ BCa. However, the use of AIs in this patient population results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluates the efficacy and safety of Zoledronic acid (ZA) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who are receiving adjuvant Letrozole (LET) therapy.
Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized to upfront ZA (4 mg IV q 6 mos) vs delayed ZA in 94 centers in the US and Canada. The delayed group receives ZA when either the post-baseline T-score decreases to <-2 or a clinical fracture occurs. All patients (pts) are treated with calcium and vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone mineral density (BMD) at 12 mos, was reported at ASCO 2005. The results of 36 mos follow-up are reported here.
Results: Baseline characteristics were similar between groups. At 36 mos, the upfront ZA group (n=189) showed a mean increase of 3.72% in LS BMD while the delayed group (n=188) showed a mean decrease of 2.95%, resulting in an absolute difference of 6.7% (p<0.001). The upfront group (n=189) showed a mean increase of 1.66% in total hip (TH) BMD while the delayed group (n=187) showed a mean decrease of 3.51%, resulting in an absolute difference of 5.2% (p<0.001). The overall difference in LS and TH BMD between the two groups was 8.2% and 6.7%, respectively, when BMD data in the delayed group was excluded after pts started ZA. Among pts with baseline T score between -1 and -2, 40.4% of upfront pts (7.6% of delayed pts) returned to normal T score (T score >-1) and 13.4% of delayed pts (2.1% of upfront pts) became severely osteopenic (T <-2). 15% of delayed pts had a decrease in BMD that required initiation of ZA. Fractures occurred in 5.6% of upfront pts and 6.3% of delayed pts. 199 upfront pts and 191 delayed pts had baseline and 36 mos spinal x-rays. 0.5% upfront pts and 0.52% delayed pts had a radiological fracture detected at 36 mos. The study was not designed to detect a significant difference in the fracture rate between treatment arms. Administration of ZA q 6 mos for up to 36 mos was safe and well tolerated. No serious renal adverse events and no confirmed osteonecrosis of the jaw cases were reported. Disease recurrence was reported in 9 (3.0%) pts in the upfront group, and 14 (4.7%) pts in the delayed group (p=0.24).
Discussion: The 36 mos follow-up of the Z-FAST trial show that the overall difference in the percentage change in BMD between the upfront and delayed ZA treatment groups, at both LS and TH, progressively increased from baseline through 36 mos. These data demonstrate that ZA 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in PMW with EBC.
BREAST MRIS DETECT CANCER BETTER
[1001] Effect of magnetic resonance imaging on the clinical management of women with newly diagnosed breast cancer.
Newstead GM, Abe H, Jansen SA, Shimauchi A, Sennett CA, Schmidt RA, Zak L, Olopade O, Jaskowiak N. University of Chicago; University of Chicago, Chicago, IL
Background: Magnetic resonance imaging (MRI) has been shown to identify multifocal, multicentric and contralateral breast cancer, not identified by clinical examination, mammography and ultrasound. Although the biological importance of additional areas of disease identified by histopathology has been questioned, we sought to evaluate the contribution of MRI to the initial staging of newly diagnosed breast cancer patients, and to document the effect of MRI assessment on patient management.
Materials and Methods: MRI has been routinely and non-selectively used for breast cancer staging at our institution since 2002. We identified 459 consecutive patients with 465 newly diagnosed breast cancers who underwent MRI between July 1 2002 and December 31 2006. Excluded were patients with clinical findings of inflammatory cancer. All patients were assessed by clinical examination, bilateral mammography (MG) and ultrasound (US) of the affected breast. Location, number and size of the cancers were documented. Mean patient age was 56.5 yrs (range 26-82). Histology of the index lesion: invasive duct carcinoma (IDC) n=201 (43.2%), invasive lobular carcinoma (ILC) n=40 (8.6%), ductal carcinoma-in-situ (DCIS) n=69 (14.8%) and IDC with DCIS n=155 (33.3%). Dynamic bilateral MR contrast-enhanced protocol:1 pre and 4-6 post-contrast images acquired in the coronal or axial plane, with 60-75 s timing. Analysis of lesion morphology and kinetic curve shape was classified according to the BIRADS lexicon. Location, number and size of unsuspected areas of additional tumor were documented, and classified according to their location: within the same quadrant (multifocal), within a different quadrant and at least 3 cms away (multicentric), and in the contralateral breast. Patients with positive MR for additional lesions underwent second look directed MG and US to search for additional tumor, and selected patients underwent biopsy and/or localization of additional tumor under US or MR guidance. All imaging and histologic findings were discussed at an interdisciplinary treatment conference.
Results: Analysis of the MRI staging data with pathology review, demonstrated secondary disease to be present in 106 (23.1%) patients, mean age 51.2 years (5 years younger than mean age of all). Distribution of additional disease: multifocal n=58 (12.6%), multicentric n=27 (5.9%), contralateral breast n=21(4.5%). Additional cancer histology: IDC n=36 (33.9%), IDC + DCIS n=26 (24.5%), DCIS n=29 (27.4%), ILC n=15 (14.2%). Management change: More extensive cancer surgery with breast conservation n= 86 (81.1%), mastectomy rather than conservation n=10 (9.4%) and Neoadjuvant chemotherapy n=5 (4.7%).
Conclusion: MR imaging offers more precise assessment of tumor extent than mammography or ultrasound imaging. Therapeutic management was changed in 23.1% patients (n=106), resulting in a change from breast conservation to mastectomy in 9.4% patients.
PRIOR USE OF HRT INCREASES ODDS OF
LOBULAR BREAST CANCER
[1055] Impact of hormone replacement therapy on breast cancer: Womens Healthy Eating and Living (WHEL) study experience.
Parker BA, Flatt SW, Mortimer JA, Natarajan L, Gold EB, Bardwell WA, Jones LA, Hollenbach KA, Pierce JP. University of California, San Diego, La Jolla, CA; University of California, Davis, Davis, CA; The University of Texas, Houston, TX
Prior hormone replacement therapy (HRT) has been associated with an increased incidence of breast cancer. Conflicting information exists regarding the impact of prior HRT on subsequent breast cancer development. We utilized data from the Womens Healthy Eating and Living (WHEL) Study to determine the natural history of breast cancer in women who reported HRT prior to their diagnosis of breast cancer. Our aim was to determine the features of breast cancer, the severity of vasomotor symptoms, and the disease-free survival in women with breast cancer and reported prior HRT as compared with no reported prior HRT. The WHEL Study is a multi-institutional randomized trial of dietary change to a diet high in vegetables and fruits in Stage I-IIIA breast cancer patients within 4 years of diagnosis. Baseline data regarding tumor characteristics, demographics, and the Thoughts and Feelings questionnaire regarding vasomotor symptoms were analyzed. A total of 1544 patients randomized to the non-intervention group were included in this analysis. We used bivariate statistics to assess the association of reported prior HRT with covariates, logistic regression to analyze tumor histology, and a proportional hazards model for disease-free survival. A total of 706 patients reported prior HRT including 453 who received combined estrogen and progesterone HRT for a mean of 6.8 years and 216 women with estrogen alone HRT for a mean of 9.3 years. The results of our analysis indicate that patients reporting prior HRT as compared with no prior HRT were older (mean 57 versus 48 years), had a higher incidence of lobular cancer (10.2 % versus 6.2%), had lower grade tumors (18.4% Grade 1 versus 13.6%), were more likely to report hot flashes (74.9% versus 60.6%), were more likely to report night sweats (58.3% versus 48.0%), were more likely have ER+PR+ tumors (63.6% versus 59.3%), and had a greater likelihood of being disease-free at 7.3 years follow-up (84.7% versus 81.3% as of June 1, 2006). In multivariate models, reported prior HRT weakly predicted lobular histology of the original primary tumor (OR = 1.53, 95% CI = 0.99 2.36) but did not predict disease-free survival (HR 0.78, 95% CI = 0.58-1.06). However, the significant predictive effect on disease-free survival of low tumor stage, low tumor grade and presence of hot flashes remained. These results add to reports suggesting that prior HRT is associated with an increased incidence of lobular histology at diagnosis. In our study, prognosis was similar regardless of prior reported HRT.
HER2 POSITIVE PATIENTS WHO GET LUMPECTOMIES ARE MORE LIKELY TO GET LOCAL RECURRANCES THAN THOSE WHO OPT FOR MASTECTOMIES
[1060] The prognostic significance of human epidermal growth factor receptor-2 over-expression for the development of local recurrence after newly diagnosed breast cancer.
Gabos Z, Thoms J, Hanson J, Ghosh S, Deschenes J, Mackey J, Abdulkarim B. Cross Cancer Institute, Edmonton, AB, Canada; University of Alberta, Edmonton, AB, Canada
Background: Human epidermal growth factor receptor-2 (Her-2) over-expression occurs in 20-30% of invasive breast cancer and results in aggressive disease and high-risk of recurrence. The impact of Her-2 over-expression on the risk of local recurrence is unclear.
Objectives: In this population-based study, we have investigated the incidence of local recurrence in newly diagnosed breast cancer patients with Her-2 over-expression.
Methods: Newly diagnosed breast cancer patients between 01/1998 and 12/2003 with uniform Her-2 testing were identified from a cancer registry. A total of 460 Her-2 over-expressing patients were reviewed. A random sample of 500 patients with Her-2 negative disease was also reviewed. Patients were excluded if there was a breast cancer diagnosed before 01/ 1998 or other cancer. A total of 266 Her-2 positive and 338 Her-2 negative patients were included for this analysis. The groups were stratified based on surgical treatment, lumpectomy versus mastectomy. The association between histological features and local recurrence was evaluated with univariate and multivariate analyses.
Results: In patients treated by lumpectomy, Her-2 over-expression was the only factor to be associated with increased risk of local recurrence, on both univariate and multivariate analysis, hazard ratio 7.4 (95% CI, 1.6-33.9, p=0.01). In patients treated by mastectomy it was not associated with increased risk of local recurrence.
Conclusions: In our population-based study, Her-2/neu over-expression is significantly associated with increased risk of local recurrence in newly diagnosed breast cancer patients treated by lumpectomy. In patients treated by mastectomy, Her-2 over-expression is not associated with an increased risk of local recurrence.
BETTER DRUG COMBO TO PREVENT DELAYED NAUSEA AND VOMITING FROM CHEMOTHERAPY
[1086] Dexamethasone, metoclopropamide and omperazole combination is simple, safe and effective for delayed nausea and vomiting control in adjuvant chemotheray for early breast cancer.
Sanchetee SC. Sanchetee Hospital and Cancer Insitute, Jodhpur, Rajasthan, India
BACKGROUND: Delayed nausea and vomitting in chemotherapy are the most frequently of side effect. Our study aimed to determine the effectiveness of Dexa+omeprazol versus Dexa+omeprazol+metoclopramide in the prophylaxis of dealyed emesis after emetogenic chemotheray.
METHODS: Patients after treated with FAC regimen-adjuvant chemotherapy for early stage breast cancer, receive dexamethasone 4mg oral, twice time daily and omeprazol 20mg oral, twice time daily, all for five days (Daxo) or dexamethoasone 4mg oral, twice time daily, omeprazol 20mg oral, twice time daily and metoclopramide 20mg oral, thrice time daily, all for five days (DexoPrim). Patient diary with nausea and vomiting module and toxicity criteria were used to monitor and evaluate patient outcomes.
RESULTS: From Jan 2004 to Dec 2005, 122 (mean=45,7years) outpatients were randomized with 60 Dexo and 62 DexoPrim confirmed eligible. Patient characteristics were similar between the two groups. No drug related serious adverse evetns were reported. During first cycle fo chemotherapy, DexoPrim was complete protection against vomiting better Dexo(78vs.52%;p=0.05). For the entire study period, there was better DexoPrim (69vs, 48%;p=0.02), lower average nausea score (0.02 vs. 0.39, p=0.04) and no cases must entry hospital for recuing anti eetic. Global QoL declined in both groups during chemotherapy but DexoPrim was less than Dexo (p=0.03). Appetite was the same in both groups. There were no significant differences in toxicity.
CONCLUSION: The use of combination DexoPrim oral daily for five day after chemotherapy is simple, cheap cost, safe, and effective in preventing vomiting, reducing nausea and preserving QoL.
YES THERE IS SUCH A THING AS CHEMOBRAIN!
[1094] Memory loss after adjuvant chemotherapy for breast cancer: a preliminary analysis of mediating variables utilizing cross-sectional correlations and multilevel longitudinal analysis.
Beadle G, Rolfe M, Vearncombe K, Andrew B, Mengersen K, Wright M. Queensland Institute of Medical Research, Brisbane, Queensland, Australia; Southern Cross University, Lismore, New South Wales, Australia; University of Queensland, Brisbane, Queensland, Australia; Queensland University of Technology, Brisbane, Queensland, Australia
BACKGROUND
Cognitive impairment is a well recognized complication of adjuvant chemotherapy but further research is required to identify factors that mediate cognitive change in breast cancer survivors.
METHODS
This study investigated cognitive change in verbal memory in 119 women aged less than 70 years before, at completion of, and 6 months after adjuvant chemotherapy. Verbal memory was assessed with the auditory verbal learning test trials 1-5 (AVLT1-5) and executive processing of immediate and delayed recall with the AVLT7 and the AVLT8 respectively. Cross-sectional correlations were performed with time invariant variables of age, years of education and general cognitive ability utilizing the national adult reading test (NART). Correlations with time varying variables included quality of life measures (HADS, FACT-B and FACT-F) and changing hormonal phenotype (cessation of hormone replacement therapy after diagnosis of breast cancer and changing menstrual function after chemotherapy). Unconditional random intercept quadratic regression models were fitted to AVLT1-5, AVLT7 and AVLT8, with temporal and subject level variances estimated by restricted maximum likelihood.
RESULTS
In this exploratory analysis, age, NART and years of education were significantly correlated with AVLT1-5, AVLT7 and AVLT8 at all time points (all p values <0.05). Quality of life correlates were inconsistent at most time points but statistically significant when all time points were combined (HADS depression <0.05 and FACT fatigue <0.05 for AVLT8; FACT-B <0.05 for AVLT1-5, and <0.01 for AVLT7 and AVLT8). Age, NART and years of education were significant predictors of these changes (p <0.01). In particular, a high NART predicted a less steep decline of memory over time. There was no evidence of a statistically significant association between AVLT and self-report measures of quality of life or changing hormonal phenotype after adjustment for age and NART.
CONCLUSION
A significant decline of the AVLT occurred during and after treatment with adjuvant chemotherapy. Age, NART and years of education were strongly associated with AVLT at all time points but not quality of life or changing hormonal phenotype. Further investigation of memory and executive functioning is currently underway in a larger sample of patients followed over a longer time. Multilevel longitudinal analysis is a promising tool for investigating longitudinal data that contain multiple changing covariates.
THE EFFECT OF BREAST CANCER ON COUPLES
[1097] Appraisals, coping and distress among couples dealing with breast cancer.
Hernandez AM, Bigatti SM. Indiana University Purdue University Indianapolis, Indianapolis, IN
This study aimed to investigate the cognitive appraisals, coping styles and levels of distress of couples dealing with breast cancer. Cognitive appraisals are evaluations individuals make of stressful situations in order to categorize them as benign/irrelevant, challenge, threat, or harm. These cognitive appraisals predict coping mechanisms, which in turn impact levels of distress. Studying couples, or dyads, is important because the coping style of one individual in the dyad is associated with outcomes in the other. One adaptive form of coping is emotional approach coping, which consists of emotional processing and emotional expression. Breast cancer patients currently undergoing chemotherapy treatment (n = 22) and their spouses (n = 22) were recruited from a breast cancer clinic. Both the patient and spouse completed surveys at home and returned them by mail. Stantons Emotional Approach Coping Scale, Kesslers Cognitive Appraisal of Health Scale, and the Profile of Mood States (POMS) were included in the questionnaire packages. Most of the patients had stage IV breast cancer (68.2%). The average age for patients was 53.55 (SD = 11.571) and for husbands was 54.49 (SD = 11.784). Participants were married an average of 27.28 years (13.99). Most reported a yearly income above $70,000. Husbands scored higher in the anxiety subscale of the POMS and were more likely to appraise the cancer as a threat than the patients themselves. We grouped couples into those who matched on appraisals and those who did not and examined the groups level of distress and coping. We found no differences by group for husbands on either variable, or for wives on the POMS. However, wives who did not match on appraisals with their husbands engaged in more emotional approach coping F(1,20)= 6.474, p=.019), and more specifically emotional expression F(1,20) = 4.969, p = .037) and emotional processing coping F (1,20) = 6.089, p = .023). These findings suggest that patients who have a different view of the cancer than their partners may need to engage in more coping efforts than those who have the same view. Possibly agreement, regardless of the appraisal agreed upon, relieves the patient from reappraising. On the other hand disagreement may require both processing and expression to determine whether the appraisal is in fact correct or should be reconsidered. Because appraisals change throughout the cancer experience, it may be that one impetus for reappraisals is disagreement with a spouse and subsequent emotional work.
COQ10, RIBOFLAVIN AND NIACIN INCREASES EFFECTIVENESS FOR DISEASE FREE SURVIVAL IN WOMEN WHO TAKE TAMOXIFEN
[1104] Anti-angiogenic potential of coenzyme Q10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy.
Panchanatham S. DR. A.L.M.P-G.I.B.M.S., University of Madras, Tarmani Campus, Chennai, Tamilnadu, India
Background: To evaluate the anti-angiogenesis effect of CoenzymeQ10, riboflavin and niacin (CoRN) in breast cancer patients undergoing tamoxifen therapy. Efficacy of the combinatorial (CT) drug was correlated with serum angiogenic marker levels.
Methods: Eighty four women with breast cancer undergoing tamoxifen therapy were treated with 100 mg CoenzymeQ10, 10 mg Riboflavin and 30 mg Niacin for 90 days. Blood samples were collected at the start of the study, at 45 days and 90 days of the treatment regimen. Circulating markers such as Vascular endothelial growth factor (VEGF), Matrix metalloproteinase (MMP) - 2, MMP-9, Tissue Inhibitor of metalloproteinase (TIMP) - 1, TIMP-2, Interleukin (IL) -1, IL-6, IL-8, Tumour necrosis factor (TNF) -, Extracellular domain (ECD) Her-2/neu, c-myc, Epidermal growth factor (EGFR), VCAM-1, E-selectin, Tumour growth factor (TGF) , Angiogenin, Carcinoembryonic antigen (CEA) and Carbohydrate antigen (CA) 15-3 were evaluated to determine the anti-angiogenic of this CT drug.
Results and Discussion: We found a statistically significant correlation between CoRN supplementation and reduction in angiogenesis markers. There was a reduction in the levels of serum IL-1, IL-6, IL-8, TNF-, MMP-2, MMP-9, Angiogenin, E-selectin, VCAM-1 EGFR, TGF- and VEGF levels, which are stimulators of angiogenesis as well as factors for cancer cell proliferation and growth. There was a significant reduction in tumour marker levels of CEA, CA15-3, ECD Her-2/neu and c-myc. In conclusion, this study suggests that supplementation of CoRN to tamoxifen therapy may provide good treatment prognosis by reducing the risk of cancer recurrence and metastases by decreasing the levels of angiogenic and tumour markers and importantly, the relation between dietary supplementation and cancer treatment may also have therapeutic implications in the future.
OSTEONECROSIS OF THE JAW CAN BE PREVENTED
[2056] Application of preventative measures minimizes the occurence of the osteonecrosis of the jaw (ONJ) in solid tumors patients with bone metastases treated with bisphosphonates
Ripamonti C, Maniezzo M, Cislaghi E, Campa T, Fagnoni E, Saibene G, Bareggi C, Ascani L, Pigni A, Brunelli C. National Cancer Institute, IRCCS Foundation, Milano, Italy
Background: ONJ is an uncommon side effect reported in cancer patients receiving cancer treatment regimens including BPs. Dental problems or mouth interventions were identified as the most important risk factors to develop ONJ in these pts. As consequence, screening of the oral cavity was suggested as preventive measure (Ruggiero J Oral Max Surg 2004). We investigated the occurrence rate of ONJ in our Institution before and after the implementation of dental preventive measures.
Material and Methods: Since April 2005, 153 consecutive pts treated with BPs (group POST), underwent a baseline mouth assessment (dentists visit panoramic jaw radiograph) to assess potential dental pathologies and dental care when required. Regular dental examination was maintained along BPs treatment. From Jan 1999 to Feb 2007, a retrospective review of 813 consecutive cancer patients with bone metastases (group PRE) treated with BPs in our clinic but not undergoing any preventive measure, has been conducted. Occurrence of ONJ will be presented both as row percentages (n of cases by n pts at risk) and as incidence rates (IR) (n of cases by person-time at risk). Differences between the two groups (PRE and POST preventive measures) have been analyzed through one-tailed Fishers exact test and will be presented as incidence rate difference (IRD) and its 95% CI.
Results: In the overall pts population (966 pts; M/F=255/711), 73% had breast cancer. The type of BP received was: Zoledronic Acid (ZOL) administered to 244 pts, Pamidronate (PAM) to 600, PAM followed by ZOL to 79, and Clodronate (CLO) or PAM/CLO to 43. Overall ONJ observed rate was 2.9% (ZOL/PAM+ZOL = 19 ONJ cases, PAM = 9). In group PRE and POST, ONJ cases observed were 27 (3.3%) and 1 (0.6%), respectively (p =0.048). Considering pts exposed to ZOL/PAM+ZOL, the application of dental assessment succeeded to a consistent reduction of ONJ rate (Group PRE 8.7% vs group POST 0.9%, p =0.002). The IR of ONJ in all 966 patients treated with BPs was 0.03/yr for group PRE and 0.007/yr for group POST (IRD=0.023, 95% CI from 0.0045 to 0.041).
Conclusion: According to our experience the routinely application of preventive measures before starting, and during the treatment with BPs, lead to a reduction of 75% in the incidence of ONJ. This evidence supports the relevance of applying prevention measures in all patients receiving BPs treatment.
PRIOR HRT USE INCREASES JOINT PROBLEMS
ASSOCIATED WITH ENDOCRINE THERAPY
[2071] Risk factors for joint symptoms in the ATAC trial.
Sestak I, on Behalf of the ATAC Trialists' Group. Wolfson Institute of Preventive Medicine, London, United Kingdom
Background: Joint symptoms are a well-known side effect of aromatase inhibitors. Low oestrogen levels and postmenopausal status are associated with the development of joint symptoms. Furthermore, it is known that chemotherapy induces joint symptoms. Tamoxifen seems to have little impact on the development of joint symptoms.
Methods: The two monotherapy arms of the ATAC trial randomised 6,241 postmenopausal women to anastrozole (1mg/day) or tamoxifen (20mg/day) in a double dummy double blind fashion. Here we investigate other risk factors that might have an influence on the development of joint symptoms, and examine if there was an interaction with either endocrine treatment. Pre-existing joint symptoms will be examined in the final analysis.
Results: After a median of 68 months of follow-up, a total of 2,011 joint symptoms were reported (1,100 (35.6%) anastrozole vs. 911 (29.4%) tamoxifen, OR=1.32 (1.19-1.47)). For women who used hormone replacement therapy (HRT) before trial entry, 40.1% developed joint symptoms compared with 28.3% without previous HRT use (OR=1.70 (1.52-1.89)). Women who had chemotherapy as part of their treatment developed significantly more joint symptoms than those without chemotherapy (37.2% vs. 31.2%, OR=1.31 (1.15-1.48)). The Figure shows plots of joint symptoms in each treatment arm according to prior HRT or prior chemotherapy use. It can be seen that the factors were import in both arms of the trial and that their magnitude was similar to the difference between tamoxifen and anastrozole. Women with hormone receptor negative tumours developed significantly fewer joint symptoms than those with hormone receptor positive tumours (25.8% vs. 34.0%, OR=0.67 (0.55-0.83)). Furthermore, women from North America (USACanada) developed significantly more joint symptoms than those from the United Kingdom (UK) or the rest of the world (ROW). Obese women also had significantly more join symptoms as did women who smoke. Age and prior radiotherapy showed no influence on the development of joint symptoms. Significant risk factors from the univariate analysis were included in a multivariate analysis. All of them, except smoking status at entry, persisted in that analysis.
Conclusions: In this trial, the major risk factors for developing joint symptoms were prior HRT use, treatment with anastrozole, prior chemotherapy, and obesity, leading to significant increases of 11.8%, 6.1%, 6.0%, and 5.4% respectively. There was no clear indication of any interaction between these factors.
PATIENTS WITH ADVERSE SIDE EFFECTS SHOULD TRY
DIFFERENT ENDOCRINE THERAPY FOR RELIEF
[2072] Comparison of joint problems as reported by patients in a randomised adjuvant trial of anastrozole and letrozole.
Renshaw L, McHugh M, Williams L, Dixon OM, Fallowfield LJ, Evans DB, Dixon JM. Western General Hospital, Edinburgh, Scotland, United Kingdom; University of Edinburgh, Edinburgh, Scotland, United Kingdom; Brighton Sussex Medical School, Falmer, Sussex, United Kingdom; Novartis Institutes for BioMedical Research Basel, Basel, Basel, Switzerland
Background: Anastrozole (A) and letrozole (L) are well tolerated potent non-steroidal aromatase inhibitors (AIs). Musculoskeletal problems are reported frequently by patients on these drugs. This study aimed specifically to compare reported side effects of L, A and tamoxifen (T).
Patients and Methods: 182 postmenopausal women with invasive ER positive breast cancer were randomised as part of their adjuvant hormone therapy to receive
12 weeks of L followed by 12 weeks of A or
12 weeks of A followed by 12 weeks of L.
106 had L or A after surgery and were then switched to T and 76 took L or A after 5 years of T.
Detailed side effect profiles were collected by a nurse from patient interviews after 4, 8 and 12 weeks of each drug.
This analysis specifically relates to musculoskeletal side effects. Data were available on 181 patients. 11 patients failed to complete at least one month of each drug. This leaves an effective sample size of 170 patients. An analysis was performed to look specifically at side effects that were reported on one drug that were not reported by the same patient on other drugs. Statistical analysis was by McNemars test for matched data.
Results:
Letrozole vs. Anastrozole: Muscle pain was reported by only 3 patients. Joint pain was reported by 131 patients with no differences in frequency between L and A. Joint stiffness was reported by only 10 patients but was significantly more common with A compared with L (p=0.014). These two joint symptoms have been combined as joint problems in subsequent analyses.
46 of 83 patients (56%) reporting joint problems on L did not have the same problems on A and 46 of 83 (55%) patients with problems on A did not report joint symptoms on L. The % improvement was similar whether or not patients had taken prior T. Joint problems did increase over time irrespective of drug sequence (p=0.0009).
Letrozole and Anastrozole vs. Tamoxifen: Joint problems continued on T with 13/68 patients who did not get joint problems on L and 17/65 who did not get problems on A reporting these symptoms on T.
57% (13/23) with joint problems on T did not have these when taking L and 74% (17/23) who had problems on T did not have these on A. Conversely 74% (28/38) of patients with joint problems on L and 35/41 (85%) of patients with joint problems on A did not have these on T.
Conclusions:
Over half of patients with joint symptoms on one non steroidal AI did not have the same problems on the other AI.
Three quarters of patients who had joint symptoms on a non steroidal AI did not have these problems on tamoxifen.
This study suggests that for women with significant joint problems switching hormonal therapy to another agent is likely to improve their symptoms.
AI THERAPY BETTER AS FIRST LINE TREATMENT
THAN TAMOXIFEN
[2083] Survival analysis of first-line tamoxifen versus aromatase inhibitors for estrogen-positive metastatic breast cancer in postmenopausal women a BC perspective.
Kyritsis V, De Lemos M, Walker B, Kennecke H, Nakashima L. BC Cancer Agency, Vancouver, BC, Canada; Queens University Belfast, Belfast, Belfast, Ireland
Background: Tamoxifen has been the gold standard of treatment in postmenopausal women with estrogen receptor positive (ER+) metastatic breast cancer (MBC). Over the past decade, new aromatase inhibitors (AIs) anastrozole, letrozole, exemestane have emerged as equally efficacious alternatives to tamoxifen. Recent data suggest that first-line AI therapy may even confer a moderate increase ( 4months) in overall survival compared to tamoxifen. We performed a population-based analysis of survival associated with first-line tamoxifen versus AIs for ER+ MBC to examine whether the above findings hold true for patients in BC.
Methods: This is a population-based retrospective analysis. Patients were identified from the BC Cancer Agency Information System (CAIS), systemic therapy drug database, and the provincial registry (Breast Cancer Outcomes Unit). Data was analyzed for all postmenopausal women treated with first-line tamoxifen and AIs (anastrozole, exemestane, letrozole) for ER+ MBC (stage IV disease) from January 1998 through September 2004 in BC. Patients treated with other first-line hormonal agents were excluded. The primary outcome is overall survival, defined as the time to death by any cause from the date of first-line tamoxifen or AI therapy. Overall survival was compared between patients treated with tamoxifen versus AI.
Results: We found that there is an overall survival benefit with the use of first line AI therapy in comparison to tamoxifen in our patient population. Survival data will be presented as Kaplan-Meier curves and a 2-tailed log-rank test will be used to compare the hazard rates of the survival curves.
Discussion: This analysis will provide pertinent information regarding the survival benefit between the use of first-line treatment with tamoxifen and AI. The preliminary data provided by this analysis will assist in decision making regarding appropriate first-line hormonal therapy for ER+ MBC. We hope to disseminate these findings to the rest of the communities oncology network centers in BC.
BETTER THERAPY NEEDED FOR TRIPLE NEGATIVE DISEASE
[3070] T1N0 triple negative breast cancer: adjuvant chemotherapy treatment and risk of recurrence.
Kaplan HG, Malmgren JA, Atwood MK. Swedish Cancer Institute, Seattle, WA; HealthSTAT Consulting, Inc, Seattle, WA
Background: Triple negative (TN) breast cancer (BC) has a high recurrence rate warranting more aggressive therapy at all stages.
Materials and methods: From a prospective cohort of registry patients at our institution diagnosed with primary breast cancer between 1999 and 2004 we identified a subset of TNM Stage I (T1N0) BC. Estrogen (ER) and progesterone receptor (PR)/her2-neu (her2) negative (TN) (N=91) patients were compared to ER+/PR+/her2- (HR+/her2-) (N=770) patients. Patients with equivocal her2 results unconfirmed by FISH testing were excluded (n=24). Clinical variables including age, race, t stage, and surgical, radiation and adjuvant chemotherapy treatment method were chart abstracted and vital and disease status was updated annually. Length of follow up was at least 2 years with an average follow up of 3.76 years. Pearson chi square and Fishers Exact testing were used for bivariate analysis. Relapse free survival (RFS) was calculated using the Kaplan-Meier procedure and hazard ratios using the Cox proportional hazards model.
Results: Average patient age was 59 years, ranging from 23 to 88 years with no difference between the two groups. 5.6% of the TN patients were black vs. .7% of the HR+/her2- patients (chi square =18.12, p<.001). Distribution by t stage was 10% t1a (<.5 cm), 32% t1b (>.5 - <1 cm), and 58% t1c (>1cm - <2 cm). 80% of the TN vs. 56% of the HR+/her2- were t1c (chi square = 20.97, p<.001). Among all TNM Stage I patients 88% had lumpectomy + radiation and 12% had mastectomies. Seventy percent of the TN patients had adjuvant chemotherapy vs. 20% of the HR+/her2- patients (chi square = 109.92, p<.001) with 86% of the HR+/her2- receiving hormone therapy. In both groups women less than 60 years of age were more likely to receive adjuvant chemotherapy. TN patients were more likely to receive adriamycin/cytoxan/taxane combination adjuvant chemotherapy, 25% vs. 8% (chi square = 20.97, p<.001). In total there were 3 local, 1 regional and 11 distant recurrence. The 4 local/regional all received radiation as part of initial treatment and 3/4 were TN. The rate of any recurrence was 8.8% in the TN group vs. .9% in the HR+/her2 group (chi square = 29.54, p<.001) and distant recurrence was 5.5% vs. .8% (chi square = 33.13, p<.001). The rate of recurrence was 0% in TN t1a (0/5), 7.7% in t1b (1/13), and highest in the TN t1c group, 9.6% (7/73). Five year RFS was 99% in the HR+/her2- group and 91% in the TN group (log rank test = 32.84, p<.001). In a Cox proportional hazards model comparing TN to HR+/her2- patients, the hazard ratio of any recurrence was 3.53 for TN patients (95% CI = 1.96, 6.33) adjusted for t stage (t1a/t1b vs. t1c) and chemotherapy treatment (yes/no).
Conclusions: In early stage BC triple negative patients have more than three times greater risk of recurrence in spite of more aggressive treatment by number treated and type of adjuvant chemotherapy. Triple negative specific treatment modalities and protocols need to be developed to reduce recurrence in this high risk group.
ILC Shows Better Response to Endocrine Therapy
More Prone to Bone Metastasis than Lung Metastasis
Compared with IDC
[3078] Do patients with infiltrating lobular carcinoma (ILC) have an increased risk of contralateral, local, or distant recurrences compared with patients with infiltrating ductal carcinoma (IDC)?
Pestalozzi BC, Zahrieh D, Mallon E, Gusterson B, Gelber R, Price K, Castiglione-Gertsch M, Coates A, Goldhirsch A. International Breast Cancer Study Group, Berne, Switzerland
Background: ILC differs from IDC in many respects including increased frequency of multifocality and bilaterality, undefined margins, metastatic pattern. Differences in prognosis are controversial.
Patients (pts) and methods: We analyzed data from 13,220 breast cancer (BC) pts who were entered onto IBCSG trials I through 15-95 between 1978 and 2002. Median follow-up is 13 years. Histology was based on central pathology review for trials I through V, VIII through 15-95, and local assessments for Trials VI and VII.
Results: 767 (6.2%) tumors were classified as ILC, 8,607 (70.5%) as IDC, 2,832 (23.2%) as other, and 1,014 (7.6%) unknown. This analysis is based on the 9,374 patients categorized as IDC or ILC. Selected baseline characteristics are shown in Table 1. Compared with IDC, ILC is associated with older pts, larger, better differentiated and ER-positive tumors with less vessel invasion.
Conclusion: Compared with IDC, ILC is associated with an increased frequency of contralateral BC while local relapse is not increased. In terms of distant recurrence, we observed a significant increase in bone metastases and a significant decrease in lung metastases for pts with ILC. These findings may be related to the higher level of endocrine responsiveness of ILC.
Topical Estrogen Safe for Hormone Receptor Positive Patients
[3085] The effects of vaginal estrogens on plasma estradiol levels in women taking aromatase inhibitors.
Howard G, Wills S, Kresge C, McConnell D, Balasubramaniam M, Decker D. William Beaumont Hospital, Royal Oak, MI; School of Public Health, University of Michigan, Ann Arbor, MI
Background: Absorption of vaginal estrogens (VE)s in breast cancer survivors on an aromatase inhibitor (AI), has been reported in one small series with short term follow-up 3 months (Ann Onc 17:584, 2006). We hypothesized that over time, the initial absorption of VEs would decrease, as a result of estrogen driven vaginal epithelial expansion. Methods: Twenty-four postmenopausal women with estrogen receptor positive breast cancer (12 cases taking AIs daily 180d as adjuvant therapy and VE (Vagifem) 2 x per week for 180d and 12 controls receiving an AIs daily >14d not on VE) were recruited after informed consent. Blood was drawn in the morning prior to VE insertion and the morning post insertion. Blood was drawn in controls >2 weeks after beginning an AI. Serum samples were assayed for estrogen (E2) concentrations. Patients on VEs were asked to rate their dyspareunia on a scale of 1-5 (1=good; 5=poor). Statistical analyses on the E2 levels were performed using the Students t-test and the Wilcoxon signed rank test. Results: Table. The mean E2 levels in AI cases pre-insertion of VE was 14.8 pg/mL (standard deviation [SD] 6.5 95% confidence interval [CI] 10.9-18.7) and for controls on AI alone 12.01 pg/mL (SD 1.94, 95% CI 10.8-13.2) with a p-value of 0.1633. A comparison of the median in pre-insertion and post-insertion E2 levels in cases yielded a p-value of 0.0117. In five patients (42%) there was no difference (E2 change < 2 pg/mL) between the pre and post-insertion E2 levels. We found no correlation between symptom relief, time to insertion, duration of VE and post-insertion E2 levels.
Conclusions: In this small convenience sample, we found no statistical correlation between E2 levels in controls and the pre-insertion E2 level of patients on an AI and using VE 180d. For patients receiving VEs there was a significant difference between the pre-insertion E2 levels and the post-insertion levels. The clinical significance with short term elevation is unknown. However, this elevation was heterogeneous and was not observed in 5 of 12 receiving VEs. These data suggest that a subset of women taking AIs might be able to use VEs safely to treat vaginal atrophy.
WHY WE FIND BROKEN RIBS?
[5092] Rib fractures: a complication of radiation therapy and tissue expansion for breast reconstruction.
Huang AH, Wong MS, Whetzel TP, Stevenson TR. University of California-Davis Medical Center, Sacramento, CA
Introduction: Tissue expansion remains a mainstay of breast reconstruction. Despite increased complications associated with the use of expanders in irradiated fields, tissue expansion for breast reconstruction continues to be used in this setting. We present a previously unreported complication of rib fractures caused by breast tissue expansion following radiation therapy.
Materials Methods: A six-year retrospective review of tissue expander use for breast reconstruction was conducted. Patients were categorized by age, body mass index (BMI), indication for mastectomy, history of radiation therapy, timing of tissue expander placement relative to mastectomy, minimum and maximum expansion volumes in a single visit, and final tissue expander volume prior to placing permanent saline implants.
Results: There were 144 tissue expanders placed in a total of 91 patients, with an average age of 48 (range 22 to 78) years, and an average BMI of 26.5 (range 17.4 to 42.1). Of the 53 (58%) patients who underwent bilateral tissue expansion, nine patients had biopsy-proven breast cancer or carcinoma-in-situ bilaterally and two patients underwent bilateral prophylactic mastectomies. The remaining 42 patients requested prophylactic contralateral mastectomies with bilateral tissue expander reconstruction after the discovery of their unilateral breast cancer. Only fifteen (16%) patients had a history of irradiation to their affected breast, though five additional patients underwent radiation therapy immediately after tissue expansion was completed, and two other patients had histories of irradiation for other malignancies involving the thorax. Of the fifteen patients with breast tissue expansion in an irradiated field, two patients eventually had evidence of rib fractures discovered after both patients complained of pain at their follow-up visits after tissue expansion. The first patient had a total of ten separate tissue expansions with a mean single-volume expansion of 37 mL and a mean of nineteen days between expansions. A CT scan was obtained after the expander had been filled to a total of 430 mL, revealing a healing anterolateral fifth rib fracture and a concave chest wall deformity deep to the implant. The second patient had five separate expansions with a mean single-volume expansion of 75 mL and a mean of fourteen days between expansions. She had evidence of a mobile rib segment intraoperatively when the expander was removed after having been filled to a total volume of 390 mL. A subsequent CT scan revealed an anterior fifth rib fracture with radiation-induced changes to the adjacent ribs.
Conclusion: Radiation is known to weaken the skeletal bony matrix and stiffen overlying soft tissues. We present two cases of rib fracture due to tissue expansion following chest wall radiation. We recommend any breast reconstruction patient utilizing tissue expanders in an irradiated field be cautioned about the possibility of rib fracture, which may change the course or timeline of the patients future reconstruction.
PROOF WE NEED TO TAKE 10,000 STEPS A DAY!
[4050] A pilot study to increase physical activity in sedentary women at risk for breast cancer.
Korde L, Venzon D, Smith AW, Nehrebecky M, Calhoun T, Sebring N, Drinkard B, Smith M, Prindiville S, Zujewski J, Eng-Wong J. NCI; NIH Clinical Center
Background: Epidemiologic data indicate that physical activity (PA) is associated with a decreased incidence of breast cancer. One study also suggested that physically active breast cancer survivors are at lower risk of recurrence compared with inactive survivors. Thus, PA may be beneficial for both the primary and secondary breast cancer prevention.
Methods: We designed a feasibility study to assess a 12 week PA intervention in women at risk for breast cancer. Eligible women were those at increased risk of breast cancer (by Gail model, family history, atypia on biopsy, or history of Stage 0-III breast cancer). All participants completed a one week baseline PA evaluation. Sedentary women (those with an average daily pedometer step count of <6000 steps per day) were randomized to either PA intervention or control. Intervention group participants received a pedometer, a physician exercise prescription and a motivational/ educational booklet, and were asked to incrementally increase their daily steps to a goal of 10,000 steps per day. Control participants received instruction on daily stretching exercises. The primary objective of the study was to evaluate the feasibility and success of the PA intervention in this population. Secondary objectives included assessing the effect of short-term moderate activity on biomarkers and quality of life. The study was powered to detect a mean increase of 3,000 steps per day in intervention subjects. The Wilcoxon rank sum test was used to evaluate the difference in mean change in step counts between intervention and control participants.
Results: Ninety women were evaluated; of these 45 were at high risk for breast cancer (HR) and 45 were breast cancer survivors (S). The mean age of participants was 54.8 years. The mean baseline step count was 4578 steps per day (SD 2080, range 510 to 9983), and was not significantly different in the two groups (S=4348, HR=4809, p=0.29). Of the 90 participants, 37 (20/45 HR, 17/45 S) were not sedentary and thus not eligible for randomization. The 53 randomized participants had a mean baseline step count of 3190 (SD 1226, range 510-5749). Follow-up step count data were available for 41 participants, (24 intervention, 17 control), of whom 36 completed the 12 week study. The mean increase in step count was 3796 among intervention participants and 2149 among controls (p=0.039). Three intervention participants achieved a final week step count of > 10,000 steps per day.
Conclusion: This moderate intensity intervention was effective in increasing PA in this selected population. Few participants reached the final goal of 10,000 steps per day. Analysis of secondary endpoints is underway. Additional research is needed to determine if this level of PA has an effect on breast cancer related outcomes.
ANTHRACYCLINE THERAPY, BENEFITS HER2+ PATIENTS MORE THAN HER2- PATIENTS AND OTHER AGENTS SHOULD BE CONSIDERED FOR ADJUVANT TREATMENT IN EARLY STAGE BREAST CANCER
[13] Role of anthracycline-based therapy in the adjuvant treatment of breast cancer: efficacy analyses determined by molecular subtypes of the disease.
Slamon DJ, Mackey J, Robert N, Crown J, Martin M, Eiremann W, Pienkowski T, Bee V, Taupin H, Villalobos I, Lindsay M-A, Riva A, Hurvitz S, Glaspy J, Pauletti G, Sauter G, Press M. Cancer International Research Group (CIRG), Edmonton, AB, Canada
Background: The use of anthracycline-based therapies for the adjuvant treatment of high-risk breast cancer has now become a common standard part of clinical practice. The evidence supporting this approach was initially controversial but finally thought to be resolved when the Oxford overview demonstrated a 4-5 % survival advantage in favor of anthracycline-based therapies over those that did not contain an anthracycline.
Materials and Methods: We performed a systematic review of published data from randomized, controlled adjuvant chemotherapy trials reporting HER2 subtype, i.e. HER2 positive vs. HER2 normal breast cancers. In addition, the analysis of two recent and separately conducted adjuvant trials of HER2 positive and HER2 normal breast cancers respectively, that were further sub-classified by whether or not they contained co-amplification of the topoisomerase II alpha (topo IIa) gene were included.
Results: The published data demonstrate a remarkably consistent finding. Specifically, the incremental efficacy benefit attributed to anthracycline-based therapies is restricted to the HER2 positive subgroup. A recent analysis of the BCIRG 006 (HER2+) and 005 (HER2-) studies reveals that topo IIa amplification is confined to cancers that contain the HER2 amplicon. In >1,600 HER2 FISH negative samples there is not a single topo IIa amplified case. Conversely, deletion of topo IIa was found in 5% of HER2+ and 3% of HER2 tumors respectively. An analysis of the impact of topo IIa co-amplification demonstrates that the improved efficacy imparted by an anthracycline vs. a non anthracycline-based regimen is restricted to the HER2/topo IIa co-amplified cancers. These constitute 35% of the HER2+ cancers. In these cancers the efficacy resulting from an anthracycline-based regimen alone was similar in magnitude to the addition of trastuzumab to adjuvant therapy.
Conclusion: The use of anthracyclines in the adjuvant treatment of all breast cancer is not supported by the existing data. Given the known long-term cardiac and leukemogenic/MDS toxicities of anthracyclines and the lack of an incremental benefit in non HER2/topoIIa co-amplified cancers (which is 92% of the overall breast cancer population), other approaches to the adjuvant treatment of breast cancer should now be adopted.
ADRIAMYCIN IS SHOWN TO REDUCE RECURRENCE
[3077] Annual hazard rates of recurrence for early breast cancer. What has changed in the last 10 years? Results from the NORA study.
Cazzaniga ME, Mustacchi G, Pronzato P, De Matteis A, Di Costanzo F, Nardi M, Barberis G, D'Aprile M, Rulli E, Floriani I. Az Osp Treviglio-Caravaggio, Treviglio, Bergamo, Italy
BACKGROUND: 10 years ago, Saphner et Al (J Clin Oncol 14: 2738-2746, 1996) analyzed 3585 breast cancer (BC) patients (pts) in terms of annual hazard rates (HRs) of recurrence; 2661 (74.2%) were N+ve, 429 (11.9%) high-risk N-ve, 1965 (54.8%) were treated with CMF-based chemotherapy (CHT), 650 (18.1%) with anthracycline-based CHT, with or without tamoxifen (T) and 87 (2.4%) with T alone. The remaining pts were followed up. For the entire group, highest HRs of recurrence occurred during first and second year (13.30.7).
PURPOSE: to analyze in a cohort of early BC pts prospectively followed up for a median interval of 3.4 years whether the widespread of adjuvant therapy and the use of more active regimens, mainly 3-drug anthracycline-based, have induced modifications in the magnitude of recurrence peaks or in the appearance time.
METHODS: NORA is a cohort study aimed at investigating treatment modalities and clinical outcome in 3515 early BC pts radically resected in 71 oncological Italian centers. 56.5% of the pts were N-ve and 17.1% had >4 positive axillary nodes. Results concerning treatment details have been already published (Cazzaniga ME et Al, Ann Oncol 17: 1386-1392, 2006). Adjuvant medical treatment was delivered in 97.8% of the cases. Briefly, 1234 (35.1%) were treated with anthracycline-based CHT and 82 (2.3%) with taxanes, with or without T or aromatase inhibitors (AIs). CMF was delivered in 963 pts (27.3%). 3433 pts (97.7%), for whom full data concerning relapse are available, were analyzed in terms of annual HRs of recurrence, defined as the fraction of pts who recur during a 1-year interval.
RESULTS: for the entire group, the peak hazard of recurrence occurred in the interval from 3rd to 4th year (HR=3.4 0.5). The peak hazard of recurrence in all pts traditionally considered at high risk (N>10; T4) remained in the interval from 1st to 2nd year (18.2 3.6, 11.5 3.8, respectively), even if in some cases 2-3 fold reduced in comparison a decade ago. Details are listed in Table 1.
CONCLUSION: our results suggest that the widespread of adjuvant systemic therapy and the use of more active drugs, mainly anthracyclines, have delayed and reduced the peak hazard of recurrence in some groups of early BC pts. High risk pts showed a significant reduction of recurrence number but not a delay in the time of appearance.
CANCER TREATMENT RELATED BONE LOSS AND THE USE OF ZOLENDRIC ACID TO IMPROVE BONE MINERAL DENSITY
[27] The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up.
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group; Novartis Pharmaceuticals, East Hanover, NJ
Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ BCa. However, the use of AIs in this patient population results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluates the efficacy and safety of Zoledronic acid (ZA) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who are receiving adjuvant Letrozole (LET) therapy.
Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized to upfront ZA (4 mg IV q 6 mos) vs delayed ZA in 94 centers in the US and Canada. The delayed group receives ZA when either the post-baseline T-score decreases to <-2 or a clinical fracture occurs. All patients (pts) are treated with calcium and vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone mineral density (BMD) at 12 mos, was reported at ASCO 2005. The results of 36 mos follow-up are reported here.
Results: Baseline characteristics were similar between groups. At 36 mos, the upfront ZA group (n=189) showed a mean increase of 3.72% in LS BMD while the delayed group (n=188) showed a mean decrease of 2.95%, resulting in an absolute difference of 6.7% (p<0.001). The upfront group (n=189) showed a mean increase of 1.66% in total hip (TH) BMD while the delayed group (n=187) showed a mean decrease of 3.51%, resulting in an absolute difference of 5.2% (p<0.001). The overall difference in LS and TH BMD between the two groups was 8.2% and 6.7%, respectively, when BMD data in the delayed group was excluded after pts started ZA. Among pts with baseline T score between -1 and -2, 40.4% of upfront pts (7.6% of delayed pts) returned to normal T score (T score >-1) and 13.4% of delayed pts (2.1% of upfront pts) became severely osteopenic (T <-2). 15% of delayed pts had a decrease in BMD that required initiation of ZA. Fractures occurred in 5.6% of upfront pts and 6.3% of delayed pts. 199 upfront pts and 191 delayed pts had baseline and 36 mos spinal x-rays. 0.5% upfront pts and 0.52% delayed pts had a radiological fracture detected at 36 mos. The study was not designed to detect a significant difference in the fracture rate between treatment arms. Administration of ZA q 6 mos for up to 36 mos was safe and well tolerated. No serious renal adverse events and no confirmed osteonecrosis of the jaw cases were reported. Disease recurrence was reported in 9 (3.0%) pts in the upfront group, and 14 (4.7%) pts in the delayed group (p=0.24).
Discussion: The 36 mos follow-up of the Z-FAST trial show that the overall difference in the percentage change in BMD between the upfront and delayed ZA treatment groups, at both LS and TH, progressively increased from baseline through 36 mos. These data demonstrate that ZA 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in PMW with EBC.
BREAST MRIS DETECT CANCER BETTER
[1001] Effect of magnetic resonance imaging on the clinical management of women with newly diagnosed breast cancer.
Newstead GM, Abe H, Jansen SA, Shimauchi A, Sennett CA, Schmidt RA, Zak L, Olopade O, Jaskowiak N. University of Chicago; University of Chicago, Chicago, IL
Background: Magnetic resonance imaging (MRI) has been shown to identify multifocal, multicentric and contralateral breast cancer, not identified by clinical examination, mammography and ultrasound. Although the biological importance of additional areas of disease identified by histopathology has been questioned, we sought to evaluate the contribution of MRI to the initial staging of newly diagnosed breast cancer patients, and to document the effect of MRI assessment on patient management.
Materials and Methods: MRI has been routinely and non-selectively used for breast cancer staging at our institution since 2002. We identified 459 consecutive patients with 465 newly diagnosed breast cancers who underwent MRI between July 1 2002 and December 31 2006. Excluded were patients with clinical findings of inflammatory cancer. All patients were assessed by clinical examination, bilateral mammography (MG) and ultrasound (US) of the affected breast. Location, number and size of the cancers were documented. Mean patient age was 56.5 yrs (range 26-82). Histology of the index lesion: invasive duct carcinoma (IDC) n=201 (43.2%), invasive lobular carcinoma (ILC) n=40 (8.6%), ductal carcinoma-in-situ (DCIS) n=69 (14.8%) and IDC with DCIS n=155 (33.3%). Dynamic bilateral MR contrast-enhanced protocol:1 pre and 4-6 post-contrast images acquired in the coronal or axial plane, with 60-75 s timing. Analysis of lesion morphology and kinetic curve shape was classified according to the BIRADS lexicon. Location, number and size of unsuspected areas of additional tumor were documented, and classified according to their location: within the same quadrant (multifocal), within a different quadrant and at least 3 cms away (multicentric), and in the contralateral breast. Patients with positive MR for additional lesions underwent second look directed MG and US to search for additional tumor, and selected patients underwent biopsy and/or localization of additional tumor under US or MR guidance. All imaging and histologic findings were discussed at an interdisciplinary treatment conference.
Results: Analysis of the MRI staging data with pathology review, demonstrated secondary disease to be present in 106 (23.1%) patients, mean age 51.2 years (5 years younger than mean age of all). Distribution of additional disease: multifocal n=58 (12.6%), multicentric n=27 (5.9%), contralateral breast n=21(4.5%). Additional cancer histology: IDC n=36 (33.9%), IDC + DCIS n=26 (24.5%), DCIS n=29 (27.4%), ILC n=15 (14.2%). Management change: More extensive cancer surgery with breast conservation n= 86 (81.1%), mastectomy rather than conservation n=10 (9.4%) and Neoadjuvant chemotherapy n=5 (4.7%).
Conclusion: MR imaging offers more precise assessment of tumor extent than mammography or ultrasound imaging. Therapeutic management was changed in 23.1% patients (n=106), resulting in a change from breast conservation to mastectomy in 9.4% patients.
PRIOR USE OF HRT INCREASES ODDS OF
LOBULAR BREAST CANCER
[1055] Impact of hormone replacement therapy on breast cancer: Womens Healthy Eating and Living (WHEL) study experience.
Parker BA, Flatt SW, Mortimer JA, Natarajan L, Gold EB, Bardwell WA, Jones LA, Hollenbach KA, Pierce JP. University of California, San Diego, La Jolla, CA; University of California, Davis, Davis, CA; The University of Texas, Houston, TX
Prior hormone replacement therapy (HRT) has been associated with an increased incidence of breast cancer. Conflicting information exists regarding the impact of prior HRT on subsequent breast cancer development. We utilized data from the Womens Healthy Eating and Living (WHEL) Study to determine the natural history of breast cancer in women who reported HRT prior to their diagnosis of breast cancer. Our aim was to determine the features of breast cancer, the severity of vasomotor symptoms, and the disease-free survival in women with breast cancer and reported prior HRT as compared with no reported prior HRT. The WHEL Study is a multi-institutional randomized trial of dietary change to a diet high in vegetables and fruits in Stage I-IIIA breast cancer patients within 4 years of diagnosis. Baseline data regarding tumor characteristics, demographics, and the Thoughts and Feelings questionnaire regarding vasomotor symptoms were analyzed. A total of 1544 patients randomized to the non-intervention group were included in this analysis. We used bivariate statistics to assess the association of reported prior HRT with covariates, logistic regression to analyze tumor histology, and a proportional hazards model for disease-free survival. A total of 706 patients reported prior HRT including 453 who received combined estrogen and progesterone HRT for a mean of 6.8 years and 216 women with estrogen alone HRT for a mean of 9.3 years. The results of our analysis indicate that patients reporting prior HRT as compared with no prior HRT were older (mean 57 versus 48 years), had a higher incidence of lobular cancer (10.2 % versus 6.2%), had lower grade tumors (18.4% Grade 1 versus 13.6%), were more likely to report hot flashes (74.9% versus 60.6%), were more likely to report night sweats (58.3% versus 48.0%), were more likely have ER+PR+ tumors (63.6% versus 59.3%), and had a greater likelihood of being disease-free at 7.3 years follow-up (84.7% versus 81.3% as of June 1, 2006). In multivariate models, reported prior HRT weakly predicted lobular histology of the original primary tumor (OR = 1.53, 95% CI = 0.99 2.36) but did not predict disease-free survival (HR 0.78, 95% CI = 0.58-1.06). However, the significant predictive effect on disease-free survival of low tumor stage, low tumor grade and presence of hot flashes remained. These results add to reports suggesting that prior HRT is associated with an increased incidence of lobular histology at diagnosis. In our study, prognosis was similar regardless of prior reported HRT.
HER2 POSITIVE PATIENTS WHO GET LUMPECTOMIES ARE MORE LIKELY TO GET LOCAL RECURRANCES THAN THOSE WHO OPT FOR MASTECTOMIES
[1060] The prognostic significance of human epidermal growth factor receptor-2 over-expression for the development of local recurrence after newly diagnosed breast cancer.
Gabos Z, Thoms J, Hanson J, Ghosh S, Deschenes J, Mackey J, Abdulkarim B. Cross Cancer Institute, Edmonton, AB, Canada; University of Alberta, Edmonton, AB, Canada
Background: Human epidermal growth factor receptor-2 (Her-2) over-expression occurs in 20-30% of invasive breast cancer and results in aggressive disease and high-risk of recurrence. The impact of Her-2 over-expression on the risk of local recurrence is unclear.
Objectives: In this population-based study, we have investigated the incidence of local recurrence in newly diagnosed breast cancer patients with Her-2 over-expression.
Methods: Newly diagnosed breast cancer patients between 01/1998 and 12/2003 with uniform Her-2 testing were identified from a cancer registry. A total of 460 Her-2 over-expressing patients were reviewed. A random sample of 500 patients with Her-2 negative disease was also reviewed. Patients were excluded if there was a breast cancer diagnosed before 01/ 1998 or other cancer. A total of 266 Her-2 positive and 338 Her-2 negative patients were included for this analysis. The groups were stratified based on surgical treatment, lumpectomy versus mastectomy. The association between histological features and local recurrence was evaluated with univariate and multivariate analyses.
Results: In patients treated by lumpectomy, Her-2 over-expression was the only factor to be associated with increased risk of local recurrence, on both univariate and multivariate analysis, hazard ratio 7.4 (95% CI, 1.6-33.9, p=0.01). In patients treated by mastectomy it was not associated with increased risk of local recurrence.
Conclusions: In our population-based study, Her-2/neu over-expression is significantly associated with increased risk of local recurrence in newly diagnosed breast cancer patients treated by lumpectomy. In patients treated by mastectomy, Her-2 over-expression is not associated with an increased risk of local recurrence.
BETTER DRUG COMBO TO PREVENT DELAYED NAUSEA AND VOMITING FROM CHEMOTHERAPY
[1086] Dexamethasone, metoclopropamide and omperazole combination is simple, safe and effective for delayed nausea and vomiting control in adjuvant chemotheray for early breast cancer.
Sanchetee SC. Sanchetee Hospital and Cancer Insitute, Jodhpur, Rajasthan, India
BACKGROUND: Delayed nausea and vomitting in chemotherapy are the most frequently of side effect. Our study aimed to determine the effectiveness of Dexa+omeprazol versus Dexa+omeprazol+metoclopramide in the prophylaxis of dealyed emesis after emetogenic chemotheray.
METHODS: Patients after treated with FAC regimen-adjuvant chemotherapy for early stage breast cancer, receive dexamethasone 4mg oral, twice time daily and omeprazol 20mg oral, twice time daily, all for five days (Daxo) or dexamethoasone 4mg oral, twice time daily, omeprazol 20mg oral, twice time daily and metoclopramide 20mg oral, thrice time daily, all for five days (DexoPrim). Patient diary with nausea and vomiting module and toxicity criteria were used to monitor and evaluate patient outcomes.
RESULTS: From Jan 2004 to Dec 2005, 122 (mean=45,7years) outpatients were randomized with 60 Dexo and 62 DexoPrim confirmed eligible. Patient characteristics were similar between the two groups. No drug related serious adverse evetns were reported. During first cycle fo chemotherapy, DexoPrim was complete protection against vomiting better Dexo(78vs.52%;p=0.05). For the entire study period, there was better DexoPrim (69vs, 48%;p=0.02), lower average nausea score (0.02 vs. 0.39, p=0.04) and no cases must entry hospital for recuing anti eetic. Global QoL declined in both groups during chemotherapy but DexoPrim was less than Dexo (p=0.03). Appetite was the same in both groups. There were no significant differences in toxicity.
CONCLUSION: The use of combination DexoPrim oral daily for five day after chemotherapy is simple, cheap cost, safe, and effective in preventing vomiting, reducing nausea and preserving QoL.
YES THERE IS SUCH A THING AS CHEMOBRAIN!
[1094] Memory loss after adjuvant chemotherapy for breast cancer: a preliminary analysis of mediating variables utilizing cross-sectional correlations and multilevel longitudinal analysis.
Beadle G, Rolfe M, Vearncombe K, Andrew B, Mengersen K, Wright M. Queensland Institute of Medical Research, Brisbane, Queensland, Australia; Southern Cross University, Lismore, New South Wales, Australia; University of Queensland, Brisbane, Queensland, Australia; Queensland University of Technology, Brisbane, Queensland, Australia
BACKGROUND
Cognitive impairment is a well recognized complication of adjuvant chemotherapy but further research is required to identify factors that mediate cognitive change in breast cancer survivors.
METHODS
This study investigated cognitive change in verbal memory in 119 women aged less than 70 years before, at completion of, and 6 months after adjuvant chemotherapy. Verbal memory was assessed with the auditory verbal learning test trials 1-5 (AVLT1-5) and executive processing of immediate and delayed recall with the AVLT7 and the AVLT8 respectively. Cross-sectional correlations were performed with time invariant variables of age, years of education and general cognitive ability utilizing the national adult reading test (NART). Correlations with time varying variables included quality of life measures (HADS, FACT-B and FACT-F) and changing hormonal phenotype (cessation of hormone replacement therapy after diagnosis of breast cancer and changing menstrual function after chemotherapy). Unconditional random intercept quadratic regression models were fitted to AVLT1-5, AVLT7 and AVLT8, with temporal and subject level variances estimated by restricted maximum likelihood.
RESULTS
In this exploratory analysis, age, NART and years of education were significantly correlated with AVLT1-5, AVLT7 and AVLT8 at all time points (all p values <0.05). Quality of life correlates were inconsistent at most time points but statistically significant when all time points were combined (HADS depression <0.05 and FACT fatigue <0.05 for AVLT8; FACT-B <0.05 for AVLT1-5, and <0.01 for AVLT7 and AVLT8). Age, NART and years of education were significant predictors of these changes (p <0.01). In particular, a high NART predicted a less steep decline of memory over time. There was no evidence of a statistically significant association between AVLT and self-report measures of quality of life or changing hormonal phenotype after adjustment for age and NART.
CONCLUSION
A significant decline of the AVLT occurred during and after treatment with adjuvant chemotherapy. Age, NART and years of education were strongly associated with AVLT at all time points but not quality of life or changing hormonal phenotype. Further investigation of memory and executive functioning is currently underway in a larger sample of patients followed over a longer time. Multilevel longitudinal analysis is a promising tool for investigating longitudinal data that contain multiple changing covariates.
THE EFFECT OF BREAST CANCER ON COUPLES
[1097] Appraisals, coping and distress among couples dealing with breast cancer.
Hernandez AM, Bigatti SM. Indiana University Purdue University Indianapolis, Indianapolis, IN
This study aimed to investigate the cognitive appraisals, coping styles and levels of distress of couples dealing with breast cancer. Cognitive appraisals are evaluations individuals make of stressful situations in order to categorize them as benign/irrelevant, challenge, threat, or harm. These cognitive appraisals predict coping mechanisms, which in turn impact levels of distress. Studying couples, or dyads, is important because the coping style of one individual in the dyad is associated with outcomes in the other. One adaptive form of coping is emotional approach coping, which consists of emotional processing and emotional expression. Breast cancer patients currently undergoing chemotherapy treatment (n = 22) and their spouses (n = 22) were recruited from a breast cancer clinic. Both the patient and spouse completed surveys at home and returned them by mail. Stantons Emotional Approach Coping Scale, Kesslers Cognitive Appraisal of Health Scale, and the Profile of Mood States (POMS) were included in the questionnaire packages. Most of the patients had stage IV breast cancer (68.2%). The average age for patients was 53.55 (SD = 11.571) and for husbands was 54.49 (SD = 11.784). Participants were married an average of 27.28 years (13.99). Most reported a yearly income above $70,000. Husbands scored higher in the anxiety subscale of the POMS and were more likely to appraise the cancer as a threat than the patients themselves. We grouped couples into those who matched on appraisals and those who did not and examined the groups level of distress and coping. We found no differences by group for husbands on either variable, or for wives on the POMS. However, wives who did not match on appraisals with their husbands engaged in more emotional approach coping F(1,20)= 6.474, p=.019), and more specifically emotional expression F(1,20) = 4.969, p = .037) and emotional processing coping F (1,20) = 6.089, p = .023). These findings suggest that patients who have a different view of the cancer than their partners may need to engage in more coping efforts than those who have the same view. Possibly agreement, regardless of the appraisal agreed upon, relieves the patient from reappraising. On the other hand disagreement may require both processing and expression to determine whether the appraisal is in fact correct or should be reconsidered. Because appraisals change throughout the cancer experience, it may be that one impetus for reappraisals is disagreement with a spouse and subsequent emotional work.
COQ10, RIBOFLAVIN AND NIACIN INCREASES EFFECTIVENESS FOR DISEASE FREE SURVIVAL IN WOMEN WHO TAKE TAMOXIFEN
[1104] Anti-angiogenic potential of coenzyme Q10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy.
Panchanatham S. DR. A.L.M.P-G.I.B.M.S., University of Madras, Tarmani Campus, Chennai, Tamilnadu, India
Background: To evaluate the anti-angiogenesis effect of CoenzymeQ10, riboflavin and niacin (CoRN) in breast cancer patients undergoing tamoxifen therapy. Efficacy of the combinatorial (CT) drug was correlated with serum angiogenic marker levels.
Methods: Eighty four women with breast cancer undergoing tamoxifen therapy were treated with 100 mg CoenzymeQ10, 10 mg Riboflavin and 30 mg Niacin for 90 days. Blood samples were collected at the start of the study, at 45 days and 90 days of the treatment regimen. Circulating markers such as Vascular endothelial growth factor (VEGF), Matrix metalloproteinase (MMP) - 2, MMP-9, Tissue Inhibitor of metalloproteinase (TIMP) - 1, TIMP-2, Interleukin (IL) -1, IL-6, IL-8, Tumour necrosis factor (TNF) -, Extracellular domain (ECD) Her-2/neu, c-myc, Epidermal growth factor (EGFR), VCAM-1, E-selectin, Tumour growth factor (TGF) , Angiogenin, Carcinoembryonic antigen (CEA) and Carbohydrate antigen (CA) 15-3 were evaluated to determine the anti-angiogenic of this CT drug.
Results and Discussion: We found a statistically significant correlation between CoRN supplementation and reduction in angiogenesis markers. There was a reduction in the levels of serum IL-1, IL-6, IL-8, TNF-, MMP-2, MMP-9, Angiogenin, E-selectin, VCAM-1 EGFR, TGF- and VEGF levels, which are stimulators of angiogenesis as well as factors for cancer cell proliferation and growth. There was a significant reduction in tumour marker levels of CEA, CA15-3, ECD Her-2/neu and c-myc. In conclusion, this study suggests that supplementation of CoRN to tamoxifen therapy may provide good treatment prognosis by reducing the risk of cancer recurrence and metastases by decreasing the levels of angiogenic and tumour markers and importantly, the relation between dietary supplementation and cancer treatment may also have therapeutic implications in the future.
OSTEONECROSIS OF THE JAW CAN BE PREVENTED
[2056] Application of preventative measures minimizes the occurence of the osteonecrosis of the jaw (ONJ) in solid tumors patients with bone metastases treated with bisphosphonates
Ripamonti C, Maniezzo M, Cislaghi E, Campa T, Fagnoni E, Saibene G, Bareggi C, Ascani L, Pigni A, Brunelli C. National Cancer Institute, IRCCS Foundation, Milano, Italy
Background: ONJ is an uncommon side effect reported in cancer patients receiving cancer treatment regimens including BPs. Dental problems or mouth interventions were identified as the most important risk factors to develop ONJ in these pts. As consequence, screening of the oral cavity was suggested as preventive measure (Ruggiero J Oral Max Surg 2004). We investigated the occurrence rate of ONJ in our Institution before and after the implementation of dental preventive measures.
Material and Methods: Since April 2005, 153 consecutive pts treated with BPs (group POST), underwent a baseline mouth assessment (dentists visit panoramic jaw radiograph) to assess potential dental pathologies and dental care when required. Regular dental examination was maintained along BPs treatment. From Jan 1999 to Feb 2007, a retrospective review of 813 consecutive cancer patients with bone metastases (group PRE) treated with BPs in our clinic but not undergoing any preventive measure, has been conducted. Occurrence of ONJ will be presented both as row percentages (n of cases by n pts at risk) and as incidence rates (IR) (n of cases by person-time at risk). Differences between the two groups (PRE and POST preventive measures) have been analyzed through one-tailed Fishers exact test and will be presented as incidence rate difference (IRD) and its 95% CI.
Results: In the overall pts population (966 pts; M/F=255/711), 73% had breast cancer. The type of BP received was: Zoledronic Acid (ZOL) administered to 244 pts, Pamidronate (PAM) to 600, PAM followed by ZOL to 79, and Clodronate (CLO) or PAM/CLO to 43. Overall ONJ observed rate was 2.9% (ZOL/PAM+ZOL = 19 ONJ cases, PAM = 9). In group PRE and POST, ONJ cases observed were 27 (3.3%) and 1 (0.6%), respectively (p =0.048). Considering pts exposed to ZOL/PAM+ZOL, the application of dental assessment succeeded to a consistent reduction of ONJ rate (Group PRE 8.7% vs group POST 0.9%, p =0.002). The IR of ONJ in all 966 patients treated with BPs was 0.03/yr for group PRE and 0.007/yr for group POST (IRD=0.023, 95% CI from 0.0045 to 0.041).
Conclusion: According to our experience the routinely application of preventive measures before starting, and during the treatment with BPs, lead to a reduction of 75% in the incidence of ONJ. This evidence supports the relevance of applying prevention measures in all patients receiving BPs treatment.
PRIOR HRT USE INCREASES JOINT PROBLEMS
ASSOCIATED WITH ENDOCRINE THERAPY
[2071] Risk factors for joint symptoms in the ATAC trial.
Sestak I, on Behalf of the ATAC Trialists' Group. Wolfson Institute of Preventive Medicine, London, United Kingdom
Background: Joint symptoms are a well-known side effect of aromatase inhibitors. Low oestrogen levels and postmenopausal status are associated with the development of joint symptoms. Furthermore, it is known that chemotherapy induces joint symptoms. Tamoxifen seems to have little impact on the development of joint symptoms.
Methods: The two monotherapy arms of the ATAC trial randomised 6,241 postmenopausal women to anastrozole (1mg/day) or tamoxifen (20mg/day) in a double dummy double blind fashion. Here we investigate other risk factors that might have an influence on the development of joint symptoms, and examine if there was an interaction with either endocrine treatment. Pre-existing joint symptoms will be examined in the final analysis.
Results: After a median of 68 months of follow-up, a total of 2,011 joint symptoms were reported (1,100 (35.6%) anastrozole vs. 911 (29.4%) tamoxifen, OR=1.32 (1.19-1.47)). For women who used hormone replacement therapy (HRT) before trial entry, 40.1% developed joint symptoms compared with 28.3% without previous HRT use (OR=1.70 (1.52-1.89)). Women who had chemotherapy as part of their treatment developed significantly more joint symptoms than those without chemotherapy (37.2% vs. 31.2%, OR=1.31 (1.15-1.48)). The Figure shows plots of joint symptoms in each treatment arm according to prior HRT or prior chemotherapy use. It can be seen that the factors were import in both arms of the trial and that their magnitude was similar to the difference between tamoxifen and anastrozole. Women with hormone receptor negative tumours developed significantly fewer joint symptoms than those with hormone receptor positive tumours (25.8% vs. 34.0%, OR=0.67 (0.55-0.83)). Furthermore, women from North America (USACanada) developed significantly more joint symptoms than those from the United Kingdom (UK) or the rest of the world (ROW). Obese women also had significantly more join symptoms as did women who smoke. Age and prior radiotherapy showed no influence on the development of joint symptoms. Significant risk factors from the univariate analysis were included in a multivariate analysis. All of them, except smoking status at entry, persisted in that analysis.
Conclusions: In this trial, the major risk factors for developing joint symptoms were prior HRT use, treatment with anastrozole, prior chemotherapy, and obesity, leading to significant increases of 11.8%, 6.1%, 6.0%, and 5.4% respectively. There was no clear indication of any interaction between these factors.
PATIENTS WITH ADVERSE SIDE EFFECTS SHOULD TRY
DIFFERENT ENDOCRINE THERAPY FOR RELIEF
[2072] Comparison of joint problems as reported by patients in a randomised adjuvant trial of anastrozole and letrozole.
Renshaw L, McHugh M, Williams L, Dixon OM, Fallowfield LJ, Evans DB, Dixon JM. Western General Hospital, Edinburgh, Scotland, United Kingdom; University of Edinburgh, Edinburgh, Scotland, United Kingdom; Brighton Sussex Medical School, Falmer, Sussex, United Kingdom; Novartis Institutes for BioMedical Research Basel, Basel, Basel, Switzerland
Background: Anastrozole (A) and letrozole (L) are well tolerated potent non-steroidal aromatase inhibitors (AIs). Musculoskeletal problems are reported frequently by patients on these drugs. This study aimed specifically to compare reported side effects of L, A and tamoxifen (T).
Patients and Methods: 182 postmenopausal women with invasive ER positive breast cancer were randomised as part of their adjuvant hormone therapy to receive
12 weeks of L followed by 12 weeks of A or
12 weeks of A followed by 12 weeks of L.
106 had L or A after surgery and were then switched to T and 76 took L or A after 5 years of T.
Detailed side effect profiles were collected by a nurse from patient interviews after 4, 8 and 12 weeks of each drug.
This analysis specifically relates to musculoskeletal side effects. Data were available on 181 patients. 11 patients failed to complete at least one month of each drug. This leaves an effective sample size of 170 patients. An analysis was performed to look specifically at side effects that were reported on one drug that were not reported by the same patient on other drugs. Statistical analysis was by McNemars test for matched data.
Results:
Letrozole vs. Anastrozole: Muscle pain was reported by only 3 patients. Joint pain was reported by 131 patients with no differences in frequency between L and A. Joint stiffness was reported by only 10 patients but was significantly more common with A compared with L (p=0.014). These two joint symptoms have been combined as joint problems in subsequent analyses.
46 of 83 patients (56%) reporting joint problems on L did not have the same problems on A and 46 of 83 (55%) patients with problems on A did not report joint symptoms on L. The % improvement was similar whether or not patients had taken prior T. Joint problems did increase over time irrespective of drug sequence (p=0.0009).
Letrozole and Anastrozole vs. Tamoxifen: Joint problems continued on T with 13/68 patients who did not get joint problems on L and 17/65 who did not get problems on A reporting these symptoms on T.
57% (13/23) with joint problems on T did not have these when taking L and 74% (17/23) who had problems on T did not have these on A. Conversely 74% (28/38) of patients with joint problems on L and 35/41 (85%) of patients with joint problems on A did not have these on T.
Conclusions:
Over half of patients with joint symptoms on one non steroidal AI did not have the same problems on the other AI.
Three quarters of patients who had joint symptoms on a non steroidal AI did not have these problems on tamoxifen.
This study suggests that for women with significant joint problems switching hormonal therapy to another agent is likely to improve their symptoms.
AI THERAPY BETTER AS FIRST LINE TREATMENT
THAN TAMOXIFEN
[2083] Survival analysis of first-line tamoxifen versus aromatase inhibitors for estrogen-positive metastatic breast cancer in postmenopausal women a BC perspective.
Kyritsis V, De Lemos M, Walker B, Kennecke H, Nakashima L. BC Cancer Agency, Vancouver, BC, Canada; Queens University Belfast, Belfast, Belfast, Ireland
Background: Tamoxifen has been the gold standard of treatment in postmenopausal women with estrogen receptor positive (ER+) metastatic breast cancer (MBC). Over the past decade, new aromatase inhibitors (AIs) anastrozole, letrozole, exemestane have emerged as equally efficacious alternatives to tamoxifen. Recent data suggest that first-line AI therapy may even confer a moderate increase ( 4months) in overall survival compared to tamoxifen. We performed a population-based analysis of survival associated with first-line tamoxifen versus AIs for ER+ MBC to examine whether the above findings hold true for patients in BC.
Methods: This is a population-based retrospective analysis. Patients were identified from the BC Cancer Agency Information System (CAIS), systemic therapy drug database, and the provincial registry (Breast Cancer Outcomes Unit). Data was analyzed for all postmenopausal women treated with first-line tamoxifen and AIs (anastrozole, exemestane, letrozole) for ER+ MBC (stage IV disease) from January 1998 through September 2004 in BC. Patients treated with other first-line hormonal agents were excluded. The primary outcome is overall survival, defined as the time to death by any cause from the date of first-line tamoxifen or AI therapy. Overall survival was compared between patients treated with tamoxifen versus AI.
Results: We found that there is an overall survival benefit with the use of first line AI therapy in comparison to tamoxifen in our patient population. Survival data will be presented as Kaplan-Meier curves and a 2-tailed log-rank test will be used to compare the hazard rates of the survival curves.
Discussion: This analysis will provide pertinent information regarding the survival benefit between the use of first-line treatment with tamoxifen and AI. The preliminary data provided by this analysis will assist in decision making regarding appropriate first-line hormonal therapy for ER+ MBC. We hope to disseminate these findings to the rest of the communities oncology network centers in BC.
BETTER THERAPY NEEDED FOR TRIPLE NEGATIVE DISEASE
[3070] T1N0 triple negative breast cancer: adjuvant chemotherapy treatment and risk of recurrence.
Kaplan HG, Malmgren JA, Atwood MK. Swedish Cancer Institute, Seattle, WA; HealthSTAT Consulting, Inc, Seattle, WA
Background: Triple negative (TN) breast cancer (BC) has a high recurrence rate warranting more aggressive therapy at all stages.
Materials and methods: From a prospective cohort of registry patients at our institution diagnosed with primary breast cancer between 1999 and 2004 we identified a subset of TNM Stage I (T1N0) BC. Estrogen (ER) and progesterone receptor (PR)/her2-neu (her2) negative (TN) (N=91) patients were compared to ER+/PR+/her2- (HR+/her2-) (N=770) patients. Patients with equivocal her2 results unconfirmed by FISH testing were excluded (n=24). Clinical variables including age, race, t stage, and surgical, radiation and adjuvant chemotherapy treatment method were chart abstracted and vital and disease status was updated annually. Length of follow up was at least 2 years with an average follow up of 3.76 years. Pearson chi square and Fishers Exact testing were used for bivariate analysis. Relapse free survival (RFS) was calculated using the Kaplan-Meier procedure and hazard ratios using the Cox proportional hazards model.
Results: Average patient age was 59 years, ranging from 23 to 88 years with no difference between the two groups. 5.6% of the TN patients were black vs. .7% of the HR+/her2- patients (chi square =18.12, p<.001). Distribution by t stage was 10% t1a (<.5 cm), 32% t1b (>.5 - <1 cm), and 58% t1c (>1cm - <2 cm). 80% of the TN vs. 56% of the HR+/her2- were t1c (chi square = 20.97, p<.001). Among all TNM Stage I patients 88% had lumpectomy + radiation and 12% had mastectomies. Seventy percent of the TN patients had adjuvant chemotherapy vs. 20% of the HR+/her2- patients (chi square = 109.92, p<.001) with 86% of the HR+/her2- receiving hormone therapy. In both groups women less than 60 years of age were more likely to receive adjuvant chemotherapy. TN patients were more likely to receive adriamycin/cytoxan/taxane combination adjuvant chemotherapy, 25% vs. 8% (chi square = 20.97, p<.001). In total there were 3 local, 1 regional and 11 distant recurrence. The 4 local/regional all received radiation as part of initial treatment and 3/4 were TN. The rate of any recurrence was 8.8% in the TN group vs. .9% in the HR+/her2 group (chi square = 29.54, p<.001) and distant recurrence was 5.5% vs. .8% (chi square = 33.13, p<.001). The rate of recurrence was 0% in TN t1a (0/5), 7.7% in t1b (1/13), and highest in the TN t1c group, 9.6% (7/73). Five year RFS was 99% in the HR+/her2- group and 91% in the TN group (log rank test = 32.84, p<.001). In a Cox proportional hazards model comparing TN to HR+/her2- patients, the hazard ratio of any recurrence was 3.53 for TN patients (95% CI = 1.96, 6.33) adjusted for t stage (t1a/t1b vs. t1c) and chemotherapy treatment (yes/no).
Conclusions: In early stage BC triple negative patients have more than three times greater risk of recurrence in spite of more aggressive treatment by number treated and type of adjuvant chemotherapy. Triple negative specific treatment modalities and protocols need to be developed to reduce recurrence in this high risk group.
ILC Shows Better Response to Endocrine Therapy
More Prone to Bone Metastasis than Lung Metastasis
Compared with IDC
[3078] Do patients with infiltrating lobular carcinoma (ILC) have an increased risk of contralateral, local, or distant recurrences compared with patients with infiltrating ductal carcinoma (IDC)?
Pestalozzi BC, Zahrieh D, Mallon E, Gusterson B, Gelber R, Price K, Castiglione-Gertsch M, Coates A, Goldhirsch A. International Breast Cancer Study Group, Berne, Switzerland
Background: ILC differs from IDC in many respects including increased frequency of multifocality and bilaterality, undefined margins, metastatic pattern. Differences in prognosis are controversial.
Patients (pts) and methods: We analyzed data from 13,220 breast cancer (BC) pts who were entered onto IBCSG trials I through 15-95 between 1978 and 2002. Median follow-up is 13 years. Histology was based on central pathology review for trials I through V, VIII through 15-95, and local assessments for Trials VI and VII.
Results: 767 (6.2%) tumors were classified as ILC, 8,607 (70.5%) as IDC, 2,832 (23.2%) as other, and 1,014 (7.6%) unknown. This analysis is based on the 9,374 patients categorized as IDC or ILC. Selected baseline characteristics are shown in Table 1. Compared with IDC, ILC is associated with older pts, larger, better differentiated and ER-positive tumors with less vessel invasion.
Conclusion: Compared with IDC, ILC is associated with an increased frequency of contralateral BC while local relapse is not increased. In terms of distant recurrence, we observed a significant increase in bone metastases and a significant decrease in lung metastases for pts with ILC. These findings may be related to the higher level of endocrine responsiveness of ILC.
Topical Estrogen Safe for Hormone Receptor Positive Patients
[3085] The effects of vaginal estrogens on plasma estradiol levels in women taking aromatase inhibitors.
Howard G, Wills S, Kresge C, McConnell D, Balasubramaniam M, Decker D. William Beaumont Hospital, Royal Oak, MI; School of Public Health, University of Michigan, Ann Arbor, MI
Background: Absorption of vaginal estrogens (VE)s in breast cancer survivors on an aromatase inhibitor (AI), has been reported in one small series with short term follow-up 3 months (Ann Onc 17:584, 2006). We hypothesized that over time, the initial absorption of VEs would decrease, as a result of estrogen driven vaginal epithelial expansion. Methods: Twenty-four postmenopausal women with estrogen receptor positive breast cancer (12 cases taking AIs daily 180d as adjuvant therapy and VE (Vagifem) 2 x per week for 180d and 12 controls receiving an AIs daily >14d not on VE) were recruited after informed consent. Blood was drawn in the morning prior to VE insertion and the morning post insertion. Blood was drawn in controls >2 weeks after beginning an AI. Serum samples were assayed for estrogen (E2) concentrations. Patients on VEs were asked to rate their dyspareunia on a scale of 1-5 (1=good; 5=poor). Statistical analyses on the E2 levels were performed using the Students t-test and the Wilcoxon signed rank test. Results: Table. The mean E2 levels in AI cases pre-insertion of VE was 14.8 pg/mL (standard deviation [SD] 6.5 95% confidence interval [CI] 10.9-18.7) and for controls on AI alone 12.01 pg/mL (SD 1.94, 95% CI 10.8-13.2) with a p-value of 0.1633. A comparison of the median in pre-insertion and post-insertion E2 levels in cases yielded a p-value of 0.0117. In five patients (42%) there was no difference (E2 change < 2 pg/mL) between the pre and post-insertion E2 levels. We found no correlation between symptom relief, time to insertion, duration of VE and post-insertion E2 levels.
Conclusions: In this small convenience sample, we found no statistical correlation between E2 levels in controls and the pre-insertion E2 level of patients on an AI and using VE 180d. For patients receiving VEs there was a significant difference between the pre-insertion E2 levels and the post-insertion levels. The clinical significance with short term elevation is unknown. However, this elevation was heterogeneous and was not observed in 5 of 12 receiving VEs. These data suggest that a subset of women taking AIs might be able to use VEs safely to treat vaginal atrophy.
WHY WE FIND BROKEN RIBS?
[5092] Rib fractures: a complication of radiation therapy and tissue expansion for breast reconstruction.
Huang AH, Wong MS, Whetzel TP, Stevenson TR. University of California-Davis Medical Center, Sacramento, CA
Introduction: Tissue expansion remains a mainstay of breast reconstruction. Despite increased complications associated with the use of expanders in irradiated fields, tissue expansion for breast reconstruction continues to be used in this setting. We present a previously unreported complication of rib fractures caused by breast tissue expansion following radiation therapy.
Materials Methods: A six-year retrospective review of tissue expander use for breast reconstruction was conducted. Patients were categorized by age, body mass index (BMI), indication for mastectomy, history of radiation therapy, timing of tissue expander placement relative to mastectomy, minimum and maximum expansion volumes in a single visit, and final tissue expander volume prior to placing permanent saline implants.
Results: There were 144 tissue expanders placed in a total of 91 patients, with an average age of 48 (range 22 to 78) years, and an average BMI of 26.5 (range 17.4 to 42.1). Of the 53 (58%) patients who underwent bilateral tissue expansion, nine patients had biopsy-proven breast cancer or carcinoma-in-situ bilaterally and two patients underwent bilateral prophylactic mastectomies. The remaining 42 patients requested prophylactic contralateral mastectomies with bilateral tissue expander reconstruction after the discovery of their unilateral breast cancer. Only fifteen (16%) patients had a history of irradiation to their affected breast, though five additional patients underwent radiation therapy immediately after tissue expansion was completed, and two other patients had histories of irradiation for other malignancies involving the thorax. Of the fifteen patients with breast tissue expansion in an irradiated field, two patients eventually had evidence of rib fractures discovered after both patients complained of pain at their follow-up visits after tissue expansion. The first patient had a total of ten separate tissue expansions with a mean single-volume expansion of 37 mL and a mean of nineteen days between expansions. A CT scan was obtained after the expander had been filled to a total of 430 mL, revealing a healing anterolateral fifth rib fracture and a concave chest wall deformity deep to the implant. The second patient had five separate expansions with a mean single-volume expansion of 75 mL and a mean of fourteen days between expansions. She had evidence of a mobile rib segment intraoperatively when the expander was removed after having been filled to a total volume of 390 mL. A subsequent CT scan revealed an anterior fifth rib fracture with radiation-induced changes to the adjacent ribs.
Conclusion: Radiation is known to weaken the skeletal bony matrix and stiffen overlying soft tissues. We present two cases of rib fracture due to tissue expansion following chest wall radiation. We recommend any breast reconstruction patient utilizing tissue expanders in an irradiated field be cautioned about the possibility of rib fracture, which may change the course or timeline of the patients future reconstruction.
PROOF WE NEED TO TAKE 10,000 STEPS A DAY!
[4050] A pilot study to increase physical activity in sedentary women at risk for breast cancer.
Korde L, Venzon D, Smith AW, Nehrebecky M, Calhoun T, Sebring N, Drinkard B, Smith M, Prindiville S, Zujewski J, Eng-Wong J. NCI; NIH Clinical Center
Background: Epidemiologic data indicate that physical activity (PA) is associated with a decreased incidence of breast cancer. One study also suggested that physically active breast cancer survivors are at lower risk of recurrence compared with inactive survivors. Thus, PA may be beneficial for both the primary and secondary breast cancer prevention.
Methods: We designed a feasibility study to assess a 12 week PA intervention in women at risk for breast cancer. Eligible women were those at increased risk of breast cancer (by Gail model, family history, atypia on biopsy, or history of Stage 0-III breast cancer). All participants completed a one week baseline PA evaluation. Sedentary women (those with an average daily pedometer step count of <6000 steps per day) were randomized to either PA intervention or control. Intervention group participants received a pedometer, a physician exercise prescription and a motivational/ educational booklet, and were asked to incrementally increase their daily steps to a goal of 10,000 steps per day. Control participants received instruction on daily stretching exercises. The primary objective of the study was to evaluate the feasibility and success of the PA intervention in this population. Secondary objectives included assessing the effect of short-term moderate activity on biomarkers and quality of life. The study was powered to detect a mean increase of 3,000 steps per day in intervention subjects. The Wilcoxon rank sum test was used to evaluate the difference in mean change in step counts between intervention and control participants.
Results: Ninety women were evaluated; of these 45 were at high risk for breast cancer (HR) and 45 were breast cancer survivors (S). The mean age of participants was 54.8 years. The mean baseline step count was 4578 steps per day (SD 2080, range 510 to 9983), and was not significantly different in the two groups (S=4348, HR=4809, p=0.29). Of the 90 participants, 37 (20/45 HR, 17/45 S) were not sedentary and thus not eligible for randomization. The 53 randomized participants had a mean baseline step count of 3190 (SD 1226, range 510-5749). Follow-up step count data were available for 41 participants, (24 intervention, 17 control), of whom 36 completed the 12 week study. The mean increase in step count was 3796 among intervention participants and 2149 among controls (p=0.039). Three intervention participants achieved a final week step count of > 10,000 steps per day.
Conclusion: This moderate intensity intervention was effective in increasing PA in this selected population. Few participants reached the final goal of 10,000 steps per day. Analysis of secondary endpoints is underway. Additional research is needed to determine if this level of PA has an effect on breast cancer related outcomes.
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