If you have been diagnosed with triple negative breast cancer then you have also been given a less than enthusiastic prognosis for a bright and happy future. This is simply not true. First, the name it has acquired is terrible. It sounds foreboding. Here is what it means:
You tested negative for estrogen and progesterone receptors. This means that your body’s naturally occurring hormones are not feeding your cancer cells. Because of this you cannot benefit from anti-hormonal drugs such as Tamoxifen and Armidex. Why? Because you don’t need them! Your cancer is impervious to estrogen and its effects so you do not need a drug to stop the estrogen and progesterone in your body.
That is two negatives. Here is the third.
You tested negative for the Her2/nue oncogene. This means your cancer does not overproduce a protein that promotes cancer growth. This is a good thing. You do not want to be Her2 positive. It is good to be Her2 negative. It also means you cannot benefit from Herceptin, the anti-Her2 drug. That is fine. You don’t need it so why should you take it?
So there are your three negatives.
Here are your positives:
Your tumor responds better to chemotherapy than tumors that are estrogen and progesterone positive. Chemo works better on you.
If you remain disease free for four or more years the chances are your cancer will not EVER return.
You do not have to take endocrine therapy drugs that have a whole host of side effects that are not pleasant.
And there is emerging research every day into this type of breast cancer that is making the “poor prognosis” moniker a thing of the past.
The following is an up to the minute report on the latest trends and breakthroughs in Triple Negative treatment. You will see that there is a tremendous amount of HOPE.
Please do not despair with this diagnosis. It CAN be beaten.
I would like to thank Constantine Kaniklidis, our resident cancer researcher, for providing this thorough and hopeful report on the POSITIVE FUTURE of Triple negative disease.
The Frontier Edge: New Appreciation of Triple Negative Disease
by Constantine Kaniklidis
Three Myths of Triple Negative Disease
It has been standard wisdom to date to say, and believe, (1) that patients with triple negative disease (ER- / PR- /HER- tumors) intrinsically have a poor prognosis relative to those with endocrine-positive disease (ER+ and/or PR+) or HER2+ disease; (2) that triple negative tumors are responsive to, and hence treatable by, only chemotherapy (this is known as the "triple-negative paradox", coined by Dr. Lisa Carey at UNC); and (3) that there is some essential association between triple negative disease and BRCA1-deficient breast carcinoma. All of these judgments are unwarranted, the first by virtue of resting on a misunderstanding of the pattern and velocity of recurrence in triple negative disease, and hence, a half-truth, as I discuss below, and the second by virtue of being "just plain wrong" which I'll expand upon momentarily in this introduction; the third is unwarranted by virtue of what's called lack of corollary, which I expand upon below, but in essence means that from the fact that most BRCA1-deficient carcinomas are triple negative (this is true), it does not follow (in reverse) that most triple negative disease exhibits BRCA-deficiency (this is false).
Myth 1: Chemotherapy Only
As to the first myth, the point to remember is that there are three classes of oncotherapy (cancer therapy), not two. There is endocrine therapy (aka, hormonal therapy) for endocrine-responsive disease (ER+ and/or PR+) which includes the SERM tamoxifen, the aromatase inhibitors (AIs), the pure antiestrogen (technically, SERD) fulvestrant (Faslodex), and ovarian suppression (oophorectomy if surgical, and via LHRH/GnRH analogs like goserelin (Zoladex), leuprolide (Lupron) if medical); all endocrine therapy is cytostatic therapy, that is tumor cell growth-inhibitive and hence anti-proliferative, without direct tumor cell kill activity. Then there is chemotherapy which is definitionally cytotoxic (tumor cell kill) that includes of course a very broad array of agents and regimens, from traditional to new generation (an example of the latter being the just approved epothilone agent ixabepilone (Ixempra) ).
But there is also the third class of oncotherapy, biological therapy, which is neither cytostatic like endocrine therapy nor cytotoxic like chemotherapy, using biological agents or "biologics", that target intrinsic molecular (signaling) pathways underlying fundamental onco-processes like carcinogenesis, tumorigenesis, angiogenesis, metastasis, cell adhesion and motility, etc. So there is monoclonal antibody (MoAb) therapy such the anti-HER2 MoAb trastuzumab (Herceptin) and there is also TKI (tyrosine kinase inhibitor) biological therapy such as dual-TKI anti-HER1/HER2 therapy such as lapatinib (Tykerb) , and in addition to MoAb (monoclonal antibody) and TKI ((tyrosine kinase inhibitor) biological therapies, there are an extraordinary range of other biologics that can and have been leveraged in breast cancer, and many of these have demonstrable value in the treatment of triple negative disease. These include the anti-VEGF MoAb bevacizumab (Avastin) that is both antiangiogenic, and chemotherapy-synergistic; the EGFR-inhibitor MoAb cetuximab (Erbitux) and the SM-TKI (small molecule-TKI) dasatinib (Sprycel) ; as well as PARP inhibitors, mTOR inhibitors, and HSP (heat shock proteins) , all found active against triple negative disease (all discussed below).
So the full truth is that oncotherapy for triple negative disease can deploy chemotherapy and appropriate triple-negative-targeting biological therapy, and these can be combined into a regimen "backbone" of chemobiotherapy (biological + chemotherapy); and example would be the ABX-BEV combination chemobiotherapy regimen, that is, chemotherapy via nab-paclitaxel (Abraxane) + bevacizumab (Avastin) anti-VEGF biological therapy. This is one of many deployable and effective therapies against triple negative tumors. So in sum, as Lisa Carey at UNC, an expert in triple negative disease, said in her exceptional presentation on the Biology and Therapy of Basal Breast Cancer [click on link to download as pdf] at the Controversies in Breast Cancer conference I recently attended, triple negative disease is challenging to treat, but it's also highly treatable; at this point in time, triple negative disease therefore no longer needs to be defined by limited options, by an increasingly broad spectrum of highly motivated and targeted therapeutic interventions, much the way a new breed of forward-thinking breast oncologists no longer accepts the inevitability of metastatic disease mortality (the great Neil Rosen at Memorial Sloan-Kettering Cancer Center recently at the same conference observed radically but no longer a lonely voice - that he believes in curing metastatic disease, as I do myself].
Myth 2: Prognosis
Now let me first address the second myth and the issue of prognosis in triple negative disease. This has been critically elucidated recently by Rebecca Dent's team at Sunnybrook who demonstrated that triple negative disease exhibits a unique recurrence pattern and that not only is there a very sharp decline in recurrence risk of triple negative disease after the fourth year post-diagnosis, but that the risk of distant recurrence falls to absolute zero! - unheard of in any other type of breast cancer - from eight years and after (and is in any event extremely small, almost negligible, even from five years forward), and in addition, although local recurrence is a risk factor for later distant recurrence among women with all other types of breast carcinomas, this does NOT hold true for triple-negative tumors it was found that any local recurrence in triple negative disease is not associated with increased metastatic risk.
All in all, we are finally beginning to arrive at a new understanding that triple negative disease is more a matter of a qualitatively different pattern of recurrence and risk, rather than as traditionally thought, a radically different low-prognostic disease entity. Indeed, Marina Cazzaniga and her colleagues at Treviglio Hospital, Italy found in the NORA study contrary to other observations, that triple negative patients did not have worse prognosis, in terms of disease-free (DFS) or overall survival (OS), than others in the total cohort of 3515 patients treated in 77 cancer centers in Italy from to 2000 to 2003. The NORA study used a median follow up of 27 months, while we know from the Dent findings that the distant recurrence risk peaks at approx. 36 months. Therefore survival past the 3 year peak would appear a seminal hurdle for ultimate survival and mortality in triple negative disease.
Myth 3: Triple Negative Disease and BRCA Deficiency
The final myth I wish to address is the garbled association between triple negative disease, BRCA1-deficient breast carcinoma and the basal molecular subtype. What's critical to note here is that:
(1) Although ER-positive tumors fall predominantly into the molecular subtypes called luminal A or luminal B, a small percentage of basal-like and HER2+/ER- tumors also appear to be classified as ER positive, confirmed in the research of Charles Perou at UNC which found that 78% of basal-like tumors are indeed triple negative, and interestingly some 6% of these basal-like tumors actually are ER+, something that of course triple negative cannot be, definitionally. Thus, although “triple negative” is often used as a surrogate identifier for the basal-like tumor subtype, this is not the whole truth, and would lead to a misclassification of a non-trivial proportion of ER+ and/or PR+ tumors as triple negative.
(2) Although approx. 80% - 90% of women with a BRCA1 gene mutation, and about 14% of women with a BRCA2 gene mutation, are triple negative, AND that most BRCA1 gene mutations exhibit the basal-like pattern, it is NOT the case, although widely misunderstood, that the preponderance of triple negative disease is associated with BRCA-deficiency (either BRCA1 or BRCA2 gene mutation): the incidence of triple negative disease (relative to all breast carcinomas) is roughly 12.5%, while only about 3.3% of breast cancer patients in the US carry a BRCA1-mutated gene, so that that only a very small percentage of women with triple negative breast cancer are BRCA1-deficient.
What is true, and what is clinically important for reasons suggested below, is that the vast preponderance of women with triple negative disease, and also the vast preponderance of women with BRCA-1-deficiency, exhibit the basal phenotype. This is the clinically significant insight as it indicates (1) that triple negative disease and BRCA1-deficient breast cancer share features and behavior associated with the basal-like molecular subtype, and (2) that therapies effectively targeting the basal carcinoma molecular subtype should be highly effective in both the treatment of triple negative disease, and the treatment of BRCA1-deficient breast carcinomas.
Triple Negative Disease: The Molecular Era
The recent breakthroughs in the molecular classification and profiling using DNA microarray analysis of breast cancers has demonstrated that breast tumors can be classified according to their genetic profile into well-defined subtypes and this has served to enrich our understanding of triple negative disease, showing, as it has, associations with loss of expression of the androgen receptor and E-cadherin and P-cadherin, positive expression of basal cytokeratins CK5 and CK17 (basal phenotype), p53, vimentin, a high MIB1 labeling index, vascular-endothelial growth factor (VEGF), and in addition appears to be strongly EGFR-driven. And Torsten Nielsen in Vancouver showed a relationship between c-KIT expression and the basal-like breast cancer subtype, with the majority of c-KIT-positive breast tumors belonging to the basal-like breast cancer subtype. Moreover, these tumors share clinical features and gene expression profiles with tumors in patients who inherit germline mutations in the breast cancer predisposition gene BRCA1 and tumors arising in patients with BRCA1 mutations tend to exhibit a very similar histological phenotype to basal-like tumors, including similar gene expression profiles with BRCA1 tumors (which heavily fall into the basal-like category). The fact that basal-like tumors tend to have very high expression levels of VEGF suggests molecularly targeting VEGF should return special benefit in triple negative disease from the anti-VEGF agent bevacizumab (Avastin). Furthermore, recent research has observed an increased frequency of the triple negative phenotype in African-American patients.
Genotoxic (DNA-Damaging Agents) for Triple Negative Disease
But the real question is what practical in-the-clinic lessons can we draw from all these considerations of molecular classification and underlying molecular pathways? It turns out that an especially important insight culled from molecular profiling, with the potential to dramatically change our notions of the optimal treatment of triple negative disease, is that basal-like and triple negative tumors, many of which as I've already indicated, are associated with BRCA1 mutation, are particularly sensitive to genotoxic modalities, that is to those that are damaging to DNA, in part because the BRCA1 pathway activity appears to be significantly impaired in many triple negative tumors. Some examples of genotoxic modalities includes DNA-damaging chemotherapy - which critically prevent the tumors from reproducing and these include platinum compounds like carboplatin and cisplatin, as well as the classical alkylating agents like cyclophosphamide (Cytoxan), and the antineoplastic antibiotic anthracycline agents doxorubicin (Adriamycin) and epirubicin (Ellence), and Mitomycin C (MTC / Mitomycin / Mutamycin), which is also an antineoplastic antibiotic widely used in Japan but less well-known in breast oncology in the US. But it's important to note that it is not only chemotherapeutic agents that are DNA-damaging; radiation therapy is also genotoxic, suggesting that additional locoregional radiotherapy beyond the standard deployment may be of particular benefit to triple negative patients. And another non-chemotherapeutic intervention which is genotoxic is the class of biological agents known as PARP inhibitors (to be discussed further below). The practical upshot is that triple negative tumors are now known to be especially sensitive to genotoxic agents, listed in summary form and discussed further below.
List of Triple-Negative Sensitive Genotoxic Agents
Mitomycin C (MTC / Mitomycin / Mutamycin)
What About Taxanes?
Note that all anthracyclines are genotoxic and hence DNA-damaging, but the antimicrotubular taxanes, classed as mitotic spindle poisons, such as docetaxel (Taxotere) and paclitaxel (Taxol) are non-genotoxic. However, this does not mean they are not active in triple negative disease. Quite the contrary: Roman Rouzier found that these basal-like tumor are more sensitive (with a 45% pathologic complete response (pCR)) to taxane/anthracycline regimens in the form of paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers which only sustained a 6% responsive. I should note here that another neoadjuvant study - the infamous "The Triple Negative Paradox" study of Lisa Carey at UNC is often cited as suggesting that the clinical response (pCR) to doxorubicin and cyclophosphamide was considerably higher in patients with triple negative tumors than in those without. However, this study strikes me as somewhat methodologically compromised, as over a third of the triple negative group failed to receive any chemotherapy, and of those patients who did less than half received adjuvant anthracycline and taxane chemotherapy, casting doubt on the methodological robustness of the conclusions. Nonetheless, the weight of the evidence strongly supports both taxane and anthracycline regimens as beneficial in the treatment of triple negative disease.
New Insights about Platinum Sensitivity
An important set of data is typified in the results of the Harvard team of Chee-Onn Leong and Leif Ellisen who found that triple negative cancers independently share the cisplatin sensitivity of BRCA1-associated tumors (even in those without BRCA mutations), a sensitivity that is mediated by activation of a proapoptotic (inducing programmed cell suicide) molecular pathway p53 family member, and from this and other studies it appears that p53 is what fundamentally mediates the apoptosis induced by DNA-damaging agents.
Extending these findings John Chia's team conducted a retrospective analysis to determine the response rates of such patients treated with paclitaxel and carboplatin (TC) chemotherapy, finding that TC induces a high response rate in patients with metastatic / recurrent triple negative disease, even for patients with prior exposure to taxanes and moreover, and impressively, even for those with large volume disease.
Collectively, therefore data from preclinical and clinical studies indicate that both BRCA1 and triple negative tumors have unique sensitivities to platinum agents such as cisplatin and carboplatin, as well as to the genotoxic biological agents, the poly(ADP-ribose)polymerase (PARP) inhibitors, and these observations are helping to guide a new series of clinical trials, and at least as importantly, helping to hone and optimize the treatment of triple negative disease, and suggest for instance that adding platinum agents to taxane chemotherapy may induce high levels of efficacy for triple negative disease.
What About HDCT (High-Dose Chemotherapy)?
Triple negative disease has also been found significantly responsive to high-dose chemotherapy (HDCT) : the superiority has been shown of the (1) FEC + HDCT and (2) EC + HDCT regimens in triple negative patient subsets, as well as EP (epirubicin and paclitaxel) plus filgrastim, followed by three HDCT courses epirubicin, preceded by the cardioprotective agent dexrazoxane and paclitaxel) in high-risk triple negative breast cancer patients.
Finally, and most recently the efficacy of high-dose chemotherapy (HDCT), followed by autologous stem cell transplantation, versus dose-dense chemotherapy (DDCT) was compared, with a significantly better outcome (overall survival (OS) and event-free survival (EFS)) for patients in the basal-like, as well as the HER-2, subgroups who received HDCT in contrast to patients in largely endocrine (hormonal)-responsive) clusters who did not benefit from HDCT. Thus several studies converged to suggest the efficacy and sensitivity of high-dose chemotherapy against triple negative tumors.
HSP (Heat Shock Proteins)
Another novel insight culled from our recently gained understanding of the molecular nature and underlying pathways of triple negative disease is represented by the recent results of a study by Jose Moyana at the Robert H. Lurie Comprehensive Cancer Center and colleagues, who found that a small heat-shock protein / HSP (called alpha-basic crystalline) is commonly expressed in triple negative tumors and that this HSP overexpression increased cell migration and invasion, among other molecular activity, via the MEK/ERK pathway, suggesting that inhibition of the underlying MEK/ERK pathway may be an effective therapy for these types of basal-like breast tumors. In this connection there is a Pfizer-sponsored clinical trial exploring the novel MEK inhibitor PD-325901 in certain solid tumors including breast cancer.
I'll also note here that aspirin is known to itself be a potent MEK/ERK inhibitor suggesting a potential role in triple negative disease if further confirmed (as demonstrated early in the research of Zhongyan Wang and Peter Brecher at Boston University, Nina Vartiainen in Finland, among many others following). In addition, along with aspirin, NSAIDs like ibuprofen, and COX inhibitors (like celecoxib (Celebrex)) are independently of benefit in breast cancer risk reduction[16 19], a benefit that may be shared by natural COX inhibitory curcuminoid components of curcumin, which is activity in the regulation of COX-2, EGFR, VEGF, PI3K/Akt, MEK/ERK, p53, c-Myc, NF-kappaB, Bcl-2, e-cadherin, and apoptotic pathways all known to be critically involved in breast carcinomas in general and in triple negative disease in particular, as well as HER2 (ErbB2) [20 36], and some of which are also regulated by the activity of the EGCG (epigallocatechin-3 gallate) component of green tea[31 36].
Anti-VEGF / Antiangiogenic Chemobiotherapy
One of the best-evidenced highly effective regimens for basal-like / triple negative carcinoma would be the ABX-BEV combination chemobiotherapy regimen, that is, nab-paclitaxel (Abraxane) + bevacizumab (Avastin) . The now near-legendary results from Kathy Miller's ECOG-E2100, used what I would consider a somewhat weaker but similar regimen, the difference being that they used standard paclitaxel (Taxol) rather than nab-paclitaxel (Abraxane), yet even with this, it yielded a doubling of median progression-free survival (PFS), a larger absolute improvement than that seen with seminal trastuzumab trials. Given the efficacy data of Abraxane over standard paclitaxel, the ABX + BEV should therefore add an order of magnitude of further improvement without adding significant toxicity, indeed resulting in a more tolerable regimen. Furthermore, a subset analysis of ECOG-E2100 patients with triple negative disease suggested that this population benefited more from the paclitaxel + bevacizumab regimen than did hormone-responsive patients, so it appears to be a rare instance of a 3NEG-targeted regimen. The soon to open BEATRICE international trial is examining the benefit of adding bevacizumab (Avastin) to standard chemotherapy in triple negative disease.
Leveraging the "Right" Taxane
Furthermore, Spanish researchers Socorro Mara Rodrguez Pinilla and colleagues recently showed that CAV1 (caveolin-1) expression, a gene overexpressed with tumor progression, is associated with a triple negative phenotype in both sporadic and hereditary breast cancer. I consider the clinical impact of this insight to be substantial, given another finding from, among others, Neil Desai at American BioScience that finding being that the albumin-bound particles of nab-paclitaxel (Abraxane) preferentially deliver paclitaxel to tumors by exploiting a molecular pathway (which is called transcytosis) involving caveolin-1 (CAV-1).
In fact, nanoparticle drug carriers like nab-paclitaxel (Abraxane) preferentially accumulate in tumor beds and tissues, yielding increased antitumor activity and intratumor concentrations. Thus it appears that nab-paclitaxel (Abraxane) binds to albumin receptors inside the tumor blood vessel, resulting in the "freed" paclitaxel penetrating and killing tumor cells via microtubule binding.
So what is the upshot of all these molecular activities and interactions? Well, increased intratumoral accumulation, because nab-paclitaxel (Abraxane) appears to exploit caveolin-1 (CAV-1) to deliver more active drug (paclitaxel) selectively to tumors. This suggests that breast cancer patients with higher CAV-1 expression such as those with triple negative disease are likely to gain higher efficacy with nab-paclitaxel (Abraxane) due to CAV-1 activation, and this is a molecular advantage over the other standard formulation taxanes (paclitaxel (Taxol) and docetaxel (Taxotere) which exhibit no comparable CAV-1 specific activity. It strikes me that therefore this greatly hones our targeting of the underlying molecular pathways of triple negative disease and provides a rough but suggestive evaluation metric that nab-paclitaxel (Abraxane) might be more optimal in this context than standard taxanes for the treatment of triple negative tumors. I observe further that the TKI dasatinib (Sprycel) discussed further below - is also active against CAV1, making it to some extent triple negative-specific ("triple negative-targeting").
Enhancing the ABX-BEV Regimen Further
And as indicated above in our discussion of the platinum agents, adding such a platinum agent like carboplatin (yielding ABX + BEV + CARBO) is a increasingly deployed practice (growing out of some preclinical work, and of findings from trastuzumab (Herceptin) trial data, as well as from triple negative populations with inherited BRCA1/2 mutations).
In the introduction above, I noted that EGFR over-expression in triple negative and basal-like breast carcinoma is now well-established, as is therefore the therapeutic value of EGFR-inhibition, given that triple negative tumors are EGFR-signaling dependent, highly expressed in at least 50% of all such tumors. Preclinical evidence from Zyhiyuan Hu and colleagues with the Lineberger Comprehensive Cancer Center at UNC and Stefano Calza at the Swedish Karolinska Institutet and his coresearchers, suggests that the molecular profile of triple-negative breast cancer is characterized by a unique signature that includes EGFR gene overexpression, suggesting an important role for monoclonal antibodies (MoAbs) binding the extracellular ligand-binding domain such as cetuximab (Erbitux). Rebecca Clark-Snow at the University of Kansas is exploring in clinical trial the value of the EGFR inhibitor erlotinib (Tarceva) added to chemotherapy for triple negative disease.
EGFR-Targeted Therapies: Cetuximab (Erbitux)
It's been determined that combinations of cetuximab + carboplatin are highly synergistic at low doses of each drug, according to the preclinical research of Katherine Hoadley, along with Lisa Carey[45,46] at UNC, who showed (1) that of all breast cancer subtypes, basal-like tumors are both the most sensitive to EGFR inhibitors and carboplatin individually, (2) that the combination was synergistic as well, not just additive, and that (3) the EGFR-RAS-MEK pathway may be a requisite event for basal-like tumor formation, guiding targeted therapy. In addition, the Bali-1 trial is examining the benefits of cetuximab + cisplatin in triple negative disease.
Given this molecular foundation, there are now several trials exploring the potential of EGFR inhibitors in triple negative disease in the MBC (metastatic breast cancer) setting and evaluating a combination of EGFR-inhibitors + platinum agent. Of these considerable interest surrounds those using the MoAb (monoclonal antibody) required to above, cetuximab (Erbitux) , added to a platinum agent, carboplatin. One ongoing, actively recruiting, phase II clinical trial at MD Anderson under Francisco Esteva, principal investigator is randomizing patients to receive either cetuximab alone, with the addition of carboplatin upon progression, or cetuximab + carboplatin; this trial is due to report later this year. (A parallel trial is under Lisa Carey's group at UNC Lineberger Comprehensive Cancer Center, coordinated across UNC, the Mayo Clinic in Rochester Minnesota, and Baylor in Houston, deploys the same protocol as the MD Anderson trial).
Another still actively recruiting EGFR-inhibitor clinical trial is the ongoing US Oncology Research study under Joyce O'Shaughnessy evaluating weekly irinotecan (Iressa) + carboplatin with or without cetuximab in patients with MBC, and although not triple negative-restricted, I have ascertained from trial authorities that a substantial number of patients on this trial have triple-negative disease. This approach of this trial reflects the use of small-molecule TKIs (SM-TKIs) such as gefitinib (Iressa) and erlotinib (Tarceva) ) as ATP-competitors for binding to the intracellular tyrosine kinase domain, where ATP is a known binding site of EGFR so that such SM-TKIs compete with such binding, and hence blocking the activation of various downstream signaling pathways. And Cynthia Ma at Washington University is conducting another ongoing Cetuximab-Carbo(platin trial.
EGFR-Targeted Therapies: Sunitinib (Sutent)
Given that SM-TKIs are biological agents with multiple receptor targets (including VEGF, like Avastin, as well as several others involved in angiogenesis, and in cellular proliferation), and have not only been used successfully in treating GIST and renal cancer, but also breast cancer with some promise. Besides the SM-TKI gefitinib (Iressa) discussed above, there is interest in another such SM-TKI, sunitinib (Sutent) , and there is currently a large multi-center, multi-state, and international, actively recruiting Pfizer-sponsored trial of sunitinib (Sutent) in previously treated patients with advanced triple negative disease, that is locally recurrent or metastatic; one restriction is that no previous treatment with an angiogenesis inhibitor like bevacizumab (Avastin) is allowed for trial eligibility.
EGFR-Targeted Therapies: Dasatinib (Sprycel)
Another small molecule TKI (SM-TKI) is dasatinib (Sprycel) . Dasatinib is a novel oral multitargeted kinase inhibitor that targets several important oncogenic pathways, including SRC family kinases and BCR-ABL. Dasatinib is already established in the treatment of one prominent form of leukemia (CML), but is largely unknown in breast cancer with the exception of a single in vitro cell study by Richard Finn and colleagues at UCLA, which found basal-type / triple negative breast cancer cell lines to be preferentially inhibited by and highly sensitive to dasatinib, and this has been confirmed via gene signature exploration by Fei Huang at BMS (Bristol-Meyer Squibb). BMS is currently sponsoring a multi-center, actively recruiting trial of dasatinib in triple negative patients. The importance, and promise, of dasatinib lies in part on the fact that the SRC oncogenic pathway plays an important role downstream of vascular endothelial growth factor (VEGF) signaling, and so it is anticipated that dasatinib will also have antiangiogenic activity. In addition, because SRC plays an important role in osteoclast function, it is possible that dasatinib will benefit patients with bone metastases, in addition to its antiangiogenic activity.
Epothilones are microtubule-stabilizing agents, but they target mitotic tubules in a different location than taxanes, with several advantages over the taxanes: unlike taxanes, epothilones appear to avoid developing resistance, being less sensitive than paclitaxel to multidrug-resistant proteins, and do not require steroid pretreatment. Furthermore, epothilones have gained a reputation of benefit in difficult-to-treat breast cancers such as metastatic patients who experience disease progression on anthracycline, taxane, and capecitabine (Xeloda) chemotherapy. One epothilone, ixabepilone (Ixempra) has just (10/16/07) obtained FDA approval, under priority review, and is already available for deployment, approved for treatment via intravenous infusion, either as monotherapy or in combination with capecitabine (Xeloda), of women with metastatic or locally advanced treatment-resistant breast cancer, including tumors resistant or refractory to an anthracycline, a taxane or capecitabine. Craig Bunnell at Dana-Farber and colleagues at MD Anderson conducted a Phase I/II trial of an ixabepilone + capecitabine combination regimen in metastatic patients previously treated with a taxane and an anthracycline, 44% of whom were triple negative, finding the combination synergistic and with an overall response rate of 30%, and with manageable toxicity.
Based on these and other promising clinical results, one BMS-sponsored multicenter clinical trial of ixabepilone + bevacizumab (IXA + BEV) is actively recruiting, and another under Ellen Chuang at Weill Medical College (Cornell) is recruiting for a trial of IXA + Doxil (ixabepilone + doxorubicin HCl liposome) in a variety of cancers including in MBC with patients previously treated with a taxane and a platinum agent. And BMS is conducting a soon to recruit study of ixabepilone plus capecitabine or docetaxel plus capecitabine in metastatic breast cancer which although not triple negative-specific, is designed to explicitly track triple-negative and non-triple-negative (NTN) subjects; given the recent approval of
I should note here one caution about now-available ixabepilone (Ixempra) that is not highlighted in the official labeling, and that is the potential adverse interaction with certain natural agents, including St. John's Wort, chamomile, sage, licorice extract, the soybean components daidzein and genistein, grapefruit juice, and possibly also EPO (Evening Primrose Oil) / Borage (seed) Oil, and as opposed to just these natural agents - the widely used pharmaceutical atorvastatin (Lipitor) . The reason for this caution against coadministration of ixabepilone (Ixempra) with any of these agents, natural and pharmaceutical, is that all of these agents are potent CYP3A4-inhibitors, and the metabolism of ixabepilone (Ixempra) is dependent on the CYP3A4 hepatic enzyme, part of what's called the P450 Cytochrome system.
There are several other options for triple negative therapy, and one of the more interesting outside of clinical trials is from Robert Livingston, chair until this year of the Breast Cancer Committee of SWOG (Southwest Oncology Group) at the Arizona Cancer Center, who uses a base of metronomic therapy of lose-dose AC (using continuous daily oral cyclophosphamide (Cytoxan)) with G-CSF support followed by weekly paclitaxel in order to leverage antiangiogenic activity given the critical role of angiogenesis in triple negative disease, adding other chemotherapeutic agents to this base as needed, including the possibility of an added platinum or an antitubulin combination such as a nab-paclitaxel (Abraxane) and vinorelbine (Navelbine) regimen (Robert Livingston is the "father" of metronomic therapy in breast cancer, which leverages low-dose frequent or continuous schedules of oncotherapy to both induce angiogenic inhibition and to avoid the potential for tumor regrowth during the traditional chemotherapy breaks or rest periods, also reducing toxicity, and Dr. Livingston appropriately received a piano metronome for his 25 year service in the field from SWOG). Paul Walker at East Carolina University is conducting a Phase II clinical trial of a neoadjuvant metronomic chemotherapy for triple negative disease, where women with a diagnosed triple-negative disease, confirmed on a core biopsy and larger than 2 cm, will be treated neoadjuvantly with the what is now come to be called, appropriately, the Livingston metronomic regimen of 12 weeks of weekly doxorubicin 24 mg/m2 and daily oral cyclophosphamide 60 mg/m2 followed by 12 successive weeks of paclitaxel (Taxol) 80 mg/m2 plus carboplatin.
As I noted briefly above, PARP inhibitor biological (non-chemotherapeutic) therapy is another genotoxic, DNA-damaging intervention of considerable potential benefit in the treatment of triple negative disease. PARP1 (poly (ADP-ribose) polymerase-1) is a nuclear enzyme that is involved in repairing DNA damage (called base excision repair), mediating cell death (apoptosis) and necrosis, and regulating immune response. PARP activation occurs when cells are damaged in instances such as during chemotherapy and radiotherapy, and also in non-treatment events such as stroke, head trauma and heart ischemia. The goal of targeting PARP is to prevent tumor cells from repairing DNA themselves and developing drug resistance, which may make them more sensitive to cancer therapies. In preclinical testing, PARP inhibitors have demonstrated the ability to increase the effect of various chemotherapeutic agents (e.g., DNA topoisomerase inhibitors II like the anthracyclines, or cisplatin), as well as radiation therapy, against a broad spectrum of tumors. Given that DNA is under constant attack from endogenous toxins, such as free radicals generated by cellular metabolism and exogenous toxins, including many carcinogens, it isn't surprising that cells have evolved and developed multiple mechanisms to ensure DNA integrity, with each DNA repair mechanism correcting a different subset of lesions. The PARP-1 nuclear enzyme addresses and repairs certain types of DNA damage in lesions, and so PARP inhibitors are essentially deployed to block the repair of such DNA damage by PARP1 and hence induce tumor cell death.
Because many chemotherapeutic agents in common use are known to, or likely to, induce double-strand breaks (DSBs), and because this DNA-damaging activity of genotoxic chemotherapeutic agents converges with the ultimate goal of PARP inhibitors to block such damage and hence allow the DNA damage to go unrepaired in tumor cells, there is a natural and molecular plausibility to a synergism between genotoxic chemotherapies and PARP inhibitory agents, and to the strategy I might call PARP-inhibitor sensitization of genotoxic chemotherapy. This use of PARP-1 inhibitors in combination with standard chemotherapeutic agents also seems attractive from the point of view that sensitizing tumor cells to cytotoxic agents one might enable lower chemotherapy dosing while maintaining the same relative efficacy, and hence reducing overall treatment toxicity.
There is therefore plausible early evidence that defective DNA damage repair may make BRCA1-deficient cancer cells more sensitive to DNA damaging agents, and the benefit may not just be limited to such BRCA-1 deficient tumor cells: the NIDDKD (National Institute of Diabetes and Digestive and Kidney Diseases) team under Chu-Xia Deng found that PARP-1 inhibitors can inhibit breast cancer cells irrespective of their BRCA1 and ER status.
However, as noted also by Dr. Tito Fojo with the Center for Cancer Research at NCI, this therapeutic strategy of genotoxic chemotherapy + PARP-Inhibition has the potential to enhance chemotherapy toxicity, and possibly also the incidence of secondary malignancies, especially leukemias. Nonetheless, this potential for the emergence of higher toxicities and/or incidence of secondary leukemias remains only a theoretical concern and no robust clinical data has as yet provides confirmation or disconfirmation, to me somewhat reassuring perhaps given the deployment of PARP inhibition across an extraordinarily wide spectrum of disorders (cardiomyopathy and myocardial injury, stroke, neurotrauma, arthritis, inflammatory bowel disease, allergic encephalomyelitis, multiple sclerosis, diabetes, HIV infection, as well as various cancers, among many other conditions).
PARP-1 inhibitors also are attractive agents based on what seems to be not only few side effects but also a protective effect in normal tissue. Indeed, reports from clinical trials using PARP-1 inhibitors have successfully completed phase I studies and entered phase II studies for various ischemic disorders. Furthermore, PARP-1 inhibitors seem to protect against the nephrotoxicity of cisplatin and the cardiotoxicity of doxorubicin.
Yoon-Sim Yap at Royal Marsden Hospital and colleagues tested AZD2281 (formerly called KU-0059436), with encouraging anti-tumor activity reported in early results presented at ASCO 2007 (the presentation received an ASCO merit award), and minimal toxicity (the target dose being 600 mg bid continuously); toxicities including low grade (1 2) fatigue, anorexia, constipation and diarrhea, and some grade 4 platelet cell reduction. This study is part of the ICEBERG 1 trial, a collaborative effort with the Royal Marsden Hospital and Netherlands Cancer Institute (NKI). And although most attention has focused on this ICEBERG 1 AstraZenica trial of the AZD2281 / KU-0059436) PARP inhibitor, another equally important trial is the Phase I study of AZD0530 for Src inhibition, also reported at ASCO 2007; the Src kinases play an important role in cancer growth, and cell proliferation, focal adhesion, invasion, metastasis (through motility), and apoptosis, so Src inhibition is thought to be critical in the delay of cancer progression, and more critically may assist in the treatment of various metastases including bone while, like other PARP inhibitors, synergizing the antitumor activity of chemotherapy.
I have long been a strong advocate of the potential benefit of mTOR (mammalian target of rapamycin) inhibition in the treatment of breast cancer, and am heartened to finally observe that mTOR inhibitors are finally being explored in this capacity, including for the treatment of triple negative disease. I'll note here that the mTOR kinase is downstream of the PI3K/Akt pathway, an important regulator of cell proliferation and survival, and to also affect VEGF production at multiple levels, and breast cancers with mTOR overexpression showed a three times greater risk for disease recurrence and the mTOR inhibitor rapamycin was found to potentiate the cytotoxicity of selected chemotherapeutic agents, including paclitaxel (Taxol), carboplatin, and vinorelbine (Navelbine), and dramatically enhance paclitaxel- and carboplatin-induced apoptosis[68,69], as well as exerting antitumor activity in breast cancer via antiangiogenesis as demonstrated with findings on temsirolimus (Torisel) , an mTOR inhibitor which has already shown dramatic benefit in RCC (renal cell carcinoma). Recent results of mTOR inhibition in breast cancer are highly promising. There has also been promising activity with partial responses observed both in patients with visceral-dominant and soft tissue-dominant breast cancer metastases.
I note also here that the natural agent curcumin curcumin's anticancer activity appears to operate primarily by blocking mTOR-mediated signaling pathways in the tumor cells, also induced apoptosis and inhibiting the basal or type I insulin-like growth factor-induced motility of the cells, also inhibiting at high concentrations the phosphorylation of Akt in tumor cells[76-78]. Also intriguing in this connection is the recent finding that mTOR suppression may be associated with antitumor actions of caloric restriction, which hints that caloric restriction may be of special benefit in potentially mTOR-dependent and/or sensitive breast carcinoma such as triple negative disease. This would also help account for the disproportionately large benefit in terms of degree of recurrence risk reduction engendered by even very modest caloric restriction and weight control in breast cancer patients, a theme underlined in Carol Fabian's excellent presentation on Preventing Breast Cancer What's New
[click on link to download as pdf] at the recent 2007 Controversies in Breast Cancer conference in NY.
In terms of clinical trials of mTOR inhibition in breast cancer, Ana Gonzalez-Angulo at MD Anderson is examining in a clinical trial the use of an mTOR inhibitor (RAD001) + a taxane (paclitaxel) as neoadjuvant chemotherapy compared to the same taxane + FEC chemotherapy.
Before concluding this section on mTOR inhibitors, I note that forthcoming research from Ryan Dowling at McGill University has found that the anti-diabetes agent metformin (Glucophage) inhibits mTOR-dependent translation initiation in breast cancer cells (publication pending, November issue of the Cancer Research journal), building on and confirming earlier results from Dowling's colleague Mahvash Zakikhani that metformin-induced growth inhibition was associated with decreased mammalian target of rapamycin. This is molecularly persuasive given that insulin and insulin-like growth factors (IGF) stimulate proliferation in many cell types, and suggests antineoplastic activity by metformin via growth inhibition of breast cancer epithelial cells; indeed high mammographic breast density known to predict increased breast cancer risk is associated with higher concentrations of circulating IGF-I[82,83] and insulin-like growth factor-I (IGF-I), which also plays a critical role in carcinogenesis and tumorigenesis. These considerations would help to account the antitumor effect of caloric restriction via mTOR inhibition, as caloric restriction may involve underlying insulin and IGF pathways, and suggest that both caloric restriction and glucose / insulin control may play specific beneficial functions in triple negative disease via the new-found contribution of mTOR inhibition, and add another item of defense to the growing arsenal deployable against triple negative breast carcinoma.
Summary of Triple Negative Disease Therapy
It should be clear from the above that there are now, and more soon emerging, an extraordinarily wide range of significantly effective therapeutic interventions for the treatment of triple negative disease. These include:
Triple-Negative Sensitive Chemotherapy
Cyclophosphamide (Cytoxan) [genotoxic]
Platinum Agents: Carboplatin (Paraplatin), Cisplatin (Platinol) [genotoxic]
Anthracyclines: Doxorubicin (Adriamycin), Epirubicin (Ellence) [genotoxic]
Taxanes (Cremophor-based): Paclitaxel (Taxol), Docetaxel (Taxotere)
Nanoparticle Albumin-bound Paclitaxel: nab-paclitaxel (Abraxane)
Mitomycin C (MTC / Mitomycin / Mutamycin) [genotoxic]
HDCT (High-Dose Chemotherapy) [genotoxicity dependent on component agents]
Metronomic Chemotherapy [genotoxicity dependent on component agents]
Epothilone Therapy: Ixabepilone (Ixempra)
Triple-Negative Sensitive Genotoxic Radiotherapy
Triple-Negative Sensitive Genotoxic Biological Therapy
HSP90 (Heat Shock Protein-90)
Anti-VEGF / Antiangiogenic Chemobiotherapy
A Note of this Contribution
Although I have not included source references directly in this posting to avoid excessive technical "weight", the reference numbers are included in the form of a bracketed  number or numbers in the text and anyone interested can access the sources themselves in the technical version of this posting available online as Issue 3 of my Breast Cancer Watch Digest newsletter, where the references are also hyperlinked to the original sources. That version also contains some additional tutorial-type material on DNA damage and PARP inhibitors, and briefly describes the methodology of the review, while this special invited presentation for the No Surrender forum has additional material relating to recent conference discussions plus some hints at findings to be reported at the upcoming SABCS this December.
You can read more here:
Breast Cancer Watch
We have been encouraging No Surrender readers to take their Vitamin D since our inception. Now, a study we have been following, has yielded great results- especially if you have triple negative breast cancer. We recommend Vitamin D supplementation no matter what your receptors are and suggest that women who do not have breast cancer also supplement to keep their D levels in good range.
Vitamin D Holds Promise in Battling a Deadly Breast Cancer
Wed, 2013-01-23 11:34
In research published in the Jan. 21 issue of The Journal of Cell Biology, a team led by Susana Gonzalo, PhD, assistant professor of biochemistry and molecular biology at Saint Louis University, has discovered a molecular pathway that contributes to triple-negative breast cancer, an often deadly and treatment resistant form of cancer that tends to strike younger women. In addition, Gonzalo and her team identified vitamin D and some protease inhibitors as possible new therapies and discovered a set of three biomarkers that can help to identify patients who could benefit from the treatment.
In the recent breakthrough, which was funded in part by a $500,000 Department of Defense grant, Gonzalo’s lab identified one pathway that is activated in breast cancers with the poorest prognosis, such as those classified as triple-negative. These cancers often strike younger women and are harder to treat than any other type of breast cancer. Women who are born with BRCA1 gene mutations are at increased risk for developing breast and ovarian cancers within their lifetime, and the tumors that arise are frequently the triple-negative type. Although chemotherapy is the most effective treatment for triple-negative breast cancer, it has profound secondary effects. Understanding the biology of triple-negative breast cancers will help to develop less toxic therapeutic strategies.
Experiments performed in Gonzalo's laboratory, in collaboration with the laboratories of Xavier Matias-Guiu and Adriana Duso (IRBLleida, Spain), showed that activation of this novel pathway not only allows tumor cells to grow unchecked, but also explains the reduced sensitivity of these types of tumors to current therapeutic strategies. Importantly, vitamin D plays a role in turning off this pathway, providing a safe and cost-effective strategy to fight these types of tumors.
For molecular biologists like Gonzalo who look for answers below the cellular level to discover why some people develop cancer, the search often involves tracing a chain of events to try to understand cause and effect of the behavior between several genes and the proteins which they express. In order to understand these complex pathways, researchers often turn levels of proteins on or off by expressing one gene or suppressing another. Part of a researcher’s challenge is determining what the function of each component of a pathway is.
The cell employs a complex mechanism to protect genetic information and ensure that damaged DNA is not passed on to daughter cells. Cells have built in checkpoints and fail safes to ensure the accuracy of their DNA code and are able to slow or stop their own proliferation if the information is compromised. Loss of these checkpoints and the accumulation of damaged DNA often leads to cancer.
BRCA1 is a well-established tumor suppressor gene. Women who carry mutations in this gene have a high risk of developing breast and ovarian cancer. Tumors that arise often lack expression of three receptors: estrogen, progesterone and HER2 (thus, “triple-negative”), and do not respond to hormone therapy.
BRCA1 is important because it is involved in repairing DNA double-strand breaks, a kind of DNA damage that is especially dangerous for the integrity of our genome. BRCA1 also is involved in cell-cycle checkpoints after damage, which are control mechanisms during cell proliferation that make sure the DNA information has been accurately replicated and transferred to the daughter cells. Thus, BRCA1 is considered a safeguard of the genome.
Loss of BRCA1 is bad news for the information contained in a cell’s genetic blueprint. It results in genomic instability characterized by unrepaired DNA breaks and chromosomal aberrations that compromise cell viability. How BRCA1-mutated cells are able to form tumors has been a long-standing question. Investigators recently showed that loss of another DNA repair factor, 53BP1, allows proliferation and survival of BRCA1-deficient cells. In addition, decreased levels of 53BP1 were observed in triple-negative breast cancers, and correlated with resistance to drugs at the forefront of cancer treatment, such as PARP inhibitors.
Gonzalo’s team has found a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1 mutated and triple-negative. It turns out that loss of BRCA1 increases the expression of a protease, known as cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, maintain the integrity of the genome, and proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.
If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.
So, how to do this? In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation.
Importantly, their evidence suggests that vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis.
So, with this chain of events, Gonzalo and colleagues demonstrated a pathway by which triple-negative breast cancers proliferate: BRCA1-deficient cells activate CTSL which minimizes levels of 53BP1 to overcome genomic instability and growth arrest.
In a final exceptionally useful discovery, Gonzalo and collaborators found that high levels of nuclear CTSL and low levels of 53BP1 and nuclear vitamin D receptor (VDR) are a clear marker that identifies certain triple-negative breast cancer patients, biomarkers that offer the potential to customize future breast cancer therapies. In particular, this triple-biomarker signature will allow the identification of patients in whom the pathway is on and who might benefit the most from vitamin D treatment.
January 14, 2013
Newfound marker for aggressive breast cancer may also be a treatment target
The findings of a recent study strongly implicate the ribonucleic acid (RNA) molecule miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, which in turn makes the molecule a potential therapeutic target in metastatic breast cancer.
As explained in a statement issued by Case Western Reserve University in Cleveland, Ohio, miR-181a had never before been tied to breast cancer metastasis. However, William P. Schiemann, PhD, of the Case Comprehensive Cancer Center, and colleagues found elevated levels of the molecule in late-stage breast cancer tissues.
The investigators described in The Journal of Clinical Investigation (2013;123:150-163) their discovery that miR-181a expression was essential in driving metastasis and enhancing the lethality of late-stage mammary tumors in mice. In addition, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in humans with breast cancer.
An inhibitor of miR-181a tested in the mice prevented metastasis and extended survival.
“Overall, these findings reinforce our belief that the discovery of miR-181a will become a strong predictive biomarker for breast cancer metastasis, and that the high expression of miR-181a in tumor tissues will pave the way for the development of targeted therapies, better prognosis, and increased patient survival,” commented Schiemann in the Case Western statement.
Septemner 6, 2012
UT MD Anderson Cancer Center Launches Unprecedented Moon Shots Program
Effort sets new bar for eradicating cancer; Goal to significantly increase patient survival during the next decade
HOUSTON — The University of Texas MD Anderson Cancer Center announces the launch of the Moon Shots Program, an unprecedented effort to dramatically accelerate the pace of converting scientific discoveries into clinical advances that reduce cancer deaths.
Even as the number of cancer survivors in the US is expected to reach an estimated 11.3 million by 2015, according to the American Cancer Society, cancer remains one of the most destructive and vexing diseases. An estimated 100 million people worldwide are expected to lose their lives to cancer in this decade alone. The disease’s devastation to humanity now exceeds that of cardiovascular disease, tuberculosis, HIV and malaria – combined.
The Moon Shots Program is built upon a “disruptive paradigm” that brings together the best attributes of both academia and industry by creating cross-functional professional teams working in a goal-oriented, milestone-driven manner to convert knowledge into tests, devices, drugs and policies that can benefit patients as quickly as possible.
The Moon Shots Program takes its inspiration from President John Kennedy’s famous 1962 speech, made 50 years ago this month at Rice University, just a mile from the main MD Anderson campus. “We choose to go to the moon in this decade ... because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win,” Kennedy said.
“Generations later, the Moon Shots Program signals our confidence that the path to curing cancer is in clearer sight than at any other time in history,” said Ronald A. DePinho, M.D., MD Anderson’s president. “Humanity urgently needs bold action to defeat cancer. I believe that we have many of the tools we need to pick the fight of the 21st century. Let’s focus our energies on approaching cancer comprehensively and systematically, with the precision of an engineer, always asking ... ‘What can we do to directly impact patients?’”
The inaugural moon shots
The program, initially targeting eight cancers, will bring together sizable multidisciplinary groups of MD Anderson researchers and clinicians to mount comprehensive attacks on:
- acute myeloid leukemia/myelodysplastic syndrome;
- chronic lymphocytic leukemia;
- lung cancer;
- prostate cancer, and
- triple-negative breast and ovarian cancers – two cancers linked at the molecular level.
Six moon shot teams, representing these eight cancers, were selected based on rigorous criteria that assess not only the current state of scientific knowledge of the disease across the entire cancer care continuum from prevention to survivorship, but also the strength and breadth of the assembled teams and the potential for near-term measurable success in terms of cancer mortality.
Each moon shot will receive an infusion of funds and other resources needed to work on ambitious and innovative projects prioritized for patient impact, ranging from basic and translational research to biomarker-driven novel clinical trials, to behavioral interventions and public policy initiatives.
The platforms make the program unique
The institution-wide, high quality scientific and technical platforms will provide key infrastructure for the success of the Moon Shots Program. In the past, each investigator or group of investigators has developed their own infrastructure to support their research programs. Frequently they were under-funded and lacked the high level management and leadership required to ensure that they were of the highest caliber and in particular that they were able to adapt to the rapidly changing scientific and technological environment. The moon shot platforms will be designed and resourced to provide expertise that will support the efforts of all of moon shots teams. The platforms will provide a critical component to the success of each moon shot and of the overall Moon Shots Program. In particular, they will leverage the investment across the moon shots.
These platforms include:
Adaptive Learning in Genomic Medicine: A work flow that enables clinicians and researchers to integrate real-time patient clinical information and research genomic data, allowing understanding of the cancer genome and ultimately improving outcome.
Big Data: The capture, storage and processing of huge amounts of information, much of it coming from Next Generation Sequencing machines (genome sequencing).
Cancer Control and Prevention: Community-based efforts in cancer prevention, screening, and early detection and survivorship to educate and achieve a measureable reduction in the cancer burden. Interventions in the areas of public policy, public education, professional education and evidence-based service delivery can make a measurable and lasting difference in our community, especially among those most vulnerable - the underserved.
Center for Co-Clinical Trials: Uses mouse or cell models of human cancers to test new drugs or drug combinations and discover the subset of patients most likely to respond to the therapy.
Clinical Genomics: An infrastructure designed to bank and process tumor specimens for clinical tests that can guide medical decisions.
Diagnostics Development: The development of diagnostic tests for use in the clinic to guide targeted therapy.
Early Detection: Using imaging and proteomic technologies to discover markers that can identify patients with early-staged cancers.
Institute for Applied Cancer Science: Developing effective targeted cancer drugs.
Institute for Personalized Cancer Therapy: An extensive infrastructure that analyzes genomic abnormalities in patient tumors to direct them to the best treatments and clinical trials.
Massive Data Analytics: A computer infrastructure that develops or uses computational algorithms to analyze large-scale patient and public data.
Patient Omics: Centralizing collection of patient biospecimens (tumor samples, blood, etc.) to profile genes and proteins (genomics, proteomics) and identify mutations that can guide personalized treatment decisions and predict therapy-related toxicity to improve overall patient outcomes.
Translational Research Continuum: A framework to facilitate efficient transition of a candidate drug from preclinical studies to early stages of human clinical trial testing so effective drugs can be developed in a shorter time and clinical trials can be quicker and cheaper with higher success rates.
MD Anderson’s “Giant leap for mankind”
A year ago, when DePinho was named MD Anderson’s fourth president, he proposed the notion of a moon shot moment. “How can we envision what’s possible to reduce cancer mortality if we think boldly, adopt a more goal-oriented mentality, ignore the usual strictures on resources that encumber academic research and use the breakthrough technology available today?” he asked. Response from the faculty and staff took the form of initial moon shot proposals that targeted several major cancer types and involved large, integrated MD Anderson teams, sometimes numbering in the hundreds.
Frank McCormick, Ph.D., director of the University of California, San Francisco Cancer Center and president of the American Association for Cancer Research, led the review panel of 25 internal and external experts that narrowed the field to the inaugural six moon shots.
“Nothing on the magnitude of the Moon Shots Program has been attempted by a single academic medical institution,” McCormick said. “Moon shots take MD Anderson’s deep bench of multidisciplinary research and patient care resources and offer a collective vision on moving cancer research forward.”
McCormick added, “The process of bringing this amount of horsepower together in such a focused manner is not normally seen in academic medicine and is valuable in and of itself.”
“The Moon Shots Program holds the potential for a new approach to research that eventually can be applied to all cancers and even to other chronic diseases,” DePinho said. “History has taught us that if we put our minds to a task, the human spirit will prevail. We must do this – humanity is depending on all of us.”
For more information, including backgrounders on the inaugural moon shots, please visit www.cancermoonshots.org
STATEMENT ON ACCESS TO THE INVESTIGATIONAL AGENT INIPARIB
Many patients and advocates within the breast cancer community have been following Sanofi’s research on the investigational agent iniparib for the last several years, in the hopes that it might eventually provide a new treatment option for the patients battling metastatic triple negative breast cancer (mTNBC). However, Sanofi recently reported in February 2011, that the
Phase III study of iniparib in combination with gemcitabine and carboplatin, in patients with mTNBC, did not demonstrate an improvement in either progression‐ free survival or overall survival when compared to gemcitabine and carboplatin alone.
As such, the data from this Phase III study do not support an application for approval by the U.S. Food & Drug Administration (FDA). After extensive discussions with the FDA and external breast cancer experts – including several patient advocacy organizations – Sanofi has decided that it is
necessary to initiate new clinical studies of iniparib, in an effort to better understand how the agent works and to identify potential dosing and patient populations.
In the light of the Phase III results and the need to further investigate iniparib, Sanofi and BiPar Sciences have decided to close the current Expanded Access Program (EAP) for all new patient enrollment effective as of August 15, 2011.
In addition, Sanofi and BiPar Sciences recommend that patients currently receiving iniparib (BSI‐201) as part of the EAP discontinue treatment under this program. However, physicians may consider continuing iniparib in combination with gemcitabine and carboplatin, based on the assessment of individual patients. If the decision is made to continue iniparib, the patient needs to be re‐consented.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
At Sanofi and Bipar Sciences, we feel that closing this EAP – while difficult – is the most responsible course of action, since the clinical benefit of iniparib has not been demonstrated. Additionally, we do not want the iniparib EAP to inadvertently prevent mTNBC patients from accessing other treatment options or participating in clinical trials of other investigational agents.
Patients who are interested in finding out more about clinical trials are encouraged to visit http://www.clinicaltrials.gov.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib. To this end, Sanofi will be initiating the new iniparib clinical research program in the breast cancer setting in the next few weeks.
Patient & Patient Advocate Q&A
1. If I participated in an iniparib clinical trial and still receive it, will I be able to continue receiving iniparib from the company?
If you are receiving iniparib as a result of your participation in a metastatic triple negative breast cancer (mTNBC) clinical trial and your physician feels that it is appropriate for you to continue receiving iniparib, we do not anticipate any disruption in your access to iniparib, regardless of
whether you are receiving it in the 1st, 2nd, or 3rd line setting.
2. If I am a mTNBC patient currently enrolled in the Expanded Access Program (EAP), will I continue to receive Iniparib?
Yes, if you are already enrolled in the EAP you will continue to receive iniparib through the EAP, until your physician feels it is no longer appropriate. All patients continuing to receive iniparib through the EAP must sign a new consent form, however.
3. If I am a mTNBC patient waiting to be enrolled in the EAP, can I still get in?
Yes, if you are a 2nd, 3rd, or 4th line patient, you will be able to enroll in the EAP until August 15, 2011. Based on the analysis of the Phase III data, we are no longer accepting new 1st line patients into the EAP, because the trial did not demonstrate that iniparib provided a benefit for patients taking iniparib.
After August 15, 2011 , Sanofi will no longer be enrolling any new patients in the program, regardless of line of therapy, due to the negative Phase III study results.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib.
4. What is the timing for the discontinuation of the current EAP program and the initiation of the new clinical trial program?
The EAP will no longer be open for patient enrollment after August 15, 2011. While we are still finalizing the protocol for the new Phase 1B clinical trial of iniparib, we anticipate that it will begin enrolling patients in within the next few weeks. For more information on this study or other clinical trials, please visit www.clinicaltrials.gov.
5. Will the iniparib EAP program continue to enroll patients after the initiation of the new clinical trial program?
No. Providing access to an investigational agent through an EAP can make it very difficult – if not impossible – to simultaneously enroll a clinical trial that is designed to evaluate the same investigational agent.
Additionally, in light of the need to make significant changes to iniparib’s clinical development program, the company does not feel it is appropriate to continue the Expanded Access Program (EAP) when so many important questions about iniparib remain unanswered. Therefore, Sanofi
will be closing the EAP to new patient enrollment after August 15, 2011.
Patients currently enrolled in the EAP will be permitted to remain in the program until their disease progresses or their physicians feel they are no longer receiving benefit from iniparib, as long as they sign a new consent form.
Natural Weapon Against Triple Negative Breast Cancer
Something so simple.... nature healing nature.... Will this be the answer like mold was to penicillin?
Oncolytic Virus Kills Tumor in Triple-Negative Breast Cancer
Caroline Helwick, Medscape
October 25, 2011 (San Francisco, California) — Laboratory studies conducted at the Memorial Sloan-Kettering Cancer Center in New York City suggest that triple-negative breast cancer (TNBC) might respond to treatment with an oncolytic agent.
The findings were reported here at the American College of Surgeons 97th Annual Clinical Congress.
"We found that [the mutant herpes virus] NV1066 is an effective oncolytic agent against triple- negative breast cancer in vitro and in vivo," said Sepideh Gholami, MD, a research fellow in the laboratory of Yuman Fong, MD, which is considered to be at the forefront in oncolytic viral therapy
"Oncolytic viruses are attractive therapeutic agents that destroy tumor cells without the accompanying destruction of normal cells," she said. The mitogen-activated protein kinase (MAPK)signaling pathway is known to be important in TNBC, and activated (phosphorylated) MAPK signaling has been shown to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.
In other words, she said, TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets cells that overexpress this protein, which is the rationale for this approach. The study aimed to determine whether NV1066 could kill TNBC cells effectively. The researchers also examined the functional effects of NV1066 on the MAPK signal transduction pathway during viral infection.
Dr. Gholami and colleagues infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the downregulation of phosphorylated MAPK by 48 hours, she reported.
"TNBC cells support efficient viral replication, with over 1 million copy numbers observed, which is more than a 1000-fold increase," she said.
"Since baseline phosphorylated MAPK levels positively correlated with sensitivity to NV1066, they might therefore be used as a clinical marker for selecting patients for viral therapy," she suggested.
Tumor Regression Almost Complete
The researchers created flank tumors and injected them with NV1066 or a control compound. Within 5 days, tumor volume significantly decreased in the experimental group; within 3 weeks, they observed "near-complete tumor regression," Dr. Gholami reported.
....keep reading for more good news below!
NEW Targeted Drug Seeks and Destroys TNBC...
This could be big. Breast cancer is not one disease as we all know. Triple Negative Breast Cancer has been on the back burner in terms of new therapies, until now. PARP treatment is changing the future of metastatic TNBC patients. Now, a new, targeted therapy has identified a sub-type of TNBC tumors...
New Subtype of Breast Cancer Responds to Targeted Drug
ScienceDaily (Mar. 2, 2010) — A newly identified cancer biomarker could define a new subtype of breast cancer as well as offer a potential way to treat it, say researchers at Washington University School of Medicine in St. Louis.
Their findings will be published in the March 1 online early edition issue of the Proceedings of the National Academy of Sciences.
The research could further refine what recent breast cancer research has concluded: that breast cancer is not one disease, but many. So far, research has firmly established that at least five subtypes of breast cancer exist, each having distinct biological features, clinical outcomes and responses to traditional therapies.
The biomarker identified by the Washington University researchers is found frequently in breast cancers and especially in those that have poorer outcomes. It stems from overactivation of a gene called LRP6 (low-density lipoprotein receptor-related protein 6), which stimulates an important cell-growth signaling pathway. LRP6 can be inhibited by a protein discovered in the same laboratory, which could become an effective drug against the breast cancer type, the researchers say.
"We found increased expression of the LRP6 gene in about a quarter of breast cancer specimens we examined, and we think LRP6 overexpression could be a marker for a new class of breast cancer," says Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. "In addition, we found that this biomarker is often associated with breast cancers that are either harder to treat or more likely to recur. We already have an agent that seems to be effective against LRP6-overexpressing tumors, which could someday become a therapy for tumors that right now have few treatment options."
The research was conducted primarily by Chia-Chen Liu, a graduate student in the Bu lab, who is a fellow in the Cancer Biology Pathway Program at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.
The researchers' analysis of human breast cancer tissue samples found significant increases in LRP6 levels in 20 percent to 36 percent of the tumors. LRP6 was increased more frequently in ER (estrogen receptor)-negative or HER2 (human epidermal growth factor receptor 2)-negative samples. LRP6 was also increased more frequently in so-called triple-negative breast tumor samples, which test negative for ER, HER2 and PR (progesterone receptor).
In general, patients who have triple-negative breast cancers have an increased risk of disease recurrence after initial treatment and a poorer prognosis. Furthermore, although ER-positive and HER2-positive tumors can be targeted with specific therapies, ER-negative and HER2-negative tumors cannot. So it appears that LRP6 overexpression is often associated with tumors that are currently difficult to treat, says Bu.
Research in the lab had earlier discovered a protein that binds to and inhibits LRP6. This study showed that the protein, called Mesd (mesoderm development), was able to slow the growth of breast cancer cells in the laboratory and to inhibit mammary tumor growth in laboratory mice.
Importantly, mice treated with Mesd did not experience any of the known side effects, such as bone lesions, skin disorders or intestinal malfunctions, associated with inhibition of this growth pathway.
"Our work introduces Mesd as a promising antitumor agent that might be further developed for breast cancer therapy," Bu says. "It would be analogous to such successful breast cancer therapies as Herceptin (trastuzumab), which specifically targets HER2-positive breast cancer."
The researchers also found that a small segment of Mesd has the same effect as the larger molecule. This segment, or peptide, is more stable than the whole protein molecule and can be easily synthesized.
The researchers have patented the protein and the peptide through the university's Office of Technology Management. Recently, Raptor Pharmaceutical Corp. licensed Mesd from the university to develop it for clinical use.
Funding from the National Institutes of Health and the Siteman Cancer Center supported this research.
Got Hope? TNBC patients do now!
Doctors Review PARP
"I believe that in the next two to three years, PARP inhibitors will do for triple-negative breast cancer what trastuzumab [Herceptin] did for HER2 breast cancer." Jenny Chang, Baylor
"This development may have the potential to change patient survival . . . and appears to potentially change the natural history of at least a subclass of metastatic breast cancer [TNBC]" Clifford Hudis, MSK
“When you go home, be excited. Be really excited about this. Tell your patients there is reason to be hopeful.” Eric Winer, Dana Farber
Until now, the treatment for triple negative breast cancer has been limited. The options for metastatic patients were few and far between. Until now. The first completed studies of PARP, have shown that not only does it slow progression of disease, but patients are experiencing a complete response to the drug.
The side effects of PARP are generally well tolerated and do not include hair loss.
Where once there was no hope, no magic drug for triple negative patients, PARP is proving itself to be, as Dr. Jenny Chang, of the Baylor School of Medicine said, “What Herceptin did for HER2 breast cancer.”
“Many experts have argued that it is not possible to change survival in stage IV breast cancer. Certainly now there evidence for an alternative viewpoint; that with the use of very effective drugs, we can change overall survival, and we should aim for that." Clifford Hudis, MSK
For more information, speak to your oncologist. For information on recruiting trials for PARP click the following links:
Chang C. Interview with Neil Love. in Conversations with Oncology Investigators - Bridging the Gap between Research and Patient Care. Breast Cancer Update 2009;8(6):3-6 [Track 5; with audio].
Hudis C. Interview by L Scott Zoeller 2009 Oct 21. Extended Survival With PARP Inhibitors Changes Expectations in Metastatic Breast Cancer. Viewpoints. In OncologySTAT 2009.
Carlson R. PARP Inhibitors Show Promise Against Metastatic Triple-Negative Breast Cancer in Early Studies. Oncol Times 2009;31(15):10-11.
Triple Negative Breast Cancer News: Genome Project
Background: Drug companies have developed an array of drugs to attack cancer and other conditions influenced by genetics, but it’s difficult to tell which patients will respond to which drugs.
What’s happening: A new study will sequence the genomes of cancer tissue from 14 breast cancer patients whose tumors have progressed despite multiple treatments.
The future: Proponents of “genomic medicine” think it will become increasingly possible to use sequencing to steer individual patients to the drugs most likely to work.
A Carlsbad biotechnology company is helping launch an unusual cancer study that may eventually lead to doctors tailoring treatments to patients’ genes. Life Technologies says the study — involving sequencing the genomes of 14 patients with a tough-to-treat form of breast cancer — is a step toward a future of “genomic medicine,” a decade after the sequencing of the first human genome.
It’s evidence of how quickly work in this area is progressing, with the $2.6 billion that went into the Human Genome Project reduced to $6,000 per genome on Life Technologies’ latest sequencing instrument. “This is a pretty amazing example of how far these tools of genomics are moving into direct patient applications,” said Jeffrey Trent, president of the Phoenix-based Translational Genomics Research Institute, which is working with Life Technologies on the project.
The company will announce the study today to coincide with the opening of a two-day conference on genomic medicine in La Jolla, at which experts will discuss the latest breakthroughs and the outlook for more advances in the field. Already, biotechnology research has created numerous drugs that target genetic problems that lead to cancer and other conditions. In the case of breast cancer, at least a dozen such drugs are on the market, said Dr. Daniel D. Von Hoff, physician-in-chief at the translational genomics institute. A big problem, however, is that it’s difficult to predict which drugs will work for a particular patient. That’s where sequencing is supposed to help.
“For those mutations for which we do have drugs, we can help the physician make more informed decisions than they’re making today,” said Linh Hoang, director of personalized medicine at Life Technologies.
The study could also help scientists identify promising areas to explore for future drugs. It’s impossible to know ahead of time whether the 14 patients have genetic patterns that current drugs address, but researchers will also look for similarities in the DNA of the 14.
“It may lead to more targets that pharmaceutical companies will want to design drugs around,” Hoang said.
The study will involve patients with what’s known as triple-negative breast cancer whose tumors have progressed despite multiple therapies. That type of cancer makes up about a fifth of breast cancer cases and doesn’t respond to common drugs, such as Herceptin. Patients will be enrolled by U.S. Oncology, a Houston-area company that specializes in cancer-treatment services, and Von Hoff said the plan is to take the first 14 people who meet the study criteria.
A spokeswoman for U.S. Oncology said the company plans to enroll patients from about a half-dozen of its sites with the highest incidences of triple-negative cases. Sites in Colorado, Oregon, Texas and Virginia have already been identified.
Tissue samples will be obtained through noninvasive surgery, Von Hoff said. Then the patients will go home to await sequencing results that should be produced within a few weeks.
The idea is to then direct them to appropriate treatment, but Von Hoff declined to predict in how many cases that will be possible. “We don’t know,” Von Hoff said. “We do know there are more and more drugs out there forpatients who have mutations.”
There have been other studies that sequenced disease tumors, most notably an ongoing government effort known as the Cancer Genome Atlas that aims to produce comprehensive genetic maps of at least 20 types of cancer.
What separates the new study is its attempt use the data to drive treatment strategies, not merely to collect information “It’s a different question,” the genomics institute’s Trent said. “This is a study about how we’re going to start to use this in a precision medicine approach.”
A big effort will go into “bioinformatic” analysis, which Von Hoff said will involve a trillion pieces of data per patient. Hoang said one project in lung cancer found 30,000 mutations.
In coming years, scientists expect the cost of sequencing to decline and the sophistication of the tools to improve to the point that sequencing becomes more viable as a diagnostic device.
Hoang said Life Technologies expects the cost of the reagent chemicals that it sells, which enable genome sequencing, to drop from $6,000 to $3,000 by the end of the year. “This is really laying the foundation for a future that may take five or 10 years to materialize,” Hoang said. “But it is truly groundbreaking.”
Thomas Kupper, The Union Tribune, Uniontrib.com
The No Surrender Breast Cancer Foundation is blessed to have Constantine Kaniklidis to report to us from the front lines of breast cancer research and treatment advances. This is one of the most exciting and hopeful breakthroughs we have ever been able to provide our readers.
For all women who have triple negative breast cancer,
this is the hope we have been waiting for.
By Constantine Kaniklidis
Major Breakthrough in the Treatment of Triple Negative Breast Cancer
- A recent updated analysis of the original BS-201 PARP Inhibitor (PARPi) Trial continues to show an exceptional outcome benefit to the addition of the PARP inhibitor (PARPi) BSI-201 to the gemcitabine-carboplatin chemotherapy backbone, and although these are interim and not final results which could change in either direction, at this time the interim findings support the provisional conclusion that the PARP inhibitor essentially - and amazingly - doubles overall survival (OS) - not just PFS (progression-free survival), also improved, meaning reduction in the risk of recurrence - in the triple negative breast cancer population, and at this time sustains a 50% reduction in the risk of death.
[Disclaimer: we must wait the final results of the trial to see if these dramatic, first-ever results, are sustained at the same or reasonably comparable levels as now seen with the interim findings].
- These rather stunning survival outcomes were furthermore accompanied by highly impressive response rates: the overall response rate (ORR) was high, at 48% of patients achieving complete response (CR) or partial response (PR) which is three times as high as that obtained with chemotherapy alone, and with another 14% achieving stable disease (SD, for 6 month or greater), yielding a clinical benefit rate (CBR) of 62% (CBR = CR + PR + SD), and with no significant additional adverse effects from the addition of BSI-201 to the chemotherapy backbone (impressive, remembering that non-toxic agents are notoriously hard to come by in oncology).
- The accrual and progress of the trial has proceeded at extremely rapid pace, well beyond expectations, and the best estimation, based on feedback from investigators, is that this Phase III trial given the pace, will come to completion as early as this (First) Quarter of 2010. Interview statements - but not officially posted NCI protocol data - suggests that there are just 40 patients remaining requiring trial accounting, 20 in the PARP inhibitor arm, and another 20 in the chemotherapy only arm, confirming that completion is very close, and that a First Quarter 2010 estimate is plausible on the progress to date.
- Finally, on the regulatory front it also appears there is accelerated progress: the PARP inhibitor BSI-201 has been granted on Fast Track Designation by the FDA, very good news for patients: FDA Fast Track means that, against standard requirements, the agency will accept initial late-stage data instead of waiting for entire Phase III clinical trial results, something that is done when (1) a proposed agent is intended for treatment of a serious or life-threatening disease - a status now accepted by the FDA for mTNBC (metastatic TNBC) - and (2) demonstrates the potential to address unmet needs for such a condition. Based on this status and on a review of documents filed in the FDA regulatory pipeline process, it is now estimated that BSI-201 may actually become commercially available - and hence available to all mTNBC patients in clinical practice without being on any clinical trial - at year's end (mid November to mid December, best estimate).
Commentary: Missed, and New, Opportunities
My own sense of the ASCO BSI-201 PARP trial is that on the contrary that it may have underestimated the true benefit; this perspective stems from my own TNBC review and research which on the cumulative evidence suggests that maximal benefit of PARP inhibition is accrued when it is concurrent with a strongly genotoxic (DNA-damaging) regimen, and although carboplatin is genotoxic, as are all platinum agents, gemcitabine (Gemzar) is not, and I believe this represents a lost opportunity. Indeed, I have on several occasions advocated in this context the omission of gemcitabine (Gemzar) altogether in the PARP context, in favor either of (1) a more optimal dose of carboplatin - I consider carboplatin AUC=2 as substantially sub-optimal, and would have deployed at least AUC=6 even up to AUC=7.5, or (2) substituting another genotoxic agent instead of gemcitabine (Gemzar), my choice being an anthracycline (preferably the pegylated liposomal Doxil or Caelyx. Given this limitation - which in all fairness the principal investigator Joyce O'Shaughnessy has acknowledged (due to expediency, not oversight) - of the failure to maximize the potential synergy of genotoxicity and PARP inhibition, in my mind therefore the trial's findings are actually therefore even more impressive by extrapolation, ad I would predict that an all-genotoxic chemotherapy + PARP inhibitor (BSI-201) will achieve significantly greater outcome benefit than even doubling of survival and halving of mortality for metastatic TNBC patients.
And this is where the opportunity can be regained, in the earlier availability of BSI-201 by this year's end, since at that point clinicians are no longer constrained to conform to the trial protocol's chemotherapy regimen, and I would advocated for them to instead adopt a more optimal all-genotoxic regimen which should translate to even more dramatic outcome gains. I am also of the opinion for molecular and other reasons that the failure of response of the PARP inhibitor regimen for some patients may be due in part to the absence of pure genotoxicity in the combination regimen, which therefore I am hoping innovative oncologists will recognize and overcome through appropriate DNA-damaging agent substitutions for the non-genotoxic gemcitabine (Gemzar) component, allowing more patients to be responsive to this breakthrough for metastatic TNBC disease.
Come The Revolution
Finally, remember the last time we heard of a 50% gain in breast cancer survival? That was with the revolutionary, practice-changing (virtually overnight) findings from Dennis Slamon's trial on trastuzumab (Herceptin) for HER2-positive disease, heralded correctly as the greatest breakthrough in breast cancer treatment since tamoxifen 30+ years ago. I believe an optimally genotoxic PARP inhibitor therapy can do for triple negative disease what Herceptin did for HER2+ patients, and the provisional results of the Phase III PARP Inhibitor to date appear to support and imply that contention.
These are the kind of times that researchers like me - and dedicated and brilliant investigators, and soon also patients - live to see as their reward for their commitment.
- Constantine Kaniklidis