brain mets triple neg current issue
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constantine kaniklidis
  : : : :   Breast Cancer Watch Digest  
issue 3  |  Feb 6, 2009 (revised)  
New Appreciation of Triple Negative Disease - A Review

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. 

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 at the Controversies in Breast Cancer conference I recently attended, triple negative disease is challenging to treat, but it's also highly treatable.

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's1 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 colleagues2 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 Nielsen3  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

  • Cyclophosphamide (Cytoxan)
  • Carboplatin (Paraplatin)
  • Cisplatin (Platinol)
  • Doxorubicin (Adriamycin)
  • Epirubicin (Ellence)
  • Mitomycin C (MTC / Mitomycin / Mutamycin)
  • Radiation (Radiotherapy
  • PARP Inhibitors

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 Rouzier4 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 Carey5 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 Ellisen6 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 (called TAp73), 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 team7 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 PARP (poly(ADP-ribose)polymerase) 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): Sjoerd Rodenhuis8 of the Netherlands Cancer Institute and colleagues compared five courses of FEC versus four FEC courses plus a single HDCT dose consisting of cyclophosphamide (Cytoxan), thiotepa (Thioplex) and carboplatin (Paraplatin) in high-risk breast cancer, finding for the superiority of the FEC + HDCT combination in subgroups of triple negative patients. And in a related study Ulrike Nitz and colleagues9 compared an EC + HDCT regimen of two courses of accelerated EC (the anthracycline epirubicin plus cyclophosphamide) followed by two courses of an HDCT regimen of standard-dose epirubicin  and high doses of cyclophosphamide and thiotepa, to a dose-dense conventional regimen consisting of four identical cycles of EC followed by three cycles of accelerated CMF in patients with more than 9 positive lymph nodes, finding that younger patients with triple negative tumors accrued the largest benefit.  And Ugo De Giorgi and Italian coresearchers10 investigated a high-dose dense chemotherapy regimen consisting of a mobilizing course with epirubicin and paclitaxel plus filgrastim, followed by three HDCT courses with epirubicin, preceded by the cardioprotective agent dexrazoxane and paclitaxel in high-risk breast cancer patients, also finding benefit in a small subgroup of triple negative patients. 

Finally, and most recently Raihanatou Diallo-Danebrock11 at the Heinrich-Heine-University compared the efficacy of high-dose chemotherapy (HDCT), followed by autologous stem cell transplantation, versus dose-dense chemotherapy (DDCT), and found a significantly better outcome for patients in the basal-like, as well as the HER-2, subgroups who received HDCT, both with respect to overall survival (OS) and event-free survival EFS, in contrast to patients in the luminal-A and luminal-B (that is, 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 Moyana12 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 trial13 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 Brecher14 at Boston University, Nina Vartiainen15 in Finland, among many others following). In addition, along with aspirin, NSAIDs like ibuprofen, and COX inhibitors are independently of benefit in breast cancer risk reduction16, 17, 18, 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 tea31 - 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-E210037, 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 triple negative-targeted regimen.  The soon to open BEATRICE international trial38 is examining the benefit of adding bevacizumab (Avastin) to standard chemotherapy in triple negative disease.

Leveraging the "Right" Taxane
Furthermore, Spanish researchers Socorro María Rodríguez Pinilla and colleagues39 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 BioScience40 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 via an enhanced permeation and retention effect, yielding increased antitumor activity and intratumor concentrations secondary to the biological pathway of albumin-mediated receptor transport of the drug across the endothelial cell wall within blood vessels directly into the tumor itself.  Thus it appears that nab-paclitaxel (Abraxane) binds to albumin receptors (albondin or gp60) inside the tumor blood vessel, activating caveolin-1 and resulting in the formation of caveoli (sacs), which transport albumin and other plasma constituents across the endothelial cell to the tumor  interstitial space. Once inside the interstitum, the albumin/drug complex binds to SPARC (Secreted Protein Acidic Rich in Cysteine), an extracellular matrix (ECM) protein found in the tumor cell surface (and possibly also secreted by tumor cells), and is rapidly internalized into the tumor cell.  This results in the "freed" paclitaxel penetrating and killing tumor cells via microtubule binding (the mechanism of taxane agents).

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).

EGFR-Targeted Therapies
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 colleagues41 with the Lineberger Comprehensive Cancer Center at UNC and Stefano Calza42 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-Snow43 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 Hoadley44, along with Lisa Carey45, 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 trial47 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 Esteva48, 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's49 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'Shaughnessy49 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 trial50.

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)51 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 colleagues52 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 Huang53 at BMS (Bristol-Meyer Squibb). BMS is currently sponsoring a multi-center, actively recruiting trial54 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.

Epothilone Therapy
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 Bunnell55 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 + bevacizumab56 (IXA + BEV) is actively recruiting, and another under Ellen Chuang56 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 cancer57 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

Metronomic Chemotherapy
There are several other options for triple negative therapy, and one of the more interesting  outside of clinical trials is from Robert Livingston58, 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 obviate the potential for tumor regrowth during the traditional chemotherapy breaks or rest periods, also reducing toxicity, and appropriately received a piano metronome for his 25 year service in the field at the 2006 SWOG Plenary Session of the Spring Group Meeting).  Paul Walker at East Carolina University is conducting a Phase II clinical trial of a neoadjuvant metronomic chemotherapy for triple negative disease59, 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.  

PARP Inhibitors
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. methylating agents, DNA topoisomerase inhibitors, cisplatin), as well as radiation therapy, against a broad spectrum of tumors (e.g. glioma, melanoma, lymphoma, colorectal cancer, head and neck 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 chemotherapeutic agents in common use, including alkylating agents (cisplatin, carboplatin, and nitrogen mustards, such as melphalan), inhibitors of DNA topoisomerase II (including the anthracyclines, etoposide, and teniposide), and inhibitors of topoisomerase I and antimetabolites, are all known to, or likely to, induce DSBs, and because this DNA-damaging activity of genotoxic chemotherapeutic agents converges with the ultimate goal of PARP inhibitors to block DSB and hence allow the 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 Deng60 found that PARP-1 inhibitors can inhibit breast cancer cells irrespective of their BRCA1 and ER status.

However, as noted also by Dr. Tito Fojo61 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. For example, in breast cancer patients, secondary leukemias are most likely to occur following the administration of alkylating agents like Cyclophosphamide (Cytoxan) and topoisomerase II (TOPO II) inhibitors such as the anthracyclines (doxorubicin (Adriamycin) and epirubicin (Ellence)), as these are some of the most effective agents at inducing DSBs. Given that the addition of agents that interfere with DNA repair is in effect a dose intensity strategy (greater damage comparable to that obtained with higher doses), an increase in secondary leukemias seems a real possibility.  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 cisplatin62 and the cardiotoxicity of doxorubicin63.

Yoon-Sim Yap64 at Royal Marsden Hospital and colleagues tested AZD2281 (formerly called KU-0059436), with encouraging antitumor 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 inhibition65, 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.

Note: KuDOS (a wholly own subsidiary of AstraZenica) /AstraZenica's other ICEBERG trial,  ICEBERG 266, begun June 13th of this (2007) year, a phase II open-label, noncomparative, international, multicentre study to assess the efficacy and safety of the KU-0059436 PARP inhibitor in patients with advanced BRCA1- or BRCA2-associated ovarian cancer, has at this time been suspended; unfortunately no further information has been provided as to the motivation for this premature suspension, although my suspicion, soon to be tested, is a likely recruitment issue rather than any clinically significant cause of concern. 

mTOR Inhibitors
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 recurrence67 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 apoptosis68, 69, as well as exerting antitumor activity in breast cancer via antiangiogenesis as demonstrated with findings on temsirolimus (Torisel)70, an mTOR inhibitor which has already shown dramatic benefit in RCC (renal cell carcinoma).  Recent results of mTOR inhibition in breast cancer are highly promising71-74. There has also been promising activity with partial responses observed both in patients with visceral-dominant and soft tissue-dominant breast cancer metastases75. 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 cells76, 77, 78. Also intriguing in this connection is the recent finding that mTOR suppression may be associated with antitumor actions of caloric restriction79, which hints that caloric restriction may be of special benefit in potentially mTOR-dependent and/or sensitive breast carcinoma such as triple negative disease. In terms of clinical trials of mTOR inhibition in breast cancer, Ana Gonzalez-Angulo80 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 Zakikhani81 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-I82, 83 and insulin-like growth factor-I (IGF-I), which also plays a critical role in carcinogenesis and tumorigenesis84. 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 newfound 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

1.  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)
  • HDCT (High-Dose Chemotherapy)
    [genotoxicity dependent on component agents]
  • Metronomic Chemotherapy
    [genotoxicity dependent on component agents]
  • Epothilone Therapy:
    Ixabepilone (Ixempra)

2.  Triple-Negative Sensitive Genotoxic Radiotherapy

3.  Triple-Negative Sensitive Genotoxic Biological Therapy

  • PARP Inhibitors
4.  HSP90 (Heat Shock Protein-90)

5.  Anti-VEGF / Antiangiogenic Chemobiotherapy

  • Bevacizumab (Avastin)

6.  EGFR-Targeted Therapies

  • Cetuximab (Erbitux)
  • Sunitinib (Sutent)
  • Dasatinib (Sprycel)
7.  mTOR Inhibitors


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Multiple Brain Metastases

DNA Damage and Repair
Cellular DNA is subjected to continual attack throughout the life cycle of an organism - approximately 74,000 per cell per day - both by endogenous (intracellular) factors and processes, like (1) reactive oxygen species (ROS), that is, oxygen free radicals formed as byproducts of food metabolism and energy (ATP) production, (2) inevitable errors of certain cellular processes (such as DNA duplication / replication errors, or imperfect exchanges (aka, recombination) between chromosomes), and (3) food mutagens, and also by exogenous environmental DNA damaging agents, such as ionizing radiation, ultraviolet rays (UV), air pollution, inhaled cigarette smoke (both active and secondhand), alkylating agents and chemotherapeutic drugs.

Toxic/ mutagenic consequences of these DNA-damaging assaults, called genotoxic stress, are minimized by several distinct pathways of repair, and to date, over 130+ genes have been found in human cells that are involved in these DNA damage repair pathways with the goal of assuring genetic integrity and genomic stability. These pathways need to first recognize specific types of DNA damage, then effect its removal (technically called excision), and finally replace one or more aberrant segments with normal units of DNA taken from a second undamaged copy of the chromosome (this replacement process is called homologous recombination) or if necessary by end joining of the broken strands (known as nonhomologous end joining), and such complex repair mechanisms necessarily involve highly integrated pathways of several protein factors.

PARP Inhibitors to the Rescue
One enzyme involved in such critical DNA repair is PARP1 (poly (ADP-ribose) polymerase-1), which facilitates repair by binding to DNA single-strand breaks (SSB), and this binding in turn attracts other DNA repair proteins, the entire repair mechanism being called base excision repair (BER). The fundamental goal of a PARP inhibitor is to block in the tumor the DNA repair facilitated by the PARP1 DNA repair enzyme, thus promoting tumor cell death (apoptosis). In essence, by blocking the repair of single-strand breaks (SSBs), PARP inhibitors allow relatively easy-to-repair SSBs to cascade into the far more serious double-strand breaks (DSBs), which are notoriously difficult to repair (due to both the large gaps they leave in genetic coding material, and to the absence of a complementary sequence to use as a template since both DNA strands are damaged), so that it is far more likely that such unrepaired DSBs within tumor cells will result in cell death by apoptosis.

Methodology for this Review
A search of the PUBMED database was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include clinical trials from and medical feed sources as returned from FeedNavigator provided by the National Library of Health Sciences - Terkko at the University of Helsinki. Unpublished studies were located via contextual search using Vivisimo, and scientific databases searched using COS Workbench from Community of Science. University dissertations were search via NDLDT. Sources in languages foreign to this reviewer were translated by language translation software.

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