Unmet needs in breast cancer: Which pathways will lead to solutions?
1 February 2010—During the final day of the 4th International Breast Cancer Conference (IBCC4) in Paris, presentations focused on the unmet needs of breast cancer in 2010.
Biology of triple-negative breast cancer
Plenary Session IV began with an elegant discussion given by Mark Pegram, MD (University of Miami Miller School of Medicine, Miami, United States), regarding the biology of triple-negative (estrogen receptor (ER)–negative, progesterone receptor (PR)–negative, and HER2-negative) breast cancer. Referring back to complex signaling pathways as described by Yosef Yarden, PhD, earlier in the congress, Dr Pegram stated that he is “stumped, literally, as how to interpret this information in the context of malignancy rather than normal physiology.” One possible solution is the identification of exploitable vulnerabilities in malignancy. Indeed, as the estrogen receptor and HER2 have been identified as therapeutic targets in breast cancer, it is logical to assume there should be other susceptibilities in tumors that are triple negative.
Although it is important to note that triple-negative breast cancer is not identical to basal-like breast cancer, the majority of triple-negative tumors possess a basal-like phenotype and molecular profile. In addition, the majority of BRCA1-associated breast cancers are triple-negative and basal-like. Thus, shared genome-wide expression and array patterns between BRCA1 mutants and basal breast cancer may reflect shared defects in DNA repair processes. Indeed, Dr Pegram and colleagues retrospectively tested this theorem in 125 women with locally advanced, triple-negative breast cancer (mean tumor size of 9.5 cm) who were uniformly treated with platinum-based chemotherapy in the neoadjuvant setting. A pathologic complete response (pCR) of 34% and overall survival (OS) of 55% at five years in this patient population was observed in the analysis, which is the largest single-institution cohort of locally advanced, triple-negative breast cancer uniformly treated with platinum-and-docetaxel–based chemotherapy. Further classification of this cohort using a custom expression array demonstrated upregulation of a DNA-repair gene, which implicated DNA repair processes as a vulnerability that can be exploited in triple-negative breast cancer.
Poly (ADP-ribose) polymerase-1 (PARP1), a critical enzyme involved in DNA repair, is upregulated in triple-negative breast cancer and has emerged as a therapeutic target in breast cancer. In vitro studies have demonstrated that inhibition of PARP1 results in tumor-selective synthetic lethality in BRCA1-deficient and BRCA2-deficient cells. These recent discoveries have painted a new portrait of therapeutic options for patients with triple-negative breast cancer.
Current management strategies for triple-negative breast cancer
There is a paradox surrounding the treatment of triple-negative breast cancer: though these tumors are generally more chemosensitive, clinical course at relapse is more aggressive with poorer OS. Clifford Hudis, MD (Memorial Sloan-Kettering Cancer Center, New York, United States), briefly discussed current treatment strategies for triple-negative breast cancer; unfortunately, there are no clinical trial data that support a specific role for any chemotherapeutic agent.
Interestingly, Dr Hudis discussed the role of the androgen receptor as a potential target in triple-negative breast cancer. Indeed, some ER/PR-negative tumors express the androgen receptor, and a phase II trial is currently underway to evaluate the use of bicalutamide, an anti-androgen, in patients with metastatic triple-negative breast cancer.
Exciting clinical results with PARP inhibition in triple-negative breast cancer
BSI-201, a potent inhibitor of PARP1, has been identified as a novel agent with the potential to be a first-in-class targeted therapy for breast cancer. Joyce O’Shaughnessy, MD (Baylor Sammons Cancer Center, Dallas, United States), discussed results from a recent phase II trial that was conducted to compare the therapeutic potential of BSI-201 in combination with gemcitabine/carboplatin versus chemotherapy alone in patients with metastatic triple-negative breast cancer. Results from this trial were impressive, with the combination of BSI-201 plus chemotherapy significantly improving clinical benefit rate (62% vs 21%), objective response rate (48% vs 16%), and progression-free survival (6.9 months vs 3.3 months) compared to chemotherapy alone. A significant OS benefit (12.2 months vs 7.7 months) was observed with the addition of BSI-201 despite the fact that approximately 50% of the nonresponding patients crossed over to the experimental arm. The addition of BSI-201 to gemcitabine/carboplatin was well tolerated and did not increase toxicities. Due to these positive results, a phase III trial was initiated in July 2009 to investigate the safety and efficacy of BSI-201 in combination with gemcitabine/carboplatin as first-line, second-line, and third-line therapy for patients with metastatic triple-negative breast cancer; Dr O’Shaughnessy stated that this trial had nearly completed accrual as of February 2010. Ongoing studies are also evaluating BSI-201 in a variety of other solid tumors.
Another PARP inhibitor, olaparib, has also demonstrated activity in breast cancer. Results from a recent phase II trial of single-agent olaparib in patients with BRCA-deficient, chemotherapy-refractory breast cancer demonstrated impressive response rates (41% overall response), as well as modest toxicity.
Exploitation of cellular survival pathways
The PI3K/Akt/mTOR pathway is frequently dysregulated in human cancer, and José Baselga, MD (Vall d'Hebron University Hospital, Barcelona, Spain), outlined the current knowledge and future role of this pathway in breast cancer. Several clinical trials (phase I/II) are currently ongoing to evaluate the clinical use of PI3K inhibitors, such as XL147 and XL765.
Dialogue between academia and industry
The final Session of IBCC4 concluded with an extremely lively and provocative Panel Discussion moderated by Jilly Carter, former BBC news journalist. After tackling such issues as different standards of care in low income countries and hurdles to drug discovery, it was agreed by all panelists that better collaboration between industry and academia is needed to facilitate cancer research that will result in improved patient care worldwide.
Memorable quotes from IBCC4
Mark Pegram, MD (University of Miami Miller School of Medicine, Miami,
United States): “One dumb tumor is smarter than 10 oncologists.”
Clifford Hudis, MD (Memorial Sloan-Kettering Cancer Center, New York,
United States): “Triple-negative breast cancer has no specific
target…yet, but there are a number of potential targets.”
Joyce O’Shaughnessy, MD (Baylor Sammons Cancer Center, Dallas, United
States): “BSI-201 is one of the safest and best tolerated drugs I have
ever worked with.”
José Baselga, MD (Vall d'Hebron University Hospital, Barcelona, Spain):
“We are not there yet, but we are making remarkable progress. The
mortality rate of breast cancer is clearly decreasing…”
This activity is supported by an educational grant from sanofi-aventis Groupe.
