Compelling hypotheses are emerging about the mechanisms driving triple-negative breast cancer, and they are driving drug development in this area, according to Joyce O’Shaughnessy, MD, Celebrating Women Chair of Breast Cancer Research at Baylor Charles A. Sammons Cancer Center. She is also Medical Director and Co-Chair of the Breast Cancer Research Committee for US Oncology and a practicing oncologist with Texas Oncology, Dallas. Dr. O’Shaughnessy described these new concepts and encouraging data from clinical trials at the 2016 Miami Breast Cancer Conference.
Joyce O’Shaughnessy, MD
The investigational treatments are taking advantage of the molecular portrait of triple-negative cancers: primarily basal, with a high degree of aneuploidy, genomic instability, and expression of DNA-repair proteins and activation of the PI3 kinase pathway.
“We are making good progress in understanding triple-negative breast cancer,” Dr. O’Shaughnessy said. This is largely based upon the identification of triple-negative breast cancer subtypes and the best therapeutic strategy to address their differences. Hypotheses built upon these findings are now being tested in phase III trials.
I-SPY2 Trial Yields Hypotheses
I-SPY2, which has an adaptive trial schema, has yielded discoveries as to the processes involved in triple-negative breast cancer and has evaluated agents that address these mechanisms. The study randomly assigns patients to weekly paclitaxel followed by doxorubicin/cyclophosphamide (AC) with or without a novel agent. When outcomes are sufficiently positive, the novel agents can “graduate” to phase III trials.
The biomarker and clinical data from these studies have helped formulate hypotheses about triple-negative breast cancer that are being further explored, she said. Specifically, I-SPY2 has shown that the preoperative inhibition of AKT with the oral agent MK-2206 or inhibition of phosphorylated HER1 and HER2 with neratinib can increase pathologic complete response rates achieved with paclitaxel plus AC.
Novel Strategies
Inhibition of AKT impacts the PI3K pathway, which is often active in triple-negative breast cancer. Tripathy et al reported encouraging results from this approach in a neoadjuvant study in which 93 patients received MK-2206 plus weekly paclitaxel/AC, while 59 received weekly paclitaxel/AC alone.1 A pathologic complete response was achieved by 40% of the experimental arm vs 22% of the control arm, indicating a 76% probability of success and thus graduating MK-2206 to a phase III trial.
Analysis of study samples using reverse-phase protein arrays is in progress. The aim is to identify a biomarker that will predict for even higher response rates in these patients.
Another strategy is to combine inhibitors of homologous recombination with poly [ADP-ribose] polymerase (PARP) inhibitors. This involves inhibiting homologous recombination proficiency—making the triple-negative cancer cells homologous-deficient—and then giving a PARP inhibitor to improve the sensitivity of cancer cells to DNA-damaging agents, such as doxorubicin and carboplatin.
Preclinically, a number of agents inhibit homologous recombinant proficiency, one being the pan-PI3K inhibitor buparlisib. Buparlisib impairs BRCA1/2 expression and appears to sensitize homologous recombination–proficient cells to olaparib (Lynparza), a PARP inhibitor, and a DNA-damaging agent, according to early clinical observations.
A third strategy aims to eliminate any trace of the HER family of proteins before the DNA-damaging agent is given. This has been done using the pan-ErbB inhibitor neratinib, followed by a DNA-damaging agent plus AC. Neratinib is not necessary for patients with no expression or phosphorylation of HER2, which can be determined by the highly sensitive reverse-phase protein array assay; these patients can receive the DNA-damaging agent from the start.
“This is based on a hypothesis that is emerging, which is that when you have HER2, even at the lowest levels, you are not going to get a great [pathologic complete response] rate with standard agents,” Dr. O’Shaughnessy said.
Based on reverse-phase protein array data, certain subsets may prove especially responsive to this approach. In a study of triple-negative breast cancer patients treated with weekly paclitaxel plus AC, with or without neratinib, the pathologic complete response rate overall was 37.5% in the neratinib arm, but among patients demonstrating phosphorylation of HER2 or EGFR (ie, biomarker-positive for EGFR Y1173 or ErbB2 Y1248), it rose to 63%.2
“This study suggests that if you get rid of the signaling through the HER family with neratinib and then bring in DNA-damaging agents, you will do better for these patients. I think this is a super-important hypothesis,” she commented.
Another treatment that graduated in I-SPY2 was veliparib plus carboplatin and paclitaxel, which yielded a 52% response rate (vs 26% for controls) overall and 70.9% for patients with no HER2 expression by reverse-phase protein array.3,4
Androgen Receptor as a Target
Another important target emerging in triple-negative breast cancer is the androgen receptor, which stains positive in approximately 80% of triple-negative breast cancer tumors and strongly positive in 55%. In a phase II trial of enzalutamide (Xtandi), 42% of evaluable androgen receptor–positive patients achieved clinical benefit at 16 weeks, with many responses quite durable.5
The use of gene-expression profiling to select for androgen receptor positivity identifies a subset of patients who have very good outcomes, according to a study in which such women had a median progression-free survival of 40.4 weeks on enzalutamide.6
“I am very encouraged by these results. It’s a high priority to bring these agents into the curative setting as soon as possible,” Dr. O’Shaughnessy commented.
Other Novel Targets and Drugs
Trop-2/EGP-1 is a pan-epithelial cancer antigen that is expressed in about 90% of triple-negative breast cancers. It behaves like a true oncogene, initiating signaling mechanisms that can result in increased tumorigenicity, aggressiveness, and metastasis.
Sacituzumab govitecan is an antibody-drug conjugate against Trop-2 that has shown impressive activity. In 17 heavily pretreated patients with triple-negative breast cancer, sacituzumab produced responses in 29% and stable disease in 71%.7 A phase III trial is in development.
New Approaches to Triple-Negative Breast Cancer
Intriguing hypotheses are emerging about the mechanisms driving the various subtypes of triple-negative breast cancer. Treatment strategies include inhibition of the PI3K pathway, elimination of HER2 family proteins followed by the use of DNA-damaging agents (eg, doxorubicin or carboplatin), combining inhibitors of homologous recombination with PARP inhibitors, and targeting the androgen receptor. Drugs being evaluated for these and other approaches include neratinib, veliparib, buparlisib, enzalutamide, etirinotecan pegol, PD-1/PD-L1 inhibitors, and antibody-drug conjugates.Another antibody-drug conjugate, glembatumumab vedotin, targets glycoprotein (gp) NMB, which is overexpressed in 40% to 75% of breast cancer; increased expression is associated with poor prognosis. In the EMERGE trial, triple-negative breast cancer patients with gpNMB expression experienced a doubling in overall survival, from 5.5 months to 10 months (P = .003).8 The randomized METRIC trial of glembatumumab vs capecitabine in gpNMB-overexpressing metastatic triple-negative breast cancer is ongoing.
The topoisomerase-1 inhibitor etirinotecan pegol shows promise as well, especially in patients with brain metastasis, whose median survival was 10 months with etirinotecan pegol administration, vs 4.8 months (P = .0099) with physician’s choice of treatment in the phase III BEACON trial.9 A phase III trial in this subset is planned.
Finally, research is brisk for inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in triple-negative breast cancer. In a phase II study, 18.5% of heavily pretreated patients responded to the PD-1 inhibitor pembrolizumab (Keytruda).10 In another study, 19% responded to the PD-L1 inhibitor atezolizumab, but when the agent was paired with nab-paclitaxel (Abraxane) in the first-line setting, the response rate rose to 70%.11 A phase III trial of this combination is ongoing.
Not Novel but Equally Important
Dr. O’Shaughnessy also shared a clinical pearl she took from a recent study conducted by Isakoff et al.12 “This was not a randomized trial, but these data changed my practice in the treatment of triple-negative patients,” she said.
In the first-line study of 69 patients with metastatic triple-negative breast cancer, response rates were 35% to single-agent cisplatin and 23% to carboplatin, with highly durable responses observed in 11.7% and 5.7%, respectively. Several cisplatin-treated patients were alive 3 to 6 years later, off therapy.
The “exceptional responders” were typically patients with breast, lymph node, and parenchymal lung disease, without pleural, bone, or liver disease, and BRCA wild-type. “I treat patients meeting this phenotype with single-agent cisplatin. We don’t want to miss these patients in the clinic,” she said. ■
Disclosures: Dr. O’Shaughnessy has consulted for Arno Therapeutics, AstraZeneca, Celgene, Corcept Therapeutics, Eisai, Genentech, GSK, Lilly, J&J, Merrimack, Norvartis, Pfizer, Roche, Sanofi, Takeda, and Medfusion.
References
8. Yardley DA, Weaver R, Melisko ME, et al: EMERGE. J Clin Oncol 33:1609-1619, 2015.
12. Isakoff SJ, Mayer EL, He L, et al: TBCRC009. J Clin Oncol 33:1902-1909, 2015.
