Crossing Tumor Types: BRCA Experience Points Way to New Diagnostic Paradigm

Maurie Markman, MD

It is now well recognized that the presence of a molecular abnormality shown to be actionable in one tumor type may be highly clinically relevant in other malignancies. Examples include the presence of HER2 overexpression in cancers of the breast and stomach and the role of the fusion gene bcr-abl as a driver mutation in chronic myeloid leukemia and gastrointestinal stromal sarcoma.

Conversely, it has been shown that unique molecular events in a particular malignancy that can be effectively targeted and lead to quite meaningful clinical benefit may not necessarily be impacted by a recognized useful therapy when present in a different cancer (eg, BRAF in metastatic melanoma vs other tumor types). Further, while actionable molecular abnormalities that have been shown to cross tumor type boundaries are a truly impressive demonstration of the future of precision cancer medicine, it must be acknowledged that at the present time the clinically established examples of this paradigm remain limited in number.

However, if the pace of striking reports of limited experiences with treating patients with different malignancies whose cancers possess essentially the identical molecular abnormality is any indication, it is virtually certain this situation will continue to change rapidly.

Olaparib May Prove Versatile

Consider, for example, the recent FDA approval of olaparib in the second-line treatment of patients with platinum-resistant ovarian cancer. This agent, a PARP (poly [ADP-ribose] polymerase) inhibitor,¹ has been shown in both single-agent efficacy trials and a randomized phase II study to have impressive activity in BRCA-mutation positive disease.^2-5 (Note: The approved indication for this agent in the management of ovarian cancer is very limited, which is surprising and highly questionable in light of existing peer-reviewed data that strongly support the effectiveness of the agent in additional settings in this malignancy.)

The specific point of this commentary is not to highlight the widely recognized favorable biological and clinical activity of olaparib in ovarian cancer, but rather to acknowledge a potential role for the drug in other malignancies. In a highly provocative report, investigators described the effectiveness of this agent in a heterogeneous group of patients (n = 298) with advanced cancers who also possessed a documented BRCA1 or BRCA2 germline mutation.⁶ The overall objective response rate in this trial was 26% (78 of 298 patients).

As previously established, olaparib was shown to produce objective tumor regressions in patients with ovarian cancer (31%; 60 of 193 patients). Actively was also observed in breast cancer (13%; 8 of 62 patients), a cancer type that would be suspected to respond to this class of agents based on the known association between BRCA mutations in cancers of the breast and ovary.

However, what was certainly most striking in this particular report were the documented responses observed in patients with germline BRCA mutations who had pancreatic cancer (22%; 5 of 23 patients) and the limited number of individuals with prostate cancer (50%; 4 of 8 patients). In addition, if stable disease (≥8 weeks) is included in the category of clinical benefit, this state was seen in an additional 35% and 25% of the individuals with cancers of the pancreas and prostate, respectively. To emphasize the clinical impact of these findings, the pancreas cancer population had previously received a mean number of two prior regimens (65% platinum; all but one patient prior gemcitabine), and patients with prostate cancer had received a similar number of prior therapies (all had received prior hormonal therapy; 75% prior docetaxel; 50% prior platinum). Finally, as anticipated, olaparib was reasonably well tolerated in this patient population.

Again, it must be acknowledged that this experience is limited. However, if the results reported here for patients whose cancers contain a BRCA mutation are confirmed by others, the reported objective response rates would place olaparib among the most biologically and clinically active antineoplastic agents in pancreas and prostate cancer.

Further, these data provide strong support for the suggestion that individuals either presenting with advanced cancers of the pancreas or prostate, or where progression to this state occurs later in the course of the illness, should have tumor or germline testing performed looking for the presence of a BRCA mutation. The discovery of this molecular abnormality in such patients may provide data of critical relevance to help determine future management decisions.

And, it should be anticipated that, in the near future, optimal treatment of an increasing number of cancers would be informed by this diagnostic paradigm.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

References

1. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921.
2. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial [published online July 6, 2010]. Lancet. 2010;376(9737):245-251.
3. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomized study [published online August 19, 2011]. Lancet Oncol. 2011;12(9):852-861.
4. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval [published online April 20, 2010]. J Clin Oncol. 2010;28(15):2512-2519.
5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomized phase 2 trial [published online May 29, 2014]. Lancet Oncol. 2014;15(8):852-861.
6. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA 1/2 mutation [published online November 3, 2014]. J Clin Oncol. 2015;33(3):244-250.