Washington, DC—“Triple-negative breast tumors are composed of mosaic cancer cells with distinct genetic aberrations,” said Jorge S. Reis-Filho, MD, PhD, a surgical pathologist at the Memorial Sloan-Kettering Cancer Center in New York, who combines traditional pathology, gene expression profiling, and genomics techniques to understand rare breast tumor types, including triple-negative diseases.
Through extensive genetic profiling, the breast cancer field now understands that triple-negative breast cancer (TNBC) comprises a heterogeneous set of tumor types with different mutational profiles, cellular morphology, and behaviors. To make matters even more complicated, studies are now showing that these TNBCs can comprise cells that have distinct genetic profiles, making targeted therapy approaches difficult.
Reis-Filho chaired a session at the annual meeting of the American Association for Cancer Research (AACR), held April 6–10 in Washington, DC, called “Deconstructing the Complexity of Triple-Negative Breast Cancer.” Understanding how to treat the 15% to 20% of diagnosed breast cancer cases with triple-negative disease remains a major challenge. There are targeted agents for HER2-positive, estrogen-receptor–positive, and progesterone-positive breast cancers that have improved survival for the women with these breast cancer subtypes. But triple-negative breast cancer has continued to confound researchers and clinicians, both in terms of classification of these tumors and the development of new efficacious therapies.
During the session, Nicholas C. Turner, MD, of the Institute of Cancer Research in London, discussed previous and ongoing biomarker-based strategies for treatment of TNBC.
The epidermal growth factor receptor (EGFR)–targeting antibody cetuximab has been tested for TNBC. Approximately 60% of TNBC patients express EGFR, according to Turner. Two randomized phase II trials have previously tested cetuximab in combination with cisplatin. Only a few TNBC patients appeared to benefit from the therapy. “What we learned from these trials is that there was some evidence of sensitivity to cetuximab but only at a low level that is insufficient to drive future clinical development,” said Turner.
Poly(ADP ribose) polymerase (PARP) inhibitors have also been tested for TNBC. PARP inhibitors are active in those breast tumor cells that are deficient in DNA repair mechanisms, such as those that are mutated in either BRCA1 or BRCA2. Particularly, there is a strong link between germline mutations in BRCA and basal-like triple-negative breast cancer. “Eighty percent of BRCA1 germline cancers have triple-negative breast cancer,” said Turner. However, the PARP inhibitor olaparib has not shown robust activity in recent clinical trials for patients with sporadic TNBC.
The overall lesson to be learned from these targeted studies, according to Turner, is that “the heterogeneity of triple-negative breast cancers means that unselected targeted therapies are unlikely to succeed.” Future trials, he said, need to be driven by biomarkers that break down TNBC into more homogeneous subsets.
How to parse TNBC into distinct subtypes? One current approach is to study subtypes of TNBC and target their specific features. Another way is to specifically target the genetics of these cancers. Turner discussed the potentially targetable genetic mutations found in TNBC tumors. The most common genetic mutation is in the gene that encodes for p53, which has been found mutated in approximately 75% of TNBC cases, according to sequence analysis. Other relatively common mutations include amplification of the MYC oncogene (40% of TNBC cases have an amplification of the MYC gene), loss of the RB gene found in 20% of cases, and a mutation in either BRCA1 or BRCA2 in 15% to 20% of triple-negative breast tumors.
Relatively more rare mutations include those in the PTEN gene, mutation of the PIK3CA gene, rare mutations rather than amplification of the HER2 gene, and amplification of the FGFR2 gene.
Turner focused the rest of his presentation on how to therapeutically target p53 mutations for triple-negative disease. The mutations in p53 are diverse, with several different point mutations having been previously documented. Therapeutics that target a specific p53 point mutation have been developed and are able to induce cell death and/or growth arrest of tumor cells harboring these mutations. The issue, however, is that each drug can only target a very small minority of TNBC patients who are positive for the specific p53 mutation.
In order to understand the potentially targetable events in triple-negative breast cancer, “we need to embrace a diverse molecular stratification in these cancers,” concluded Turner. Detailed, genomic, and sequencing analyses of triple-negative breast tumor samples from patients are necessary for a detailed picture of the various subtypes of TNBCs to emerge.