TNBC Studies Yield Clues for Future Directions

Joyce A. O’Shaughnessy, MD

Researchers are still at the drawing board when it comes to finding revolutionary solutions for the treatment of triple-negative breast cancer (TNBC), but recent studies have shed light on the diversity of the disease and offered hints about the directions future inquiries should take.

Joyce A. O’Shaughnessy, MD, provided an overview of those developments during the 12th International Congress on the Future of Breast Cancer, held July 18-20 in Huntington Beach, California. O’Shaughnessy, co-director of Breast Cancer Research at the Baylor Charles A. Sammons Cancer Center, co-chair for Breast Cancer Research at Texas Oncology, and a medical oncologist at Texas Oncology, served as chair of the congress.

A 2011 study of gene expression in TNBC1 identified not only a number of subsets of the disease, but also the classes of targeted therapies expected to be useful for those groups, O’Shaughnessy said. The gene-expression analysis indicated that the basal 1 and basal 2 types should respond to cisplatin; mesenchymal and mesenchymal stem-like to a PI3K/mTOR inhibitor and an abl/src inhibitor; and the luminal androgen receptor (AR) group to bicalutamide, an AR antagonist. The investigators also identified an immunomodulatory subtype of TNBC.

“These are not of clinical utility at this time,” O’Shaughnessy said, “because we’re just trying to make some sense out of this diversity.”

However, the growing understanding of TNBC has led to some promising strategies, including a technique for the treatment of basal-like, TP53-mutated TNBCs, O’Shaughnessy noted. Of interest therapeutically is the homologous recombination defect (HRD) associated with these cancers, she said.

Explored in a recent study,² that strategy involves measuring genomic instability in such cancers by counting the regions that have experienced a loss of heterozygocity and the areas of deletion on the chromosome, ultimately creating either a high or a low HRD score, O’Shaughnessy said.

“That’s promising, because it would be helpful to know which of these cancers we want to load up on the DNA-damaging agents and make sure that we give those first in trying to cure these patients,” she said. “It’s potentially the most important therapeutic implication of knowing that a patient has a basal-like breast cancer.”

O’Shaughnessy added that a clinical trial supported the idea that patients with basal-like TNBC would benefit from platinum-based treatment. ³ In the study of cisplatin versus carboplatin in TNBC patients, those with a BRCA mutation fared better, but 7% of the study’s participants who were BRCA wild-type also responded, all of them long-term survivors who had been off therapy until being treated in the trial in the first-line metastatic setting, she said.

Those results suggest that this subset should receive platinum, and doctors can identify appropriate patients clinically by their basal pattern with metastasis to the lungs, lymph nodes, or even brain; biopsies of 0 for estrogen receptor (ER), progesterone receptor, and HER2; and a Ki67 level in the range of 90%.

Recent Clinical Trials

In the luminal AR subtype, meanwhile, a trial showed that bicalutamide has activity,⁴ and O’Shaughnessy said she has used that drug with good results in an AR-positive breast cancer patient who had a low Ki67 level.Although some recent trials have been negative where TNBC is concerned, others that hold more promise are moving forward, O’Shaughnessy said.

Disappointing news came out of the BEATRICE trial, which tested the addition of bevacizumab to adjuvant chemotherapy in an unselected TNBC population, with no significant improvement in outcome. ⁵

Molecular Snapshot of Triple-Negative Breast Cancer (TNBC)¹

“Intensive biomarker analyses are ongoing, including VEGF-A and VEGFR, but there’s no clear biomarker now that a subset benefits,” O’Shaughnessy said.

The ongoing MERiDiAN trial (NCT01663727) should answer that question more fully, said O’Shaughnessy. The trial will test paclitaxel with or without bevacizumab in patients with HER2-negative, chemotherapy-naïve locally recurrent or metastatic breast cancer, stratifying for low or high VEGF-A status, adjuvant therapy, and ER status.

“We’ll get answers about what bevacizumab targets and its benefits,” O’Shaughnessy said. “That’s important, because data in triple-negative in the metastatic setting with bevacizumab have been the most promising we have.”

The TnAcity trial (NCT01881230) is also aimed at clarifying how best to use existing drugs in patients with TNBC, O’Shaughnessy said. The study, in patients with stage IV TNBC who have not received chemotherapy for metastatic disease, will compare nab-paclitaxel plus gemcitabine against nab-paclitaxel plus carboplatin, and also against gemcitabine plus carboplatin.

“The goal of the phase II will be to pick the winner among the two nab-paclitaxel regimens, and in the phase III, they’ll go head to head, with the thought being that one regimen may be superior to gemcitabine and carboplatin,” O’Shaughnessy said. “The point is to optimize our chemo selection in the metastatic first-line setting for TNBC.”

Finally, an already completed trial, study 301, which compared capecitabine and eribulin mesylate in pretreated patients with locally advanced or metastatic breast cancer, showed that the TNBC population benefited more from eribulin, O’Shaughnessy pointed out.

Looking ahead, she said that research strategies will have to take into account the complexities of the heterogeneous breast cancer subtype.

“Unfortunately, single-gene predictors like EGFR or PTEN loss are unlikely to be of clinical utility in these complex metastatic breast cancer patients,” O’Shaughnessy said, “but PI3K inhibition appears promising across subtypes, undoubtedly in combination with other agents.”

References

1. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-2767.
2. Telli ML, Jensen KC, Abkevich V, et al. Homologous recombination deficiency score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutation- associated breast cancer. Cancer Res. 2012;72(24 suppl;abstr PD09-04):141s.
3. Isakoff SJ, Goss PE, Mayer EL, et al. Impact of BRCA1/2 mutation status in TBCRC009: a multicenter phase II study of cisplatin or carboplatin for metastatic triple negative breast cancer. Cancer Res. 2012;72(24 suppl; abstr PD09-03):140s-141s.
4. Gucalp A, Tolaney SM, Isakoff SJ, et al. Targeting the androgen receptor in women with AR+ ER-/PR- metastatic breast cancer. J Clin Oncol. 2012;30(suppl; asbtr 1006).
5. Cameron D, Brown J, Dent R, et al. Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Cancer Res. 2012;72(24 suppl; abstr S6-5):108s.