Triple negative (TNBC) metastatic breast cancer is a heterogeneous disease, chemotherapy remains the mainstay of treatment, however, new treatments based on identifying molecular subtypes, stratifying TNBC based on gene expression assays with subsequent specific targeted therapy is an area of intense clinical research. In this post, I will review our current standard clinical practice and explore ongoing and future clinical directions.
Metastatic TNBC is very heterogenous, and while Basal type is most common, it only account for nearly 80% of all cases.
- Metastatic TNBC is more common in younger patients and premenopausal African American patients.
- Metastatic TNBC more commonly affecting the brain, and visceral organs, and less commonly affecting bones.
- Metastatic TNBC is more common in BRCA1 mutation patient, all TNBC younger than 60 should be screened for BRCA mutations.
- In a patient with a history of TNBC and now presenting with metastatic disease, a re-biopsy is recommended since there is reported discordance between primary tumor and metastatic disease hormone receptor status in up to 5% of cases.
A. gBRCA mutated metastatic TNBC
PARP inhibitors: the use of Olaparib in this patients subsets is clearly validated by the OlympiAD trial, where patients who are metastatic TNBC, and germline BRCA mutation treated with Olaparib was shown to have higher response rate and PFS compared to standard therapy. As of to date, Olaparib is not yet FDA approved for BRCA mutated metastatic TNBC.
Platinum chemotherapy: the support for use of platinum in BRCA1/2 mutated metastatic TNBC patients was shown in the TNT trial, in this trial Carboplatin was compared to Taxotere in metastatic TNBC, with both arms having gBRCA1/2 patients. The following was noted,
- No statistically significant difference in response rate overall
- However, in the BRCA1/2 positive population, there was high and statistically significant response rate favoring the Carboplatin arm compared to Taxotere arm.
- Also, and interestingly, in further sub analysis, patients who were not-BRCAA mutated, and nonbasal by PAM50, there was high and statistically significant response rate favoring the Taxotere arm compared to Carboplatin arm.
In conclusion, given the above, the use of PARP inhibitors and platinum compounds is of benefit specifically in BRCA1/2 mutated metastatic TNBC.
B. Non-BRCA mutated metastatic TNBC
As mentioned above chemotherapy remains the main treatment for metastatic TNBC. Few trials, e.g. the TnAcity trial looked at new front line chemotherapy agents. The majority of recent and ongoing research focuses on three major areas which will be mentioned here,
1. Given the success of PARP inhibitors and platinum agents in BRCA1/2 mutated TNBC tumors, investigators are looking at wild type BRCA TNBC tumors which share similar genetic characteristics with BRCA1/2 mutated tumors. The concept of homologous recombination score (HRD), with wild type BRCA TNBC tumors and low HRD, score expected to be sensitive to platinum was looked at. To date, such concept remains to be validated in the TNBC metastatic settings.
2. Immune check point inhibitors. Interest in using immunotherapy in metastatic breast cancer is due to several reasons,
- TNBC has the highest mutation frequency of all breast cancer, and subsequently possible immunogenicity.
- The observation of high tumor infiltrating lymphocytes association with good response to chemotherapy as well as association with immunosuppressive markers such as PD-L1
- Chemotherapy can be immunogenic thus raising the possibility of pursuing a combined immunotherapy plus chemotherapy approach.
Several small phase I trials utilizing immune check point inhibitors showed a promising result in metastatic TNBC. At the moment one large phase III trial IMpassion130 is accruing.
3. Androgen receptor targeted therapy (AR). AR is expressed in 12-55% of TNBC cases. Anti-Androgen therapy with bicalutamide was shown to have activity in TNBC, a second trial utilizing Enzalutamide also showed promising activity, further trials utilizing newer anti-androgen agent e.g. Orternol are ongoing.
Future Clinical Directions
At the moment there is at least 3 major TNBC sub-type classifying methodology Lehmann, Burnstein, and Jezequel, all of them is gene expression profiling (GEP) based, and differed on their respective sample size and clustering technique. Of note, that Lehmann method clustering did not show prognostic significance, the other two did. With TNBC subtypes reasonably identified, this should help to optimize therapy that is targeted and subtype specific. To date, such subtypes are not used outside clinical trials, and chemotherapy remains largely the main treatment modality of TNBC metastatic disease. With such advanced and GEP based sub-type classification, future targeted therapy will deliver its maximum benefit with avoidance of toxicity.