Breast Cancer: 7 Triple-Negative Subtypes and Chemotherapy Response Interview with:

Hiroko Masuda MD

Morgan Welch Inflammatory Breast Cancer Research Program and Clinic; Departments of 2Breast Medical Oncology, 3Bioinformatics and Computational Biology
The University of Texas MD Anderson Cancer Center, Houston, Texas;

W. Fraser Symmans, MD
Anderson Cancer Center, Department of Pathology, Unit 85, 1515 Holcombe Blvd., Houston, TX 77030-4009;

Naoto T. Ueno, MD
Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030. What are the main findings of the study?

Answer: Triple-negative breast cancer (TNBC) could be classified into 7 subtypes:
basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M),mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and unstable (UNS).

Using cluster analysis, Lehmann and Bauer et al. identified these TNBC subtypes in 21 public mRNA gene expression profiles of breast cancer. However, the clinical relevancy of these novel molecular subtypes has not been established. To establish the clinical relevancy, we determined if the subtypes of TNBC have different rates of pathological complete response (pCR) to standard neoadjuvant chemotherapy regimens. In this study, we confirmed that TNBC is heterogeneous and that pCR differs by TNBC subtype using the algorithm proposed by Lehmann and Bauer et al. The BL1 subtype had the highest pCR rate (52%), and BL2 and LAR had the lowest pCR rates (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P=0.022) via a likelihood ratio test. To our knowledge, this was the first study to show that the TNBC subtype can serve as an independent predictor of pCR status in patients who received standard chemotherapy regimens.

This confirms the possible clinical relevance of the 7 molecular subtypes, and these subtypes may lead to innovative clinical trials of personalized medicine for patients with TNBC. Were any of the findings unexpected?

Answer: According to the biological features of each subtype proposed by Lehmann and Bauer, we predicted that the BL1 and BL2 subtypes would have the highest pCR rate, and the LAR subtype would have the lowest pCR rate. Interestingly, although the BL1 subtype had the highest chemosensitivity (pCR rate), the BL2 subtype had the lowest pCR rate, contrary to our prediction. These subtypes have similar biology, such as high Ki-67 mRNA expression and enrichment of proliferation genes; however, BL2 has unique gene ontologies involving growth factor signaling, such as the EGF (Epidermal Growth Factor), MET (hepatocyte growth factor), and IGF1R (Insulin Growth Factor Receptor 1) pathways. The difference in gene ontologies might explain the difference in pCR rates and could provide a basis for individualized therapy. For example, BL2 tumors could be targeted with EGFR, MET, or IGF1R inhibitors. In LAR tumors, hormonally regulated pathways are heavily enriched. Consistent with the low pCR rate in the LAR subtype, which was in accord with our hypothesis, the luminal A and B intrinsic subtypes (estrogen receptor positive), which are hormonally regulated tumors, responded less to chemotherapy. Most likely because of the small sample size, we did not observe significant differences in distant metastasis-free surivval and overall surviival among subtypes; however, the clinical process in the LAR group was clearly different from that of the other subtypes. The LAR group had delayed recurrences compared with the other groups and had the highest OS rate despite having a low pCR rate. These clinical courses were similar to the clinical course of the luminal subtype. What should clinicians and patients take away from your report?

Answer: TNBC is heterogeneous. The 7 subtypes predicted pCR rates in patients who received currently offered chemotherapy regimens and may enable the selection of targeted therapies based on their biological differences. The 7 subtypes may lead to innovative clinical trials of personalized medicine for patients with TNBC. Also, it is important to recognize that Lehmann and Bauer’s classification is not the only strategy for defining the molecular subtypes of TNBC. What recommendations do you have for future research as a result of this study?

Answer: Prospective future studies are needed to establish the clinical relevance of using gene profiling to classify patients by subtype. Further, prospective validation by methods such as reverse-phase protein array or immunohistochemical staining is needed to determine whether the targets noted in the 7 subtypes are truly overexpressed or are functionally activated at the protein expression level. The clinical utility of these TNBC subtypes will not reach its full potential until markers for each subtype can be validated as predictive markers of targeted therapies.


Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes.

Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, Valero V, Lehmann BD, Pietenpol JA, Hortobagyi GN, Symmans WF, Ueno NT.

Authors’ Affiliations: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic; Departments of Breast Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Clin Cancer Res. 2013 Oct 1;19(19):5533-5540. Epub 2013 Aug 1

Last Updated on March 1, 2015 by Marie Benz MD FAAD