Biomarkers in Breast Cancer: More Than Just HER2
| Apr 8, 2013
Co-authored by Gregory Wolfe, Ph.D., Senior Consultant and Tatiana Spicakova, Ph.D., Consultant
On Sunday at the American Association for Cancer Research (AACR) 2013 annual meeting, Jose Baselga, M.D., Ph.D., physician-in-chief at the Memorial Sloan-Kettering Cancer Center, presented new data from the Phase III EMILIA trial (Abstract LB-63) that suggested a relationship between tumor biomarkers and efficacy of Kadcyla® (TDM-1, ado-trastuzumab emtansine; Roche/Genentech). Kadcyla is a novel antibody-drug conjugate that comprises a potent microtubule polymerization inhibitor conjugated to the Herceptin® (trastuzumab; Roche / Genentech) monoclonal antibody via a highly stable linker. Kadcyla is designed to take advantage of the targeted nature of the antibody to selectively deliver the cytotoxic agent to HER2+ breast cancer cells. The EMILIA trial evaluated Kadcyla monotherapy versus Xeloda® (capecitabine, Roche) plus Tykerb® (lapatinib, GlaxoSmithKline) (XT) in relapsed HER2+ metastatic breast cancer patients. The positive results led to its regulatory approval in the United States in February 2013. Roche’s Herceptin, currently dominates the HER2+ market, with about 85% utilization in front-line HER2+ metastatic breast cancer patients. Although Tykerb is approved in the second-line in combination with Xeloda, about half of U.S. patients are rechallenged with Herceptin plus chemotherapy, leaving Tykerb for later-lines of therapy.
Baselga and colleagues conducted a biomarker analysis as part of the EMILIA study to determine whether variable expression of HER2, HER3, EGFR, PTEN and mutational status of PIK3CA gene impact efficacy of Kadcyla or Tykerb plus Xeloda. Patients in both treatment arms were evaluated according to intratumoral HER2 mRNA levels (at least median HER2 mRNA level versus less than median HER2 mRNA level). Patients with tumors expressing higher levels of HER2 mRNA (median or higher) derived greater overall survival benefit from Kadcyla (34.1 months) versus patients with tumors expressing lower levels of HER2 (26.5 months). In contrast, there was no difference in overall survival benefit in patients treated with Tykerb/Xeloda when stratified by HER2 mRNA levels (24.8 months for high levels versus 23.7 months for low levels). Similar analysis based on mRNA expression levels of HER3, EGFR and PTEN revealed no relationship between these biomarkers and efficacies of Kadcyla or Tykerb/Xeloda regimens. However, the mutational status of PIK3CA was discovered to be associated with improved outcomes when treated with Kadcyla but not Tykerb/Xeloda.
The PIK3CA gene encodes the alpha isoform of PI3K catalytic subunit, which is frequently mutated in HER2+ breast cancers and is thought to represent one of the resistance mechanisms to HER2-targeted therapy. PIK3CA-activating mutations may impact efficacy of anti-HER2 therapies as PIK3CA lies downstream from HER2 in the signal transduction pathway. Therefore, efficacies of these regimens were examined in patients according to PIK3CA-activating mutational status. Indeed, for patients in the Tykerb/Xeloda arm, overall survival of patients with PIK3CA activating mutations was worse compared to patients with PIK3CA wild-type tumors (17.3 versus 27.8 months). In contrast, overall survival appeared unaffected by PIK3CA mutational status in patients in the Kadcyla arm: in patients with mutated PIK3CA Kadcyla improved median progression-free survival (mPFS) from 4.3 months to 10.9 months, and in patients with wild-type PIK3CA Kadcyla improved mPFS from 6.4 to 9.8 months. These data suggest that Kadcyla may be able to bypass a common HER2 resistance pathway that has confounded anti-HER2 therapies and offers a new treatment option to women who would have otherwise not fared as well from other HER2-targeted therapies. Prior data has suggested no significant association between PIK3CA mutation and Herceptin efficacy, similar to what is observed here for Kadcyla, suggesting that this resistance mechanism may primarily have implications for use of Tykerb or other HER2 family tyrosine kinase inhibitors.
These results are thought-provoking and set the stage for future biomarker-driven analyses to guide choice of therapy upon relapse, although it’s premature to begin integrating into clinical practice at this time. However, these data could support tighter definitions of patients eligible for therapy with these agents, possibly by raising the threshold for HER2 positivity or by using PIK3CA status to help physicians make an informed decision on whether Tykerb or Kadcyla is a better second-line option for individual patients. The field has grown adept at incorporating biomarker analyses into initial patient diagnosis to guide treatment algorithms, but we are only beginning to understand the potential importance of re-testing patients throughout the progression of disease to further optimize and individualize care.