Oct 27, 2014
By Shira Klapper, Senior Writer/Editor
For the past 15 years, anti-HER2 treatments have been used to treat women with HER2-positive breast cancer. In all that time, the HER2 biomarker has remained the sole biomarker used to predict whether patients will be sensitive to anti-HER2 treatments, which are comprised of monoclonal antibodies that work by binding to HER2 and inducing the cell’s death.
Now, a new study published in the Journal of Clinical Oncology (JCO), published online, ahead of print, October 13, asks—are there additional biomarkers, independent of HER2, that can help to identify who might benefit from anti-HER2 monoclonal antibodies, specifically the combination of pertuzumab plus trastuzumab?
The study, “Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in HER2-Positive, First-Line Metastatic Breast Cancer” found that the answer is no—HER2 remains the only biomarker that can be used to select which women have a high chance of responding to anti-HER2 treatments. However, the study found that biomarkers other than HER2 can have prognostic value—that is, they can indicate who might benefit more or less from pertuzumab plus trastuzumab in terms of progression-free survival (PFS) and other outcomes.
Data from the CLEOPATRA study
The new study has its roots in the 2012 CLEOPATRA study, which showed that adding pertuzumab to the regimen of trastuzumab plus docetaxel extended the life of women with HER2-positive metastatic breast cancer.
|José Baselga, MD,
According to José Baselga, MD, PhD, FASCO, first author of the current JCO study and the 2012 study, “The CLEOPATRA study was very positive and was the basis for the approval of trastuzumab in breast cancer. The data was amazing because we saw survival go from 41 months to 56 months, and that is striking.”
As part of that original 2012 study, the researchers planned to collect specimens of biomarkers from the 808 women enrolled in the CLEOPATRA trial, with the goal of eventually studying whether those biomarkers could predict who responds to anti-HER2 treatment—and to what extent. Those collected biomarkers, including HER2, HER3, PTEN, PIK3CA, AREG, TGF, and others, form the basis of the current study in JCO.
An interesting finding for the PIK3CA biomarker
In the current JCO study, women who received pertuzumab had better outcomes compared with women who received a placebo, regardless of the types of tumor biomarkers each patient carried, as long as the tumors were HER2-positive. However, certain biomarkers were associated with a better or worse prognosis. For example, those with high levels of the HER2 protein and HER3 mRNA had a significantly better prognosis.
Of all the biomarkers, the type of PIK3CA a woman carried had the greatest effect on outcome: women with a mutated PIK3CA had a PFS of 12.5 months, whereas those with wild—that is, standard—PIK3CA had a significantly longer PFS of 21.8 months.
This finding about the PIK3CA mutation was especially interesting to Dr. Baselga and his coauthors since it mirrored a phenomenon they had witnessed in the lab; even though PIK3CA is downstream from HER2—that is, HER2 activates PIK3CA—treatments that suppress HER2 did not result in turning “off” the activity of mutant PIK3CA.
“In the lab, it doesn't matter that there’s a block upstream because the PIK3CA pathway will still be turned on since PIK3CA is constitutively active as a result of a mutation,” said Dr. Baselga. “And that’s exactly what we showed in a clinical setting. If the tumor has the mutation, it is not shut down by HER2 because it has, so to speak, an independent mode of activation.”
A call for clinical trials on anti-PIK3CA treatments
According to Dr. Baselga, the finding that PIK3CA mutations are associated with poorer response to anti-HER2 treatments is a compelling reason to carry out studies of PIK3CA-inhibitors. “What this study is telling us is that we need to conduct clinical trials that combine PIK3CA inhibitors and HER2 therapy. And it’s one of these things in science that becomes so apparent that we’re excited to try it in clinical trials.”
José Baselga, MD, PhD, FASCO, is a Physician-In-Chief at Memorial Sloan Kettering Cancer Center. An ASCO member since 1993, he has received a Conquer Cancer Foundation of ASCO Young Investigator Award (YIA) in 1992, a Career Development Award (CDA) in 1994, and an ASCO Statesman Award in 2008. Dr. Baselga is a member of the Scientific Program Committee and is a past member of numerous other committees, including the Scientific Awards Selection Committee, the Strategic Planning Committee, and the Cancer Education Committee. He has also served as a Board Liaison to the International Affairs Committee.
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Baselga J, Cortés J, Im S, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in her2-positive, first-line metastatic breast cancer. J Clin Oncol. Epub 2014 Oct 13.
The Exclusive Coverage series on ASCO.org highlights selected research from JCO and JOP with additional perspective provided by the lead or corresponding author.
@ 2014 American Society of Clinical Oncology