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Neoadjuvant HER-2–targeted breast cancer therapies less effective in patients with PIK3CA mutations

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February 5, 2015

Patients with HER-2–positive breast cancer who harbored activating mutations in PIK3CA were considerably less likely to achieve total pathologic complete response to neoadjuvant HER-2–targeted therapies than patients who did not have PIK3CA mutations, according to findings in the randomized, phase 3 NeoALTTO trial.

PIK3CA activating mutations are present in all subtypes of breast cancer. However, they are enriched in HER-2–positive and ER-positive disease, according to study background.

José Baselga, MD, PhD

José Baselga

José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, and colleagues investigated whether an association existed between PIK3CA mutation status and patients’ response to HER-2–targeted therapy.

The analysis included 355 patients with HER-2–positive breast cancer who had been recruited to NeoALTTO, a multicenter, open-label, trial designed to assess the efficacy of dual inhibition of HER-2 in the neoadjuvant setting.

Patients received 6 weeks of anti-HER–2 therapy with trastuzumab (Herceptin, Genentech), lapatinib (Tykerb, GlaxoSmithKline) or a combination of the two agents. Paclitaxel then was added to their assigned regimen for the next 12 weeks until definitive surgery.

Researchers used mass spectrometry-based genotyping to identify activating mutations in PIK3CA.

Baselga and colleagues identified PIK3CA mutations in 23% of HER-2–positive breast tumors, and they were all associated with poorer outcomes in each of the treatment arms. The difference in pathologic complete response rate was greatest among patients treated with the combination of lapatinib and trastuzumab. In that group, the rate of pathologic complete response was 53.1% among patients with PIK3CA wild-type tumors and 28.6% among patients with PIK3CA mutations (P=.012).

“Activating mutations in PIK3CA limit the efficacy of neoadjuvant therapies that target HER-2,” Baselga told HemOnc Today. “Our findings are supported by similar reports from clinical trials in the advanced-disease setting. The phase 3 CLEOPATRA trial — which studied the effects of pertuzumab added to trastuzumab as first-line treatment for patients with HER-2–positive metastatic breast cancer — showed very similar findings, and so did the neoadjuvant German study Geparsixto.”

Data also indicated that EFS and OS did not seem to be affected by PIK3CA status. Researchers reported EFS events occurred in 15 (18.7%) patients with PIK3CA mutations and 65 (23.3%) patients with PIK3CA wild-type tumors (HR=0.78; 95% CI, 0.44-1.36). The OS analysis showed five (6.2%) patients with PIK3CA mutations died, whereas 35 (12.7%) patients with PIK3CA wild-type tumors had died (HR=0.5 (95% CI, 0.19-1.23).

“Given that PI3KCA inhibitors are currently in clinical development, we believe that in patients with HER-2–amplified PIK3CA-mutant breast cancer, the addition of PI3Ka inhibitors to anti-HER–2 therapies should be explored,” Baselga added. – by Anthony SanFilippo

Disclosure: The researchers report employment relationships with, research funding from, consultant/advisory roles with, stock ownership in and honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer AG, Eli Lilly, Genentech, GlaxoSmithKline, Invivis Pharmaceuticals, Merck, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Symphogen, Synthon and Verastem.

Jose Baselga, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: baselgaj@mskcc.org

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PERSPECTIVE
Daniel F. Hayes

Daniel F. Hayes

When we consider how tumor markers can be used to take care of patients, there are several important points to consider. First, we need to know that the assay that is used is highly validated and analytically validated. That means it’s accurate, it’s reproducible and it has a fairly narrow coefficient of variation. Second, we need to know that it has clinical validity, meaning it takes one population and splits it into two, and those populations are different in some way. The third point is that it offers clinical utility, meaning there are high levels of evidence that demonstrate that application of the marker test either improves patient outcomes, or that the outcomes are the same with lower costs, improved quality of life or less inconvenience. In other words: Is it really better for the patient to have this test done than not?

In this very nicely done study, the researchers have shown clinical validity of PIK3CA mutations in these patients. What they didn’t show — not because they didn’t understand this, but because the data didn’t support it — is that this information would in any way be useful right now to take care of patients who receive anti–HER-2 therapies. The combination of lapatinib and trastuzumab was better than either agent alone, regardless of whether patients were mutated or wild-type. Those with mutations were less likely to respond to any of the three, but the difference in prognosis was not to the extent that I would treat these patients differently.

One of the things I have learned through the years about tumor biomarkers is that, in oncology, we really don’t use them to decide who we should treat. Rather, we typically use them to decide who we should not treat. The findings in this study don’t tell me there is one group of patients who shouldn’t have received the combination vs. single-agent treatment. Patients whose cancers had the PIK3CA mutations were less likely to respond to any of the three regimens, but nothing here tells me I should withhold lapatinib or trastuzumab just because a patient’s cancer has the mutation, because there is still a chance they will respond.

Finally, the 600-pound gorilla in the room is the ALTTO study presented at last year’s ASCO Annual Meeting (Piccart-Gebhart MJ. Abstract #LBA4. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago). Everyone thought ALTTO would confirm what we “knew” — that the addition of lapatinib to trastuzumab as adjuvant treatment of early-stage, HER-2–positive breast cancer would improve outcomes. But that wasn’t the case.

Do these data from the NEO-ALTTO study justify re-evaluating the ALTTO samples to see if you can “save” the combination vs. single-agent trastuzumab by identifying a group of people who would actually benefit? Those are precious samples and you want to use them for your best bet. Is this the “best bet” or are there other markers that can be evaluated with those samples that might have a better chance of identifying patients who would benefit from the combination? I’m not sure, but I am certain the investigators who led ALTTO will think very carefully about what analyses should be done using these specimens. These deliberations will be done thoughtfully, and I believe there is a possibility we will, indeed, find a subgroup that appears to have benefited from the combination. Until we do, we all need to scratch our heads over the discordance between the neo-adjuvant studies that suggest the combination of trastuzumab and lapatinib is superior to single agent trastuzumab, and the overall results of ALTTO.


Daniel F. Hayes, MD
The University of Michigan Comprehensive Cancer Center

Disclosure: Hayes reports no relevant financial disclosures.