Neil Osterweil

December 13, 2013

SAN ANTONIO — A drug-resistance mutation common in patients with metastatic breast cancer is becoming increasingly problematic in early-stage disease in the neoadjuvant setting, German investigators report.

A mutated form of the PIK3CA gene is the second most common mutation in breast cancer, seen in approximately 20% of tumors, according to Sibylle Loibl, MD, from the German Breast Group in Neu-Isenburg.

In several recent studies, phosphatidylinositol 3-kinase (PIK3) mutations have been associated with worse prognoses, particularly in women with HER2-positive cancers, Dr. Loibl said during a media briefing held in advance of her presentation here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS).

Dr. Loibl reported that among the 737 participants in the GeparQuinto and GeparSixto studies of neoadjuvant therapy, PIK3CA was predictive of worse pathological complete response (pCR) and worse prognosis.

In GeparQuinto, patients were randomized to either lapatinib (Tykerb) or trastuzumab (Herceptin) for the treatment of HER2-positive disease. In GeparSixto, patients received both agents for HER2-positive or triple-negative disease. All patients received chemotherapy prior to surgery.

Table. pcR Rates in the GeparQuinto and GeparSixto Studies

Treatment Group PIK3CA Mutation, % No PIK3CA Mutation, %
   Lapatinib 17.6 18.6
   Trastuzumab 18.2 33.3
   Lapatinib plus trastuzumab 17.0 37.1


Previously, 2 trials of neoadjuvant therapy — the phase 3 NeoALTTO trial of trastuzumab and lapatinib and the phase 2 NeoSphere trial of pertuzumab and trastuzumab — showed that women with PIK3CA mutations had lower pCR rates than those with wildtype PIK3CA.

The data supporting the association between PIK3CA statusand prognosis in the neoadjuvant setting in early breast cancer are robust, noted Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston. However, there are still some unknowns, he explained.

"What we don't yet know is whether mutations are associated with poor prognosis in the long term. Pathological complete response doesn't always translate into long-term outcome differences, so we still don't know whether, in the average patient treated with HER2-directed therapy and chemotherapy, having a PIK3CA mutation in their breast cancer translates into a greater risk of recurrence or worse survival. In the metastatic setting, yes, it's associated with worse outcome, but in the early-disease setting, we don't know if that relationship exists," he told Medscape Medical News.

He noted that preliminary data from large adjuvant therapy trials suggest that the association between PIK3CA mutations and recurrence is not that strong.

Stage IV Disease

Various trials have shown that PIK3CA mutations are associated with worse outcomes in patients with metastatic disease.

For example, in the CLEOPATRA trial of patients with HER2-positive metastatic breast cancer treated with pertuzumab (Perjeta), presented at the SABCS in 2012, median overall survival was significantly longer in those with wildtype PIK3CA than in those with the mutation (21.5 vs. 12.5 months).

However, "the mutated tumors in CLEOPATRA did benefit from pertuzumab," noted briefing moderator Carlos L. Arteaga, MD, president-elect of the American Association for Cancer Research, and a breast cancer specialist at the Vanderbilt-Ingram Comprehensive Cancer Center in Nashville, Tennessee. But those patients "started at a lower baseline, and the impact of the benefit was smaller than in the wildtype group," he explained.

The data support the need for new agents and combinations aimed at overcoming resistance to targeted therapies, he said.

What Can Be Done About It?

In a second study presented at the SABCS, combination therapy to overcome PIK3CA mutational resistance to inhibitors of the PI3K family of proteins, of which PIK3CA is a member, was evaluated.

"Our realization, from what we've seen clinically, is that PI3 kinase inhibitors, while promising, have limited efficacy as single-agent therapy, even in PIK3CA-mutant breast cancers, which one would think would be among the most responsive cancers," said lead investigator Sadhna R. Vora, MD, an instructor in the breast oncology division at Massachusetts General Hospital in Boston, in an interview with Medscape Medical News.

Dr. Vora's team created 2 cell lines with acquired resistance to the experimental PI3K inhibitor BYL719 (Novartis), and another with resistance to the experimental pan-PI3K inhibitor GDC-0941 (Genentech).

They then submitted the cells to a combinatorial drug screen using 44 different targeted agents to see whether any of the agents could confer sensitization to a PI3K inhibitor.

The strongest candidate was LEE011 (Novartis), an oral inhibitor of the CDK4/6 enzyme, currently in early clinical trials for various malignancies, including breast cancer. The runner-up was RAD001, better known as the mTOR inhibitor everolimus (Afinitor).

"We've seen that agents that work within the PI3 kinase pathway itself, such as mTOR inhibitors and CDK4 inhibitors, are sensitizing resistant cancers to PI3 kinase inhibitors," Dr. Vora said.

She explained that the combination of a PI3K inhibitor plus a CDK 4/6 inhibitor is likely to be safe because their known toxicities do not overlap.

These preclinical data have led to a clinical trial exploring CDK4/6 inhibitors and PI3 kinase inhibitors on a letrozole backbone in patients with estrogen-receptor-positive breast cancer with advanced disease.

The phase IB/II study has just begun accruing patients, Dr. Vora noted.

The study by Dr. Loibl's team was supported by funds from the European Commission's Seventh RTD Framework Program. The study by Dr. Vora's team was supported by the National Institutes of Health, an ASCO Young Investigators Award, the Terri Brodeur Breast Cancer Foundation, and the AACR-Genentech Bio-oncology Fellowship. Dr. Vora and Dr. Arteaga have disclosed no relevant financial relationships. Dr. Krop reports serving as an adviser and consultant to Genentech.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-06 (Loibl), presented December 11, 2013; Abstracts S4-04 (Vora), presented December 12, 2013.


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