PIK3CA Mutation Thwarts Neoadjuvant Anti-HER2 Therapy in Breast Cancer

February 2014, Vol 5, No 1

San Antonio, TX—Patients with HER2-­positive breast cancer harboring a PIK3CA mutation had a significantly lower likelihood of achieving a pathologic complete response (pCR) to neoadjuvant anti-HER2 therapy, the results of 2 large clinical trials presented at the 2013 San Antonio Breast Cancer Symposium (SABCS) showed.

Patients without the mutation had a pCR rate of 37% versus 17% for those with a mutation. The pCR rate for mutated tumors was 17% to 18%, whether patients received a single anti-HER2 agent or a combination.

The findings also demonstrated how the mutation, which is traditionally associated with treatment resistance in advanced and metastatic breast cancer, has transitioned into the role of an obstacle in the treatment of patients with earlier-stage disease.

“We observed similar pCR rates for the different anti-HER2 treatments in PIK3CA-mutant HER2-positive tumors,” Sibylle Loibl, MD, Professor, German Breast Group, Neu-Isenburg, Germany, said during a press briefing. “Clearly, new treatment options need to be investigated in these cancers, such as PIK3CA-targeting agents.”

The findings have implications for a substantial number of patients, Dr Loibl noted, because a PIK3CA mutation occurs in approximately 20% of breast cancers.

“We need to integrate PIK3CA mutation analysis of breast tumors into routine practice so we can ensure that women receive the most appropriate neoadjuvant therapy for their specific tumor type,” Dr Loibl added.

Aberrations in the PI3K/AKT signaling pathway occur frequently in breast cancer, the most common being PIK3CA, which affects approximately 20% of patients with breast cancer. Despite the relatively high prevalence of the mutation, data related to its prognostic and predictive value have been sparse and inconsistent, particularly in patients with HER2-positive and triple-negative tumors.

Two previous clinical trials of patients with HER2-positive breast cancer had helped clarify the role of anti-HER2 agents in neoadjuvant therapy. The phase 3 Neoadjuvant Lapatinib and/or Trastuzumab Treat­ment Optimisation (NeoALTTO) trial showed that the combination of trastuzumab (Herceptin) and lapatinib (Tykerb) leads to a higher pCR rate than either agent alone. The phase 2 NeoSphere trial showed that the addition of pertuzumab (Perjeta) and trastuzumab to docetaxel (Taxotere) improved pCR compared with the addition of trastuzumab alone. Studies have shown that pCR correlates with survival in patients with breast cancer.

Study Details
Using data from 2 large trials of neoadjuvant chemotherapy in patients with newly diagnosed breast cancer, Dr Loibl and colleagues investigated the frequent and clinical consequences of the PIK3CA mutation in 737 patients with this mutation. They analyzed data from the German Breast Group’s GeparQuinto and GeparSixto studies, the former involving only patients with HER2-positive breast cancer.

In GeparQuinto, investigators compared the anti-HER2 agents lapatinib and trastuzumab, each added to conventional neoadjuvant chemotherapy. GeparSixto evaluated neoadjuvant chemotherapy with or without carboplatin (Paraplatin). Patients with HER2-positive tumors also received lapatinib and trastuzumab. In both trials, the primary outcome was pCR.

Consistent with previous observations, 20.8% of the patients in the 2 trials had PIK3CA-mutated tumors. The pCR rates in GeparQuinto were 17.9% in patients with PIK3CA mutations and 26.4% in patients with wild-type PIK3CA. In GeparSixto, the pCR rates were 22.4% for PIK3CA-mutated tumors and 41.6% for tumors with wild-type PIK3CA.

“Patients who had HER2-positive tumors that also were hormone receptor–positive had the worst outcomes,” said Dr Loibl, “as the pCR rate was only 6.3% in that subgroup. In contrast, patients with HER2-positive/hormone receptor–positive and no mutations had a pCR rate of 30.6%.”

“There was no difference in pCR rate by PIK3CA status in patients who had HER2-positive/hormone receptor–neg­ative breast cancer.”

The type of anti-HER2 therapy did not significantly affect the pCR rate in patients with PIK3CA-mutated tumors.

Amultivariable analysis of Gepar­Sixto showed that hormone receptor–positive tumors and PIK3CA mutations were negative predictors of pCR (hazard ratio [HR], 0.44; P = .006; HR, 0.29; P = .007, respectively).

Although PIK3CA mutation was associated with a lower rate of pCR, patients with mutant HER2-positive breast cancer have benefited from anti-HER2 therapy, at least in the metastatic setting, Carlos L. Arteaga, MD, Director, Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, TN, said during an SABCS press conference. Comparisons of patients with PIK3CA-mutated tumors have shown better outcomes in patients treated with anti-HER2 therapy, although the benefit was lower than that seen in patients without mutations.

No agents that specifically target PIK3CA are available, but mammalian target of rapamycin (mTOR) inhibitors offer a potential option.

“The problem with using an mTOR inhibitor is that mTOR inhibition has been shown to activate PI3K,” said Dr Arteaga.

Echoing Dr Loibl’s sentiments, Dr Arteaga said, “Clearly, we need new agents and combinations to overcome resistance to targeted agents.”

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