HER2 breast cancer treatment shows resistance for specific mutations


A common mutation in HER2-positive breast cancer reduced the odds of pathologic complete response to neoadjuvant therapy by 50%, according to an analysis of 2 large clinical trials.

HER2-positive tumors with the PIK3CA mutation had a pCR rate of 17% compared with 37% without the mutation. A similar disparity in pCR existed in both clinical trials.

Moreover, the lowest pCR rate occurred in women with PIK3CA mutations in HER2/hormone receptor-positive tumors treated with dual anti-HER2 therapy, Sibylle Loibl, MD, reported at the San Antonio Breast Cancer Symposium.

"In concordance with [two previous trials], PIK3CA-mutant tumors have a significantly lower pCR rate, and HER2-positive/estrogen receptor-positive/PIK3CA-mutant tumors show the lowest pCR rate," said Loibl, of the German Breast Group (GBG) in Neu-Isenburg. "New treatment options need to be investigated such as PI3K-targeting agents, which is the objective of the ongoing NeoPhoebe trial."

About 20% of breast cancers have a PIK3CA mutation, which occurs more often in hormone receptor-positive tumors than in receptor-negative disease. PIK3CA is part of the PI3K family of proteins. Alterations in the pathway (PTEN/PI3K/AKT/mTOR) are associated with HER2 resistance, said Loibl.

Two trials of neoadjuvant therapy have shown that pCR correlates with improved survival in HER2-positive breast cancer.

The NeoALTTO trial showed that dual HER2 inhibition with neoadjuvant trastuzumab (Herceptin) and lapatinib (Tykerb) led to a higher pCR rate than either agent alone. The NeoSPHERE trial showed that adding both pertuzumab (Perjeta) and trastuzumab to docetaxel neoadjuvant therapy improved pCR as compared with trastuzumab plus docetaxel.

Given that PIK3CA mutation confers HER2 resistance, Loibl and colleagues examined the impact of mutation on pCR in two other large trials of neoadjuvant therapy for breast cancer.

The GBG 44 trial (GeparQuinto) compared lapatinib and trastuzumab in combination with conventional neoadjuvant chemotherapy in patients with newly diagnosed HER2-positive breast cancer.

The GBG 66 trial (GeparSixto) evaluated neoadjuvant chemotherapy with or without carboplatin. Patients with HER2-positive tumors also received lapatinib and trastuzumab, and patients with triple-negative disease bevacizumab (Avastin).

Both of the GBG trials had pCR as the primary objective. Investigators determined PIK3CA mutation status in 225 GeparQuinto participants and in 512 GeparQuinto participants.

Overall, 20.8% of participants in each trial had one or more PIK3CA mutation. In GeparQuinto, investigators found mutations in 22.4% of HER2/hormone receptor-positive tumors and in 25.0% of HER2/receptor-negative tumors. In GeparSixto mutation rates were 21.5% in receptor-positive tumors and 16.3% in receptor-negative tumors.

Overall, pCR rates in GeparQuinto were 17.9% in patients with PIK3CA-mutated tumors and 26.4% in tumors with wild type PIK3CA. Among patients treated with trastuzumab, pCR occurred in 33.3% of patients with wild-type PIK3CA versus 18.2% of patients with mutated tumors. In the lapatinib-treated subgroups pCR rates were 17.6% in mutated tumors and 18.6% in wild-type tumors.

None of the differences achieved statistical significance.

In GeparSixto pCR rates were 22.4% in patients with PIK3CA-mutated tumors and 41.6% in tumors with wild-type PIK3CA (P=0.003). Among all HER2-positive tumors, pCR rates were 17.0% in mutated tumors and 37.1% in tumors with wild-type PIK3CA (P=0.009). The pCR rates in triple-negative breast cancer did not differ significantly between PIK3CA-mutated (35.0%) and wild-type tumors (45.%, P=0.385).

In the HER2/receptor-positive subgroup, pCR occurred in 6.3% of patients with PIK3CA mutations versus 29.9% of patients with wild-type PIK3CA (P=0.006). The hormone-receptor negative subgroup had pCR rates of 40.0% with PIK3CA mutation and 48.1% without (P=0.567).

A combined analysis of both trials showed pCR rates of 17.0% to 18.2% among in PIK3CA-mutated tumors treated with either anti-HER2 agent or the combination. Rates in tumors with wild-type PIK3CA were 18.6% with lapatinib, 33.3% with trastuzumab, and 37.1% with the combination.

A multivariable analysis of GeparSixto showed that both hormone receptor-positive tumors (OR 0.44, P=0.006) and PIK3CA mutations (OR 0.29, P=0.007) were negative predictors of pCR.

"We observed similar pCR rates for the different anti-HER2 treatments in PIK3CA-mutant HER2-positive tumors," said Loibl. "New treatment options need to be investigated in these cancers, such as PI3K-targeting agents."

No drugs targeting PI3K or PIK3CA have reached the market. However, two mTOR inhibitors have. Inhibition of mTOR with everolimus (Afinitor) might offer a strategy to overcome PIK3CA-associated resistance, said Carlos Arteaga, MD, of Vanderbilt-Ingram Comprehensive Cancer Center in Nashville, Tenn. The problem with that strategy is that mTOR inhibition activates PI3K, he added.

A drug-screening study reported here suggested a potentially effective means to overcome resistance to anti-HER2 therapy.

In three different models of PI3K resistance, the combination of a CDK4/6 inhibitor and a PI3K inhibitor had synergistic activity against resistance cells. Studies involving laboratory animals showed that the inhibitor combination led to greater tumor regression than either agent alone and delayed the emergence of PIK3CA-induced resistance, reported Sadhna R. Vora,MD, of Massachusetts General Hospital in Boston.


Source: MedPage Today: http://www.medpagetoday.com/MeetingCoverage/SABCS/43446

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