OncoGynecology Xagena

Early breast cancer: activity of neoadjiuvant Lapatinib plus Trastuzumab according to PIK3CA mutations

PIK3CA mutations are common in breast cancer. The aim of a study was to evaluate the correlation of PIK3CA mutational status with pCR in patients with HER2-positive early breast cancer treated with neoadjuvant chemotherapy plus Trastuzumab ( Herceptin ), Lapatinib ( Tyverb ) or both ( CherLOB, Guarneri, JCO 2012).

PIK3CA mutations were evaluated in 121 patients randomized to neoadjuvant anthracyclines / taxane-based chemotherapy plus Trastuzumab, Lapatinib, or both.

Exon 9 ( E542K, E545K, E545A, E545G, Q546E, Q546K ) and exon 20 ( M1043I, H1047Y, H1047R, H1047L, G1049R, G1049S ) PIK3CA mutations were evaluated on FFPE core biopsies by pyrosequencing.

An event-based pooled analysis of trials reporting pCR events according to PI3KCA mutation status was performed.

PIK3CA status was available for 106 of the 121 CherLOB patients: 22 ( 20.8% ) presented a PIK3CA mutation.

In the whole population, pCR rates are similar in PIK3CA wild type ( wt ) and PIK3CA mutated ( mut ) patients ( 33.3% vs 22.7%; p = 0.34 ).

However, for patients receiving Trastuzumab plus Lapatinib ( n = 41 ) the probability of achieving a pCR is higher in case of PIK3CA wt ( 48.5% vs 12.5%; p = 0.06 ).

Data were cumulated with those deriving from the NeoALTTO ( Baselga, ECCO-ESMO 2013 ) and GeparSixto ( Loibl, SABCS 2013 ) trials ( overall 702 pts ).

The non-overlapping 95% CIs between pCR in patients receiving Lapatinib plus Trastuzumab and those undergoing Trastuzumab or Lapatinib may suggest a higher activity of the dual HER2 inhibition in patients without PI3KCA mutation.

Conversely, no difference in pCR according to PIK3CA status seems to emerge among patients treated with single anti-HER2 agents.

In conclusion, in this hypothesis-generating analysis, the increased activity of the dual anti-HER2 blockade with Trastuzumab plus Lapatinib seems limited to tumors not harboring PIK3CA mutations.
A prospective validation testing the interaction according to the PIK3CA mutation is warranted. ( Xagena )

Guarneri V et al, Annals of Oncology 25 (Supplement 4): iv85–iv109, 2014