Results presented at the 2014 Congress of the European Society for Medical Oncology (ESMO), being held September 26 – 30, 2014 in Madrid, Spain, shows that patients with HER2 positive breast cancer benefit less from anti-HER2 drugs when they have PIK3CA mutations. The data, on the impact of PIK3CA mutations as new data in the neoadjuvant setting was,presented by Evandro de Azambuja, MD, PhD, medical director of the Br.E.A.S.T. Data Centre, Jules Bordet Institute in Brussels, Belgium. [1]
The theme for of the ESMO congress was ?Precision Medicine in Cancer Care,? and focused on helping oncologists, immunologist or pathologist, improve patient outcomes by practising precision medicine.
?The results presented at ESMO 2014 are consistent with other trials in the neoadjuvant setting and suggest that there may be a resistance to anti-HER2 drugs when PIK3CA is mutated,? De Azambuja said.
NeoALTTO Trial
The NeoALTTO trial found similar distributions of PIK3CA mutations in the whole population compared to the study presented by Guarneri at ESMO 2014. Both studies found that the pathological complete response (pCR) was lower in patients with PIK3CA mutations. The effect of PIK3CA mutations occurred in all treatment arms ? lapatinib, trastuzumab, and lapatinib plus trastuzumab ? but was most pronounced in the combination group, although this finding did not reach statistical significance in Guarneri?s study likely due to low patient numbers. [2]
These results … are consistent with other trials in the neoadjuvant setting and suggest that there may be a resistance to anti-HER2 drugs when PIK3CA is mutated…
GeparQuinto and GeparSixto
A study from the German Breast Group (GBG) which combined two neoadjuvant trials, GeparQuinto and GeparSixto, also found a significantly reduced pCR in patients with PIK3CA mutations. In particular, patients who were HER2 positive and hormone receptor positive had a much lower pCR when they had the PIK3CA mutation. [3][4]
CLEOPATRA and EMILIA
Trials of dual anti-HER2 blockade in the metastatic setting have produced similar findings to the neoadjuvant studies. Patients with PIK3CA mutations had much less benefit from trastuzumab alone or from trastuzumab and pertuzumab in the CLEOPATRA trial, and less benefit from lapatinib plus chemotherapy with capecitabine in the EMILIA trial.[5][6]
?All of this data seems to be in line and shows that patients with the PIK3CA mutation derive less benefit from anti-HER2 drugs. This is an important pathway in the cells which leads to proliferation, cell survival and tumour growth. We already know that PIK3CA is a prognostic marker but now it also appears to predict response to treatment,? De Azambuja explained.
FinHER trial
The FinHER trial investigated the impact of PIK3CA mutations on HER2 positive breast cancer patients in the adjuvant setting who received trastuzumab or no trastuzumab.?PIK3CA mutations did not predict response to trastuzumab but patient numbers were very small and I think it?s a question of power. We need more data before we can be confident about whether or not PIK3CA status predicts response to treatment in the adjuvant setting,? De Azambuja noted.[7]
NeoPHOEBE neoadjuvant
The ongoing NeoPHOEBE neoadjuvant trial in patients with HER2 positive breast cancer is randomising patients with PIK3CA wild type and PIK3CA mutations to receive the anti-HER2 drug trastuzumab either alone or in combination with a PI3K inhibitor for 6 weeks, both in addition of weekly paclitaxel for a further 12 weeks. ?The results of this trial should provide a clear answer on whether PIK3CA status can be used to stratify patients to receive, or not receive, anti-HER2 drugs,? De Azambuja, explained.[8]
The incidence of PIK3CA mutations varies according to the different breast cancer subtypes. The majority of research in this area has focused on the HER2 positive subtype. However, a number of trials are investigating the impact of PIK3CA mutations on endocrine therapy and PI3K inhibition in patients with hormone receptor positive and HER2 negative breast cancer in the neoadjuvant setting.
Commenting on the impact of the new data presented at ESMO 2014 on current practice, De Azambuja noted: ?This research adds to the scientific knowledge on PIK3CA mutations but at the moment will not change clinical practice. There is some evidence that when patients have genetic tests and are directed towards clinical trials focused on their mutation they derive more benefit from treatment. I think we will see more and more use of genetic testing for PIK3CA and other mutations to stratify patients to clinical trials, particularly in the neoadjuvant or metastatic settings. This is the way to move forward in clinical research.?
For more information:
[1] 254O: Activity of neoadjuvant lapatinib (L) plus trastuzumab (T) for early breast cancer (EBC) according to PIK3CA mutations: Pathological complete response (pCR) rate in the CherLOB study and pooled analysis of randomized trials. Monday, September 29, 2014 ? 16:00 PM ? 18:00 PM – Hall Barcelona. [Abstract]
[2] NeoALTTO Trial -Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation – Study (NCT00553358) [Study Record Detail]
[3] A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer (GeparQuinto: NCT00567554) [Study Record Detail]
[4] Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer (GeparSixto: NCT01426880) [Study Record Detail]
[5] A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA: NCT00567190) [Study Record Detail]
[6] An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer (EMILIA: NCT00829166) [Study Record Detail]
[7] Comparison of vinorelbine versus docetaxel, and trastuzumab versus no trastuzumab as adjuvant treatments of early breast cancer (FinHer: ISRCTN76560285/FBCG 00-01)[Study Record Detail]
[8] NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer (NCT01816594) [Study Record Detail]
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