Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study

Abstract

IntroductionMolecular markers that predict responses to particular therapies are invaluable for optimization of patient treatment. The TRYPHAENA study showed that pertuzumab and trastuzumab with chemotherapy was an efficacious and tolerable combination for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the neoadjuvant setting. We analyzed whether particular biomarkers correlated with the responses observed and therefore may predict outcomes in patients given pertuzumab plus trastuzumab.MethodsWe describe the analysis of a panel of biomarkers including HER2, human epidermal growth factor receptor 3 (HER3), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) by qRT-PCR, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), and PCR-based mutational analyses as appropriate. For each marker analyzed, patients were categorized into ‘low’ (generally below median) or ‘high’ (generally above median) subgroups at baseline and post-treatment.ResultsCorrelation of marker subgroups with the achievement of a pathological complete response (pCR) (ypT0/is) was analyzed. HER2 protein and mRNA expression levels were associated with pCR rate in two of the three study arms and the pooled analyses. Correlations of biomarker status with pCR occurred in one individual arm only and the pooled analyses with EGFR and PTEN; however, interpretation of these results is limited by a strong imbalance in patient numbers between the high and low subgroups and inconsistency between arms. We also found no association between expression levels of TOP2A and pCR rate in either the anthracycline-containing or free arms of TRYPHAENA.ConclusionsAccording to these analyses, and in line with other analyses of pertuzumab and trastuzumab in the neoadjuvant setting, we conclude that HER2 expression remains the only marker suitable for patient selection for this regimen at present.Trial registrationThe TRYPHAENA study was registered with ClinicalTrials.gov, NCT00976989, on September 14 2009.

The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

“…After exclusion of duplicate references, nonrelevant literature, and those that did not satisfy the inclusion criteria, 19 candidate articles were included. AHT was used for advanced breast cancer in eight studies [13][14][15][16][17][18][19][20], in eight studies in the neoadjuvant setting [21][22][23][24][25][26][27][28], in two adjuvant trials [29,30], and in one study in both metastatic and neoadjuvant disease [31]. Tables 1, 2, 3, 4, 5 and 6 outline the main study characterizes and the outcomes of the 19 included studies.…”

Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer

“…Several studies investigating the role of PIK3CA mutation in neoadjuvant anti-HER2 therapy in combination with chemotherapy revealed a significantly lower pCR rate in tumors with a PIK3CA mutation after dual anti-HER2 therapy with lapatinib and trastuzumab and only a trend for lower pCR in tumors with a PIK3CA mutation after single anti-HER2 therapy (21,31,32). PIK3CA was not predictive of pCR also in patients receiving neoadjuvant chemotherapy with double anti-HER2 treatment (pertuzumab plus trastuzumab) within the TRYPHAENA study (33). The NeoALTTO trial showed that PTEN alone is not predictive of response to HER2-targeted agents (34).…”

Precision medicine for metastatic breast cancer—limitations and solutions

“…Interestingly, this resistance to anti-HER2 therapy owing to the presence of PIK3CA mutations have not been observed when dual HER2 blockade was achieved through the use of two monoclonal antibodies, 71 or in trials performed in the early setting, where the presence of PIK3CA mutations is already evident. 72 Moreover, in the phase III BOLERO2 trial, which evaluated the administration of the mTOR inhibitor everolimus in combination with the aromatase inhibitor exemestane in patients with advanced-stage ER-positive/HER2-negative breast cancer, the presence of multiple alterations in different pathways (that is, FGFR1/2, CCDN1, PTEN and PIK3CA) translated into resistance to mTOR inhibition. 7 The identification of a driver is crucial for the success of targeted therapies, although, it is worth noting that secondary resistance will occur in the vast majority of patients presenting with advanced disease.…”