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. 2016 May 13;27(8):1519–1525. doi: 10.1093/annonc/mdw197

PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab†

S Loibl 1,*, I Majewski 2, V Guarneri 3, V Nekljudova 1, E Holmes 4, E Bria 5, C Denkert 6, C Schem 7, C Sotiriou 8, S Loi 9, M Untch 10, P Conte 3, R Bernards 2, M Piccart 8, G von Minckwitz 1, J Baselga 11
PMCID: PMC6279074  PMID: 27177864

PIK3CA mutation is associated with a lower pathological complete response (pCR) rate overall and in particular in HER2+ primary breast cancer treated with trastuzumab and lapatinib in addition to chemotherapy. Moreover, a significant interaction between the PIK3CA mutation status and the hormone-receptor status for pCR and DFS in patients who received the double blockade has been demonstrated.

Keywords: PIK3CA, HER2+ breast cancer, double anti-HER2 treatment, pathological complete response, neoadjuvant, survival

Abstract

Background

The predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.

Patients and methods

We combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.

Results

A total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P < 0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P < 0.001). In contrast, in the HER2+/HR– group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P < 0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.00–2.45], P = 0.050; Pinteraction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR– group [HR 0.72, 95% CI (0.41–1.25), P = 0.242].

Conclusion

Overall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.

introduction

In HER2-positive (HER2+) primary breast cancer (BC), pathological complete response (pCR) using neoadjuvant therapy continuously increased by different strategies: addition of trastuzumab to chemotherapy, increased duration of chemotherapy or double anti-HER2 therapy [1]. In studies using up to 24 weeks of an anthracycline- and taxane-based chemotherapy and using a double blockade, the pCR rate increased to more than 60%, approaching 75% in HER2+/hormone-receptor negative (HR−) breast cancer [2]. The only predictive marker for anti-HER2 treatment remains HER2, but resistance markers are lacking. One mechanism of interest for HER2 is the Phosphatidylinositol 3-kinase (PIK3) pathway. PIK3CA and its counterpart Phosphatase and tensine homologue (PTEN) have long been investigated. While PTEN status is difficult to be measured, mutations of the PIK3CA are common in BC and can reliably be assessed by different methods [3]. These mutations are predominantly found in hotspots located in the helical and kinase domains (exons 9 and 20), resulting in activation of the kinase. It could recently be demonstrated that PIK3CA mutations predict lower pCR to double blockade with trastuzumab and lapatinib as well as trastuzumab plus afatinib in HER2+ primary BC [4–7].

Despite the fact that data on PIK3CA mutations demonstrate significantly lower pCR rates, this has not led to an inclusion of the marker into routine diagnostics.

materials and methods

end points

The primary aim of this study was to investigate the association of pCR and PIK3CA mutations in primary HER2+ BC treated with one or two HER2 targeting agents.

Secondary aims were to determine the association of pCR and PIK3CA mutations using different pCR definitions, different subgroups defined by exon (exon 9 versus exon 20), HR status (HR+ versus HR−) and anti-HER2 treatment (trastuzumab versus lapatinib versus trastuzumab plus lapatinib) and to test how these factors influenced disease-free survival (DFS) and overall survival (OS) overall.

pCR was defined as no invasive and no non-invasive residuals in breast and lymph nodes (ypT0 ypN0). Patients with missing pCR assessment or information were regarded as no pCR.

DFS was defined as time in months from randomization to (local or distant) disease recurrence, secondary malignancy or death due to any cause. OS was defined as time in months from randomization to death due to any cause.

patients and treatment

PIK3CA mutation was assessed in pre-treatment tumour samples from patients enrolled in five prospectively randomized neoadjuvant trials investigating the dual blockade with T/L (supplementary Figure S1, available at Annals of Oncology online). In addition to taxane-based chemotherapy, patients received either trastuzumab, lapatinib or the combination of trastuzumab and lapatinib. Detailed information on the design and eligibility criteria of the included studies can be accessed elsewhere (GeparQuattro [8], GeparQuinto [9], GeparSixto [10], NeoALTTO [11], CHERLOB [12]).

For GeparQuattro and GeparQuinto, the central HER2 status (IHC3+ or ISH ratio >2.2) was determined retrospectively, and only centrally HER2-positive tumours were included in the PIK3CA mutation analysis. In GeparSixto, HER2 status was assessed centrally before randomization. In the NeoALTTO study, HER2 was assessed centrally or locally (after central laboratory accreditation) and for the CHERLOB study, central HER2 testing was available.

In the GeparSixto study, PIK3CA mutations were assessed prospectively during the recruitment phase of the study in all patients. For all other studies, PIK3CA mutations were assessed retrospectively using formalin-fixed, paraffin-embedded (FFPE) core biopsies that had been prospectively collected.

In the CHERLOB study, in 10 patients, PIK3CA was assessed on the surgical tissue.

All patients provided their written informed consent for study participation, biomaterial collection and use of biomaterial in research projects. The relevant authorities and ethics committees approved the studies. The REMARK (Reporting Recommendations for Tumour Marker Prognostic Studies) criteria were followed [13].

PIK3CA mutation assessment

PIK3CA mutations were evaluated in FFPE or fresh-frozen tumour material with a tumour content of ≥20% for the Geparstudies, ≥10% for the NeoALTTO and ≥50% for the CHERLOB samples. PIK3CA was genotyped using Sanger sequencing (Geparstudies), Sequenom mass-spectrometry genotyping (NeoALTTO) or pyrosequencing (CHERLOB). Detailed method descriptions can be found elsewhere [5–7, 14].

Various methods were used to determine PIK3CA mutation status. In 504 samples, Sanger sequencing evaluated hotspot mutations in exon 9, encoding the helical domain of PIK3CA (E542K, E545K, E547K, A533V, A533T) and in 20, encoding the catalytic domain (H1047R, H1047L, G1007S) [15]. In NeoALTTO (n = 355), the Sequenom mass-spectrometry genotyping system was used to test for hotspot mutations E542A/K, E545A/K and H1047R/L for PIK3CA [6]. In 108 samples, pyrosequencing was used. The approach permitted the identification of mutations in codons 542, 545 and 546 of exon 9 (E542K, E545K, E545A, E545G, Q546E, Q546K) and codons 1043, 1047 and 1049 of exon 20 (M1043I, H1047Y, H1047R, H1047L, G1049R, G1049S) of the PIK3CA gene [7].

statistical analysis

Associations between mutation status (wild-type versus mutant), clinico-pathologic characteristics and pCR were investigated with a (continuity corrected) χ2 tests for categorical variables. Univariate analysis using a binary logistic regression model was carried out to estimate the magnitude of the effect. Odds ratios (ORs) and 95% confidence intervals (CIs) with a two-sided Wald P value are given. A multivariable Cox regression model was fit to adjust for known baseline characteristics (age, tumour stage, nodal stage, histological type, grading, HR status, treatment and study). A Breslow day interaction test was carried out for certain (binary) subgroup analyses; an interaction term in logistic regression was used to test for interaction of subgroup factors with more than two categories. Survival analyses were carried out using the Kaplan–Meier product-limit method and the Cox proportional hazards regression models to test the prognostic value of PIK3CA mutation status [hazard ratios (HRs) and 95% CIs] for DFS and OS. An interaction term in the Cox proportional hazard model was used to test for interaction for time-to-event end points. All P values are two-sided, with a P value of ≤5% considered to be statistically significant. No adjustment for multiple testing was carried out. Statistical analysis was conducted using SAS version 9.2 under SAS Enterprise Guide 4.3 (SAS Institute Inc., Cary, NC).

results

baseline characteristics and mutation frequencies

In the overall study cohort (N = 967), the PIK3CA mutation rate was 21.7%, 21.4% in the GeparStudies, 22.5% in NeoALTTO and 20.4% in the CHERLOB study (supplementaryTable S1, available at Annals of Oncology online). Overall, the mutations in exon 20 were twice as high as in exon 9 (14.5% versus 7.2%). Similar rates were seen in the different studies (Geparstudies 13.1% versus 8.3%, NeoALTTO 16.3% versus 6.2%, CHERLOB 14.8% versus 5.6%). There was no difference in the PIK3CA mutation rate by HR status (supplementary Table S2, available at Annals of Oncology online).

correlation of mutation and pCR

Overall, pCR rates were significantly lower in the PIK3CA mutant cohort (16.2%), compared with one in the wild-type cohort [29.6% (OR 0.460; 95% CI 0.308–0.685], P < 0.001]. This difference was mainly confined to the HR+ subgroup, with a significant interaction between PIK3CA and HR status (Figure 1 and supplementary Table S3, available at Annals of Oncology online). A significantly different pCR rate between PIK3CA mutant and wild-type tumours could only be observed in the group receiving trastuzumab and lapatinib [16.7% versus 39.1%; OR 0.311 (95% CI 0.168–0.577), P < 0.001]; however, there was no significant interaction of the PIK3CA mutation status with type of anti-HER2 treatment (P = 0.189) (Figure 1). When taking treatment and HR status, a significant interaction of PIK3CA mutation with the HR status was confined to the cohort with trastuzumab and lapatinib (supplementary Figure S2, available at Annals of Oncology online). After adjustment for age, tumour stage, nodal status, histological tumour type and grading, PIK3CA mutation status, HR status and treatment provided independent predictive information for achieving a pCR (supplementary Figure S3, available at Annals of Oncology online). Treatment was only a significant independent predictor for pCR in the cohort with PIK3CA mutation (supplementary Table S3 and supplementary Figure S4 available at Annals of Oncology online).

Figure 1.

Figure 1.

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Pathological complete response rates according to PIK3CA mutation status overall, by HR status and anti-HER2 treatment.

survival analysis

The median follow-up was 47 months: 40 months for Geparstudies (68 months for GeparQuattro, 54 months for GeparQuinto and 31 months for GeparSixto), 66 months for the NeoALTTO study and 46 months for the CHERLOB study. There was no statistically significant difference in DFS (Figure 2A) (HR mutant versus wild-type 1.07; 95% CI 0.76–1.50; P = 0.691) and OS (supplementary Figure S5, available at Annals of Oncology online).

Figure 2.

Figure 2.

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Survival curves: (A) disease-free survival by PIK3CA mutation status; (B and C) disease-free survival by PIK3CA mutation status in hormone receptor negative (B) and positive (C) tumours (interaction of HR status and PIK3CAp = 0.021). (D) Disease-free survival according to pathological complete response and PIK3CA mutation status. Disease-free survival by anti-HER2 treatment (trastuzumab, lapatinib and trastuzumab plus lapatinib) in patients with PIK3CA wild-type (E) and PIK3CA mutant (F) tumours.

However, when taking into consideration HR status, there was a significant interaction between HR status and PIK3CA genotype. The HR+ cohort showed a statistically significant worse DFS for the mutant cohort [Figure 2C; HR 1.56 (95% CI 1.00–2.45), P = 0.050], while there was a non-significant trend for a better DFS of the PIK3CA mutant /HR− group [Figure 2B; HR 0.69 (95% CI 0.41–1.17), P = 0.170] with a statistically significant interaction test (P = 0.021).

Since pCR is a known prognostic factor in HER2+ BC, combined survival analyses by pCR and PIK3CA and HR status were carried out (Figure 2D). In the pCR group, patients with a PIK3CA mutation tended to have better survival than those in the wild-type group irrespective of the HR status (log-rank test mutant versus wild-type P = 0.149). Overall, there was no difference in DFS by mutation status in the non-pCR cohort (P = 0.797). But HR non-pCR patients had a better survival with a mutation [HR mut versus wt HR1.53 (95% CI 0.96–2.43) P = 0.073], whereas HR+ non-pCR patients had a better survival without a mutation [HR mut versus wt HR 0.68 (95%CI 0.39–1.17), P = 0.164] (supplementary Figure S6A and B, available at Annals of Oncology online).

An explorative analysis whether a long-term treatment effect was detectable within the PIK3CA wild-type compared with the mutant cohort suggested, although not statistically significantly different, that, similar to the pCR results, dual anti-HER2 treatment improves DFS only in the wild-type cohort but not in the mutant cohort (log rank Pinteraction=0.392) and only in the HR population [HR 0.72 (95% CI 0.41–1.25), P = 0.242] (Figure 2E and F).

discussion

We confirmed in almost 1000 HER2+ primary BC that tumours harbouring a PIK3CA mutation have a significantly lower pCR rate, especially in the group receiving T/L, although a trend within the monotherapy anti-HER2 treatment groups could be seen. Combining both groups into a monotherapy anti-HER2 cohort (n = 566 patients) demonstrated a strong trend towards a lower pCR rate in the mutant compared with the wild-type cohort (15.9% versus 22.7%; P = 0.125), suggesting a small effect for PIK3CA mutations also there. To show an absolute 7% pCR difference to be of statistical significance, a sample size of several thousands would have been needed. However, in a recent smaller study, PTEN and the PIK3 downstream marker pEBP4 added information to the PIK3CA mutation status in a trastuzumab cohort [16].

Interestingly, PIK3CA status was observed to have a significant interaction with the HR status in the group treated with trastuzumab and lapatinib.

The role of PIK3CA in assessing the predictive effect in neoadjuvant therapy using the double blockade with trastuzumab plus pertuzumab has been less thoroughly investigated showing results comparable to ours [17, 18].

The Cleopatra study reported that patients with a PIK3CA mutation in their primary tumor had a significantly worse PFS, but mutation status did not predict greater benefit from double blockade [19, 20].

In the DFS analysis, as in the pCR analysis, the HR status interacted with the PIK3CA mutation status. HR– patients had a better DFS if their tumour harboured a PIK3CA mutation, whereas in HR+ patients, DFS was worse.

Despite a significant difference in the pCR rate, there was no difference in DFS and OS for patients with tumours harbouring a PIK3CA mutation, which is consistent with the data from the NSABP-B31 trial, even though the FinHER trial showed an improved survival within the first 3 years for the PIK3CA mutant cohort [21, 22]. The data for PIK3CA are not very conclusive regarding survival. Numbers were either too small, or only a subcohort of the trial cohort was investigated or, as in the neoadjuvant setting, patients received longer anti-HER2 treatment in some trials or switched from lapatinib to trastuzumab after surgery [23]. Although exploratory, there seems to be benefit from the T/L combination in PIK3CA wt HR−/HER2+ patients. The non-pCR group of that cohort had the worst prognosis from all subgroups. A confirmation of these data in the much larger ALTTO trial would support the role of T/L in HR–/HER2+/PIK3CA wt. However in the HR+ group, the non-pCR PIK3CA mutant cohort had the worst prognosis, which warrants a chemofree quadruplet of dual blockade with anti-hormone-therapy and a more specific PI3K to be further investigated.

In the BOLERO 1 and 3 studies conducted in HER2+ metastatic BC, the effect of everolimus, an mTOR inhibitor acting downstream in the PI3Kinase pathway, was only detectable in the cohort harbouring a PIK3CA mutation [24]. Similar results were seen in Belle-2, when the pan PI3K inhibitor buparlisib in addition to fulvestrant in HER2−/HR+ metastatic BC improved PFS only in the group with a PIK3CA mutation detected in circulating tumour DNA [25]. The NeoPHOEBE study investigating buparlisib in HER2+ BC is too small and included only eight patients with a PIK3CA mutation, but demonstrated an increased response rate after 6 weeks by adding buparlisib to trastuzumab in the HR+ cohort [26].

This analysis has several strengths and limitations. The integrated analysis using data from three different projects, including five different clinical trials, has the power to demonstrate a positive interaction of PIK3CA mutation status and the HR status regarding pCR when trastuzumab and lapatinib are used. However, the power for the survival analysis is still limited. To account for the fact that data from three different studies were combined, the multivariable models were adjusted for ‘study’. The different studies have used different sequencing approaches. Sanger sequencing has been used as a standard method for a long time, while Sequenom and pyrosequencing technologies have been introduced more recently. The backgrounds of the methods are different; in particular, the Sequenom technology uses detection of DNA fragments by MALDI-TOF mass spectrometry. All three approaches, however, are focused on the analysis of defined mutational alterations. This makes them particularly suitable for the analysis of PIK3CA, which has mutations located at defined hotspots. Consequently, all three methods are well established and the PIK3CA mutation rates in the different studies are within the same range. Comparative studies have been carried out for comparison of Sequenom analysis versus targeted next-generation sequencing (NGS) and Sanger sequencing versus targeted NGS with comparable results by both methods [27, 28].

In conclusion, PIK3CA mutation is associated with a lower pCR rate overall and particularly in HER2+ primary BC treated with trastuzumab and lapatinib in addition to chemotherapy. This pooled analysis also demonstrated a significant interaction between HR and PIK3CA status and treatment for both pCR and DFS end points. The data could be used to further subdivide the HER2+ population in order to improve outcome.

funding

The individual clinical trials received funding from GSK/Novartis, Roche, Sanofi-Aventis and TEVA. The study was partially supported by a grant from the 7th EU frame work programme grant no 278659 ‘RESPONSIFY’.

disclosure

RB is an employee of Genentech Inc. South San Francisco; CD received honoraria from Roche and has ownership interest in Sividon Diagnostics; SL received research funding from Merck, Roche-Genentech, Pfizer and Novartis; MP received honoraria from Roche-Genentech and has a consulting role for Roche-Genentech; CS received expenses from Roche and has a consulting role for Oncodna, Vertex, Astellas and Cepheid; GM institution received research funding from Pfizer, Sanofi, Amgen, Roche, Novartis, Celgene, Teva, Boehringer, AstraZeneca and Myriad Genetics. All remaining authors have declared no conflict of interest.

Supplementary Material

mdw197supp
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mdw197supp_table1
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mdw197supp_table2
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mdw197supp_table3
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acknowledgements

We thank all patients, clinicians and pathologists participating in the clinical studies and the biomaterial collection. We thank the BIG headquarters and Ian Bradbury, Frontier Science for facilitating the data transfer.

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Associated Data

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Supplementary Materials

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mdw197supp_table1
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mdw197supp_table2
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mdw197supp_table3
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