PIK3CA mutations in HER2-positive breast cancer: an ongoing conundrum
2016; Elsevier BV; Volume: 27; Issue: 8 Linguagem: Inglês
10.1093/annonc/mdw246
ISSN1569-8041
Autores Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoThe routine use of therapeutic agents that specifically target the human epidermal growth factor receptor-2 (HER2) has dramatically improved outcomes for patients with HER2-positive breast cancer. Data from contemporary trials indicate that the median survival for patients with metastatic HER2-positive disease is close to 5 years, and that long-term distant recurrence rates after adjuvant therapy are low [1.Romond E. Suman V. Jeong J.-H. et al.Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831.Cancer Res. 2012; 72: 5Google Scholar, 2.Swain S.M. Baselga J. Kim S.B. et al.Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.N Engl J Med. 2015; 372: 724-734Crossref PubMed Scopus (1361) Google Scholar, 3.Tolaney S.M. Barry W.T. Dang C.T. et al.Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.N Engl J Med. 2015; 372: 134-141Crossref PubMed Scopus (495) Google Scholar]. As the number of HER2-targeted therapies has increased, it has become clear that not every patient needs to receive every available drug, and that a 'one size fits all' approach will lead to suboptimal outcomes. It is thus important that studies are carried out to identify biomarkers that determine the long-term prognosis of HER2-positive breast cancers and/or predict their responses to specific therapies. Such biomarkers would allow tailoring treatment to those patients most likely to benefit and reducing overtreatment for patients who are destined to do well with less therapy. In addition, it would potentially identify patients whose response to existing therapies is poor and for whom novel treatments should be developed. Unfortunately, despite having data and tissue from large randomized adjuvant studies of trastuzumab for over 10 years, and metastatic studies for even longer, strong, validated predictors of outcome have largely remained elusive. In this issue of Annals of Oncology, Loibl et al. [4.Loibl S. Majewski I. Guarneri V. et al.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.Ann Oncol. 2016; 27: 1519-1525Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] present results of a meta-analysis in which they specifically explore whether activating mutations in the PIK3CA gene of HER2-positive breast cancers are associated with reduced sensitivity to neoadjuvant therapy. The potential role of the PIK3CA gene as a mediator of tumor resistance to HER2-targeted therapies is well described [5.Goel S. Krop I.E. Deciphering the role of phosphatidylinositol 3-kinase mutations in human epidermal growth factor receptor 2-positive breast cancer.J Clin Oncol. 2015; 33: 1407-1409Crossref PubMed Scopus (8) Google Scholar, 6.Berns K. Horlings H.M. Hennessy B.T. et al.A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.Cancer Cell. 2007; 12: 395-402Abstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. PIK3CA encodes the p110α subunit of the lipid kinase phosphoinositide 3-kinase (PI3K). When the HER2 receptor tyrosine kinase is active (as in HER2-positive breast cancers), PI3K is stimulated to phosphorylate phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5,)-trisphosphate (PIP3) at the plasma membrane. The canonical consequence of this is activation of the AKT kinase and the propagation of a network of intracellular signals mediating tumor cell proliferation, survival, metabolism, and growth [7.Manning B.D. Cantley L.C. AKT/PKB signaling: navigating downstream.Cell. 2007; 129: 1261-1274Abstract Full Text Full Text PDF PubMed Scopus (4715) Google Scholar]. Recent preclinical studies provide clues as to why the p110α subunit of PI3K may be particularly important for HER2-positive breast cancers. These studies suggest that HER2 signaling is mediated almost entirely through p110α, rather than one of the other three catalytic subunits of PI3K [8.Wang Q. Liu P. Spangle J.M. et al.PI3K-p110alpha mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers.Oncogene. 2015; Google Scholar, 9.Utermark T. Rao T. Cheng H. et al.The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis.Genes Dev. 2012; 26: 1573-1586Crossref PubMed Scopus (106) Google Scholar]. For example, mice with both copies of the PIK3CA gene deleted are completely resistant to HER2 transgene-mediated tumor formation [9.Utermark T. Rao T. Cheng H. et al.The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis.Genes Dev. 2012; 26: 1573-1586Crossref PubMed Scopus (106) Google Scholar], and mice bearing both HER2 and a mutant PIK3CA transgenes develop mammary tumors faster than those bearing only an HER2 transgene [10.Hanker A.B. Pfefferle A.D. Balko J.M. et al.Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.Proc Natl Acad Sci USA. 2013; 110: 14372-14377Crossref PubMed Scopus (136) Google Scholar]. It is thus very plausible that mutations in PIK3CA that constitutively activate p110α, such as the relatively common 'hotspot' mutations in exons 9 and 20, could confer resistance to therapeutic HER2-blockade, because inhibiting the HER2 kinase may not be sufficient to suppress downstream PI3K signaling. Such mutations are found in ∼20% of HER2-positive breast cancers, and preclinically, they render tumors resistant to trastuzumab both in vitro and in vivo [6.Berns K. Horlings H.M. Hennessy B.T. et al.A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.Cancer Cell. 2007; 12: 395-402Abstract Full Text Full Text PDF PubMed Scopus (1317) Google Scholar]. In the present study, Loibl et al. combine individual patient data from five neoadjuvant trials. In total, their analysis includes almost 1000 patients. Patients in each of the five trials received systemic chemotherapy, either with a taxane alone or with a taxane–anthracycline regimen. Each study also administered concurrent anti-HER2 therapy—trastuzumab, lapatinib, or their combination, varying between studies (Table 1). Using a robust definition of pathological complete response (no residual invasive or non-invasive disease in either breast or axillary nodes), the authors show that the presence of a PIK3CA mutation is associated with a significantly lower rate of pCR (wild-type pCR 29.6% versus mutant pCR 16.2%, P < 0.001).Table 1Summary of the published and/or presented data detailing the impact of activating mutations in PIK3CA in HER2-positive breast cancersDisease settingTrialTreatment armsOutcomes in PIK3CA mutant versus wild-typeNeoadjuvantCALGB 40601 [11.Hoadley K.A. Barry W.T. Pitcher B.N. et al.Abstract S3-06: Mutational analysis of CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer.Cancer Res. 2015; 75Google Scholar]T-L 16 weeksT-H 16 weeksT-HL 16 weeksNo significant difference in pCR between mutant and wild-type (39% versus 47%)Neo ALTTO [12.Majewski I.J. Nuciforo P. Mittempergher L. et al.PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.J Clin Oncol. 2015; 33: 1334-1339Crossref PubMed Scopus (179) Google Scholar]aStudies included in the present analysis by Loibl et al. [4].L (6 weeks) → T-L (12 weeks)H (6 weeks) → T-H (12 weeks)HL (6 weeks) → T-HL (12 weeks)Lower pCR in mutant (21.3%) versus wild-type (34.5%) (P = 0.03)No significant difference in EFS between mutant and wild-typeCHER-LOB [13.Guarneri V. Dieci M.V. Frassoldati A. et al.Prospective biomarker analysis of the randomized CHER-LOB study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer.Oncologist. 2015; 20: 1001-1010Crossref PubMed Scopus (64) Google Scholar]aStudies included in the present analysis by Loibl et al. [4].TL (12 weeks) → FEC-L (12 weeks)TH (12 weeks) → FEC-H (12 weeks)THL (12 weeks) → FEC-HL (12 weeks)No significant difference in pCR between mutant and wild-type (22.7% versus 33.3%)GeparQuattro [14.Loibl S. von Minckwitz G. Schneeweiss A. et al.PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer.J Clin Oncol. 2014; 32: 3212-3220Crossref PubMed Scopus (204) Google Scholar]aStudies included in the present analysis by Loibl et al. [4].FEC-H (12 weeks) → D-H (12 weeks)FEC-H (12 weeks) → DX-H (12 weeks)FEC-H (12 weeks) → D-H (12 weeks) → XH (12 weeks)No significant difference in pCR between mutant and wild-type (22.2% versus 35.4%)bCombined analysis of EFS in GeparQuattro, GeparQuinto, and GeparSixto showed no difference between patients with PIK3CA-mutant or wild-type tumors.GeparQuinto [14.Loibl S. von Minckwitz G. Schneeweiss A. et al.PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer.J Clin Oncol. 2014; 32: 3212-3220Crossref PubMed Scopus (204) Google Scholar]aStudies included in the present analysis by Loibl et al. [4].EC-L (12 weeks) → D-L (12 weeks)EC-H (12 weeks) → D-H (12 weeks)No significant difference in pCR between mutant and wild-type (20.5% versus 25.5%)bCombined analysis of EFS in GeparQuattro, GeparQuinto, and GeparSixto showed no difference between patients with PIK3CA-mutant or wild-type tumors.GeparSixto [14.Loibl S. von Minckwitz G. Schneeweiss A. et al.PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer.J Clin Oncol. 2014; 32: 3212-3220Crossref PubMed Scopus (204) Google Scholar]aStudies included in the present analysis by Loibl et al. [4].T-M-HL (18 weeks)T-MCb-HL (18 weeks)Lower pCR in mutant (17.4%) versus wild-type (37.1%) (P = 0.01)bCombined analysis of EFS in GeparQuattro, GeparQuinto, and GeparSixto showed no difference between patients with PIK3CA-mutant or wild-type tumors.NeoSphere [15.Gianni L. Bianchini G. Kiermaier A. et al.San Antonio Breast Cancer Symposium.in: Neoadjuvant Pertuzumab (P) and Trastuzumab (H): Biomarker Analyses of a, 4-Arm Randomized Phase II Study (NeoSphere) in Patients (pts) with HER2-Positive Breast Cancer (BC)2011Google Scholar]HP (12 weeks)D-H (12 weeks)D-P (12 weeks)D-HP (12 weeks)Lower pCR rate in PIK3CA-mutant tumors in all treatment groups (unpublished)TRYPHAENA [16.Schneeweiss A. Chia S. Hegg R. et al.Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study.Breast Cancer Res. 2014; 16: R73Crossref PubMed Scopus (65) Google Scholar]FEC-HP (9 weeks) → D-HP (9 weeks)FEC (9 weeks) → D-HP (9 weeks)DCb-HP (18 weeks)No significant difference in pCR between mutant and wild-type (48.7% versus 64.3%)AdjuvantNSABP-B31 [17.Pogue-Geile K.L. Song N. Jeong J.-H. et al.Instrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31.J Clin Oncol. 2015; Crossref Scopus (98) Google Scholar]AC (12 weeks) → T (12 weeks)AC (12 weeks) → T-H (12 weeks) → H (39 weeks)No significant interaction between PIK3CA status and trastuzumab benefitNo significant difference in DFS between mutant and wild-typeFinHER [18.Loi S. Michiels S. Lambrechts D. et al.Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.J Natl Cancer Inst. 2013; 105: 960-967Crossref PubMed Scopus (117) Google Scholar]D or V (9 weeks) → FEC (9 weeks)D-H or V-H (9 weeks) → FEC (9 weeks)No significant interaction between PIK3CA status and trastuzumab benefitNo significant difference in DDFS or OS between mutant and wild-typeMetastaticCLEOPATRA [19.Baselga J. Cortes J. Im S.A. et al.Biomarker analyses in CLEOPATRA: a Phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer.J Clin Oncol. 2014; 32: 3753-3761Crossref PubMed Scopus (239) Google Scholar]D-H → HD-HP → HPNo significant interaction between PIK3CA status and pertuzumab benefitSignificantly worse prognosis in patients with PIK3CA-mutant tumors (control arm PFS 8.6 m versus 13.8 m; experimental arm PFS 12.5 m versus 21.8 m)EMILIA [20.Baselga J. Lewis Phillips G.D. Verma S. et al.Relationship between tumor biomarkers and efficacy in EMILIA, a phase III Study of trastuzumab emtansine in HER2-positive metastatic breast cancer.Clin Cancer Res. 2016; Crossref Scopus (122) Google Scholar]X-LT-DM1PFS and OS worse in PIK3CA-mutant tumors in XL arm (PFS 4.3 m versus 6.4 m; OS 17.3 versus 27.8 m) but not in T-DM1 arm (PFS 10.9 m versus 9.8 m, OS - NE)NB—the paper in this issue of Annals of Oncology [4.Loibl S. Majewski I. Guarneri V. et al.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.Ann Oncol. 2016; 27: 1519-1525Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] represents a combined analysis of Neo ALTTO, CHER-LOB, GeparQuattro, GeparQuinto, and GeparSixto. Definition of pCR was not identical in all neoadjuvant studies.AC, adriamycin and cyclophosphamide; Cb, carboplatin; D, docetaxel; DFS, disease-free survival; DDFS, distant disease-free survival; EFS, event-free survival; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; L, lapatinib; NE, not estimable; M, non-pegylated liposomal doxorubicin; OS, overall survival; P, pertuzumab; T, paclitaxel; T-DM1, trastuzumab emtansine; V, vinorelbine; X, capecitabine.a Studies included in the present analysis by Loibl et al. [4.Loibl S. Majewski I. Guarneri V. et al.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.Ann Oncol. 2016; 27: 1519-1525Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar].b Combined analysis of EFS in GeparQuattro, GeparQuinto, and GeparSixto showed no difference between patients with PIK3CA-mutant or wild-type tumors. Open table in a new tab NB—the paper in this issue of Annals of Oncology [4.Loibl S. Majewski I. Guarneri V. et al.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.Ann Oncol. 2016; 27: 1519-1525Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] represents a combined analysis of Neo ALTTO, CHER-LOB, GeparQuattro, GeparQuinto, and GeparSixto. Definition of pCR was not identical in all neoadjuvant studies. AC, adriamycin and cyclophosphamide; Cb, carboplatin; D, docetaxel; DFS, disease-free survival; DDFS, distant disease-free survival; EFS, event-free survival; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; L, lapatinib; NE, not estimable; M, non-pegylated liposomal doxorubicin; OS, overall survival; P, pertuzumab; T, paclitaxel; T-DM1, trastuzumab emtansine; V, vinorelbine; X, capecitabine. The data in this analysis are not new, but are rather a compilation of previously presented data from the five individual trials [12.Majewski I.J. Nuciforo P. Mittempergher L. et al.PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.J Clin Oncol. 2015; 33: 1334-1339Crossref PubMed Scopus (179) Google Scholar, 14.Loibl S. von Minckwitz G. Schneeweiss A. et al.PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer.J Clin Oncol. 2014; 32: 3212-3220Crossref PubMed Scopus (204) Google Scholar] (Table 1). Although a trend toward lower pCR rates in PIK3CA-mutant tumors was seen in each individual trial, the difference failed to reach statistical significance in the majority of them. The combining of individual patient data increases statistical power and confirms the validity of the association between PIK3CA mutations and lower rates of pCR. The more novel finding in this work is that the association between PIK3CA mutations and lower rates of pCR was much stronger in hormone receptor (HR)-positive HER2-positive cancers (wild-type pCR 24.2% versus mutant pCR 7.6%, P < 0.001) than in HR-negative tumors (wild-type pCR 36.4% versus mutant pCR 27.2%, P = 0.125) and this interaction between HR and PIK3CA mutations was statistically significant (Pinteraction = 0.036). Previous analyses hindered by smaller sample sizes did not clearly demonstrate this effect. In addition, the investigators also confirm previous data highlighting that although the rate of pCR is lower in PIK3CA-mutant tumors regardless of the anti-HER2 therapy used, the difference is numerically greatest for patients receiving dual blockade with trastuzumab and lapatinib [12.Majewski I.J. Nuciforo P. Mittempergher L. et al.PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.J Clin Oncol. 2015; 33: 1334-1339Crossref PubMed Scopus (179) Google Scholar]. These results are consistent with our understanding of HER2 biology. We might expect that HER2-positive tumors with constitutive activation of PI3K show relative resistance to HER2-targeted therapies, chiefly due to the potential failure of anti-HER2 therapy to mitigate downstream signaling. Furthermore, constitutive activation of PI3K can lead to down-regulation of upstream HER2 and HER3 kinase activity through feedback inhibition, which could in itself render tumors less sensitive to anti-HER2 therapies [10.Hanker A.B. Pfefferle A.D. Balko J.M. et al.Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.Proc Natl Acad Sci USA. 2013; 110: 14372-14377Crossref PubMed Scopus (136) Google Scholar, 21.Scaltriti M. Nuciforo P. Bradbury I. et al.High HER2 expression correlates with response to the combination of lapatinib and trastuzumab.Clin Cancer Res. 2015; 21: 569-576Crossref PubMed Scopus (62) Google Scholar]. On deeper examination, however, there are a number of questions that remain unresolved. First, we cannot determine from these data whether PIK3CA mutations are specifically associated with a worse response to chemotherapy, anti-HER2 therapy, or both, because all patients studied received concomitant chemotherapy. Secondly, it is not obvious as to why the impact of a PIK3CA mutation on pCR rates should be greater in HR-positive tumors. Indeed, if the effect of a PIK3CA mutation was independent of HR-status, one would expect the absolute difference in pCR rates between mutant and wild-type tumors to be lower in HR-positive tumors, given that they have a lower pCR rate overall. Given that the opposite was seen, it suggests that the biological impact of a HER2-positive cancer's PIK3CA mutation differs by HR status. Notably, HER2-positive tumors that are also HR-positive are much more likely to show a 'luminal' pattern of gene expression [22.Carey L.A. Berry D.A. Cirrincione C.T. et al.Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized Phase III trial of paclitaxel plus trastuzumab with or without lapatinib.J Clin Oncol. 2016; 34: 542-549Crossref PubMed Scopus (272) Google Scholar]. Given that PIK3CA mutations are associated with lower proliferation rates in HR-positive (presumably luminal) tumors more generally, the same might be true of luminal (as opposed to non-luminal) HER2-positive tumors. This in turn might be associated with a lower rate of pCR. An alternative mechanism for the greater impact of PIK3CA mutations on pCR rates in HR-positive cancers is that in these cancers, cross-talk between a mutation-activated PI3K pathway and the HR pathway leads to therapeutic resistance. This cross-talk is not relevant in HR-negative tumors, potentially explaining the lesser impact of PIK3CA mutations in these cancers. Thirdly, one might expect that a significant reduction in pCR rates for PIK3CA-mutant tumors would be associated with an inferior clinical outcome, especially since an association between attainment of pCR after neoadjuvant anti-HER2 therapy and disease-free survival (DFS) has been established [23.Cortazar P. Zhang L. Untch M. et al.Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet. 2014; 384: 164-172Abstract Full Text Full Text PDF PubMed Scopus (2613) Google Scholar]. In the analysis presented by Loibl et al., however, the inferior pCR rate seen in PIK3CA-mutant tumors is not accompanied by a measurable change in DFS (HR for PIK3CA mutant versus wild-type was 1.07, P = 0.691). In some respects, this discrepancy resembles that observed when HR status (as opposed to PIK3CA status) is used as the biomarker. HER2-positive, HR-positive cancers have a markedly lower pCR rate to neoadjuvant HER2-targeted therapy when compared with HER2-positive, HR-negative tumors and yet their DFS rates are no worse [24.Gianni L. Pienkowski T. Im Y.H. et al.5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.Lancet Oncol. 2016; Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar]. In that instance, at least a part of the discrepancy between pCR and DFS might be explained by the use of adjuvant endocrine therapy, an effective treatment given only for HR-positive tumors, the effect of which is not measured in pre-operative chemotherapy-based studies. In the present analysis, however, there is no PI3K-specific therapy given to PIK3CA-mutant tumors after surgery, so the same logic does not apply. Rather, it is possible that PIK3CA-mutant, early-stage HER2-positive tumors have an inherently more indolent biology and lower risk of recurrence, such that a failure to respond to neoadjuvant therapy does not translate into an inferior DFS [25.Sabine V.S. Crozier C. Brookes C.L. et al.Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study.J Clin Oncol. 2014; 32: 2951-2958Crossref PubMed Scopus (91) Google Scholar]. A fourth point of confusion arises when the neoadjuvant data are contrasted with studies examining HER2-positive, PIK3CA-mutated breast cancer in other contexts (summarized in Table 1). In the setting of metastatic disease, for example, PIK3CA mutations have a negative prognostic impact in patients receiving anti-HER2 therapy, but have no bearing on the magnitude of response to that therapy—essentially the opposite of what is seen in the neoadjuvant context [19.Baselga J. Cortes J. Im S.A. et al.Biomarker analyses in CLEOPATRA: a Phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer.J Clin Oncol. 2014; 32: 3753-3761Crossref PubMed Scopus (239) Google Scholar]. Furthermore, analyses of two randomized adjuvant trials comparing chemotherapy versus chemotherapy plus trastuzumab showed neither a prognostic nor a predictive association of PIK3CA mutations [17.Pogue-Geile K.L. Song N. Jeong J.-H. et al.Instrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31.J Clin Oncol. 2015; Crossref Scopus (98) Google Scholar, 18.Loi S. Michiels S. Lambrechts D. et al.Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.J Natl Cancer Inst. 2013; 105: 960-967Crossref PubMed Scopus (117) Google Scholar]. Reconciling these data is not easy—why should HER2-positive tumor cells in an early-stage cancer be less responsive to neoadjuvant anti-HER2 therapy if they harbor a PIK3CA mutation, while those in a metastatic tumor are not? And why should this treatment resistance of the early-stage tumor's cells not translate into an inferior outcome, while in a metastatic tumor, a PIK3CA mutation confers an inferior prognosis? Answers to these questions are partly confounded by the fact that studies often lack a 'no HER2-therapy' arm, rendering it difficult to assess the impact of PIK3CA mutations per se as predictors of response to therapy. It is notable, however, that a similar discrepancy between the biology of PIK3CA-mutant tumors in early versus advanced disease has been described for HR-positive, HER2-negative tumors [26.Mayer I.A. Arteaga C.L. PIK3CA activating mutations: a discordant role in early versus advanced hormone-dependent estrogen receptor-positive breast cancer?.J Clin Oncol. 2014; 32: 2932-2934Crossref PubMed Scopus (28) Google Scholar]. Despite the complexity, we do offer some clinical suggestions based upon the data from Loibl et al., as well as other reports. Most importantly, we believe that there is currently no rationale for the routine testing of PIK3CA mutation status in HER2-positive breast cancers before administering neoadjuvant therapy. The presence of a mutation cannot yet dictate choice of therapy, and has no prognostic implications. Of course, this recommendation may change as our understanding of the underlying biology deepens. In addition, we advise caution when applying the current data to tumors treated with other HER2-directed neoadjuvant regimens. At present, the 'gold-standard' neoadjuvant regimen contains dual HER2-blockade with trastuzumab and pertuzumab, and the impact of PIK3CA mutations on response to this therapy has not been comprehensively explored. Lastly, we believe that there remains a strong rationale for the development of novel targeted therapies to treat HER2-positive tumors harboring PIK3CA mutations. β-Sparing (or α-specific) PI3K inhibitors are the obvious choice, and early data suggest that the presence of a PIK3CA mutation in breast cancer might predict enhanced response to these agents [27.Juric D. Krop I.E. Ramanathan R.K. et al.GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose escalation study. [abstract].Cancer Res. 2013; 73 (abstr LB-64)Google Scholar, 28.Gonzalez-Angulo A.M. Juric D. Argiles G. et al.Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: Results from the first-in-human study.J Clin Oncol. 2013; 31Crossref PubMed Google Scholar]. Furthermore, recent preclinical data provide a strong rationale for using CDK4/6 inhibitors in tumors that are HER2-amplified and/or mutant at PIK3CA [29.Goel S. Wang Q. Watt A.C. et al.Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors.Cancer Cell. 2016; 29: 255-269Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 30.Vora S.R. Juric D. Kim N. et al.CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.Cancer Cell. 2014; 26: 136-149Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar]. In summary, we congratulate Loibl et al. for successfully compiling the data from five different neoadjuvant trials in HER2-positive breast cancer to reach important conclusions. This study highlights the benefits of meta-analysis of individual patient data, and the results are thought-provoking. At present, however, when trying to comprehend the biology and behavior of PIK3CA-mutant HER2-positive breast cancer, we appear to still have more questions than answers. I.E.K. receives funding from Susan G. Komen for the Cure (SAC100005).
Referência(s)