Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer

Giampaolo Bianchini, Astrid Kiermaier, Giulia Valeria Bianchi, Young-Hyuck Im, Tadeusz Pienkowski, Mei-Ching Liu, Ling-Ming Tseng, Mitch Dowsett, Lila Zabaglo, Sarah Kirk, Tania Szado, Jennifer Eng-Wong, Lukas C Amler, Pinuccia Valagussa, Luca Gianni, Giampaolo Bianchini, Astrid Kiermaier, Giulia Valeria Bianchi, Young-Hyuck Im, Tadeusz Pienkowski, Mei-Ching Liu, Ling-Ming Tseng, Mitch Dowsett, Lila Zabaglo, Sarah Kirk, Tania Szado, Jennifer Eng-Wong, Lukas C Amler, Pinuccia Valagussa, Luca Gianni

Abstract

Background: NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens.

Methods: Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined.

Results: No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P = 0.001) and a significant treatment interaction (P = 0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P = 0.01). Low serum transforming growth factor alpha (TGFα) was associated with higher pCR rates with pertuzumab plus trastuzumab (P = 0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab's mechanism of action). Differences in biomarker profiles according to ER status were observed.

Conclusions: The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population.

Trial registration: Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.

Keywords: Biomarker; Breast cancer; Docetaxel; HER2; Neoadjuvant; Pertuzumab; Trastuzumab.

Figures

Fig. 1
Fig. 1
Relationship between biomarkers and pathologic complete response (pCR) by treatment group. CR concentration ratio, cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, IGF1R insulin-like growth factor 1 receptor, Mem membranous, Mut mutant, Nuc nuclear, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription polymerase chain reaction, sHER2 serum HER2 extracellular domain, TGF transforming growth factor, WT wild-type
Fig. 2
Fig. 2
Human epidermal growth factor receptor 2 (HER2) membrane (Mem) analyses. a HER2 membrane scores versus outcome (pathologic complete response (pCR)) in all four treatment groups. b HER2 membrane staining intensity versus outcome in all four treatment groups (patients with missing pCR were excluded). c HER2 membrane score by outcome
Fig. 3
Fig. 3
Human epidermal growth factor receptor 2 (HER2) extracellular domain (ECD)/intracellular domain (ICD) ratio. pCR pathologic complete response
Fig. 4
Fig. 4
PIK3CA analyses. aPIK3CA status and relationship to outcome per treatment group. b Analysis of PIK3CA mutations by estrogen receptor (ER) status and relationship to outcome. Mut mutant, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase, catalytic subunit, WT wild-type
Fig. 5
Fig. 5
Matched pair analyses of serum human epidermal growth factor receptor 2 extracellular domain (sHER2) levels at baseline and at surgery (S). *P < 0.05 (exploratory analyses). BL baseline, pCR pathologic complete response
Fig. 6
Fig. 6
Insulin-like growth factor 1 receptor (IGF1R) expression according to estrogen receptor (ER) status. a Low IGF1R level/ER-positive group. b High IGF1R level/ER-positive group. c Low IGF1R level/ER-negative group. d High IGF1R level/ER-negative group. pCR pathologic complete response

References

    1. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317–28. doi: 10.1016/S1535-6108(04)00083-2.
    1. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127–37. doi: 10.1016/S1535-6108(02)00097-1.
    1. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330–6. doi: 10.1158/0008-5472.CAN-08-4597.
    1. Barok M, Isola J, Pályi-Krekk Z, Nagy P, Juhász I, Vereb G, Kauraniemi P, Kapanen A, Tanner M, Vereb G, Szöllösi J. Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol Cancer Ther. 2007;6:2065–72. doi: 10.1158/1535-7163.MCT-06-0766.
    1. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (Herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61:4744–9.
    1. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40. doi: 10.1016/j.ccr.2009.03.020.
    1. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64:2343–6. doi: 10.1158/0008-5472.CAN-03-3856.
    1. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32. doi: 10.1016/S1470-2045(11)70336-9.
    1. Baselga J, Cortés J, Kim S-B, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM, CLEOPATRA Study Group Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19. doi: 10.1056/NEJMoa1113216.
    1. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J, CLEOPATRA Study Group Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724–34. doi: 10.1056/NEJMoa1413513.
    1. Bianchini G, Prat A, Pickl M, Belousov A, Koehler A, Semiglazov V, Eiermann W, Tjulandin S, Biakhov M, Lluch A, Zambetti M, Vazquez Mazon FJ, Baselga J, Gianni L. Response to neoadjuvant trastuzumab and chemotherapy in ER+ and ER- HER2-positive breast cancers: Gene expression analysis, Poster discussion presentation. ASCO: Chicago; 2011.
    1. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M, NeoALTTO Study Team Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40. doi: 10.1016/S0140-6736(11)61847-3.
    1. Iwamoto T, Pusztai L, Matsuoka J, Callari M, Kelly CM, Qi Y, Motoki T, Taira N, Santarpia L, Doihara H, Gianni L, Bianchini G. ER+/HER2+ and ER-/HER2+ breast cancers are molecularly distinct but immune gene signatures are prognostic and predictive in both groups, Poster discussion presentation. Vienna: ESMO; 2012.
    1. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA) Ann Oncol. 2013;24:2278–84. doi: 10.1093/annonc/mdt182.
    1. Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95:142–53. doi: 10.1093/jnci/95.2.142.
    1. Sáez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, Lluch A, García-Conde J, Baselga J, Clinton GM. p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res. 2006;15:424–31. doi: 10.1158/1078-0432.CCR-05-1807.
    1. A study of pertuzumab in combination with herceptin in patients with HER2 positive breast cancer. Available at . Accessed 31 Jan 2017.
    1. Hirsch FR, Varella-Garcia M, Bunn PA, Jr, Di Maria MV, Veve R, Bremmes RM, Barón AE, Zeng C, Franklin WA. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798–807. doi: 10.1200/JCO.2003.11.069.
    1. Zabaglo L, Stoss O, Rüschoff J, Zielinski D, Salter J, Arfi M, Bradbury I, Dafni U, Piccart-Gebhart M, Procter M, Dowsett M. HERA Trial Study Team. HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab. Ann Oncol. 2013;24:2761–6. doi: 10.1093/annonc/mdt275.
    1. Krüger JM, Thomas M, Korn R, Dietmann G, Rutz C, Brockhoff G, Specht K, Hasmann M, Feuerhake F. Detection of truncated HER2 forms in formalin-fixed, paraffin-embedded breast cancer tissue captures heterogeneity and is not affected by HER2-targeted therapy. Am J Pathol. 2013;183:336–43. doi: 10.1016/j.ajpath.2013.04.010.
    1. Baselga J, Cortes J, Im S-A, Clark E, Kiermaier A, Ross G, Swain S. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC), Oral presentation. San Antonio: SABCS; 2012.
    1. Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A. 2008;105:2652–7. doi: 10.1073/pnas.0712169105.
    1. Schneeweiss A, Hegg R, Tausch C, Deb R, Ratnayake J, Kiermaier A, McNally V, Ross G, Cortés J. Biomarker analyses of a phase II study of neoadjuvant pertuzumab and trastuzumab with and without anthracycline-containing chemotherapy for treatment of HER2-positive early breast cancer (TRYPHAENA), Poster presentation. Vienna: ESMO; 2012.
    1. Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino E, Samant M, Olsen S, de Haas S, Pegram MD. 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;22(15):3755–63. doi: 10.1158/1078-0432.CCR-15-2499.
    1. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377–84. doi: 10.1016/S0140-6736(09)61964-4.
    1. Eiermann W, Baselga J, Semiglazov V, Ciruelos E, Ojeda B, Feyereislova A, Zambetti M, Valagussa P, Gianni L: Hormone-receptor status and likelihood of predicting pathological complete response (pCR) in the NOAH trial of neoadjuvant trastuzumab in patients (pts) with HER2-positive locally advanced breast cancer (LABC). Eur J Cancer. 2008;6(suppl 7; abstr 228).

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