Using Probability for Pathological Complete Response (pCR) as a Decision Support Marker for Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Patients – a Survey Among Physicians

Abstract

Background In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy.

Methods The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy.

Results 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%.

Conclusions The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.

Zusammenfassung

Hintergrund Die pathologische Komplettremission (pCR) nach neoadjuvanter Chemotherapie bei Frauen mit Brustkrebs im Frühstadium weist auf eine verbesserte Überlebenswahrscheinlichkeit hin. Ziel dieser Umfrage unter Ärzten war es, zu untersuchen, ob die Wahrscheinlichkeit, dass eine Komplettremission bei Patientinnen mit hormonrezeptorpositivem/HER2-negativem Brustkrebs erreicht wird, Ärzte ermutigen würde, eine neoadjuvante Chemotherapie zu empfehlen.

Methoden Die Studie beruht auf eine Online-Umfrage, die an 493 Ärzte und Ärztinnen geschickt wurde. Alle angeschriebenen Ärzte und Ärztinnen waren entweder Mitglieder nationaler Richtlinien-Kommissionen bzw. Leiter von Brustkrebszentren, hatten bereits viele Patientinnen in klinische Studien rekrutiert oder waren niedergelassene Ärzte bzw. Ärztinnen. Die Teilnehmer wurden nach ihrer Einschätzung eines spezifischen Falles gefragt, wobei der Fall so dargestellt wurde, dass er Ähnlichkeit mit Patientinnen hatte, bei denen die Indikationsstellung für oder gegen Chemotherapie unklar ist.

Ergebnisse Insgesamt nahmen 113 (24,5%) der angeschriebenen Ärzte an der Umfrage teil. Davon hatten 96,5% mehr als 10 Jahre Berufserfahrung, und 94,7% waren Fachärzte. Von den Studienteilnehmern gaben 84,1% an, dass sie die pathologische Komplettremission bei der Entscheidungsfindung für oder gegen neoadjuvante Chemotherapie heranziehen würden. Was die Wahrscheinlichkeit eines pCR betrifft, gaben 2,7 bzw. 10,6% der Teilnehmer an, dass sie eine pCR-Rate von mindestens 5 bzw. 10% erwarteten, wohingegen 25,7% mit einer 20%iger Wahrscheinlichkeit und weitere 25,7% mit einer pCR-Rate von 30% zufrieden wären.

Schlussfolgerungen Die überwiegende Mehrzahl der Ärzte mit langjähriger Erfahrung würden die Einführung einer weiteren Methode als Unterstützungshilfe bei der Entscheidungsfindung, beispielsweise die Voraussage der pCR-Wahrscheinlichkeit, in der klinischen Praxis begrüßen. Ein Schwellenwert von rund 30% für die Wahrscheinlichkeit eines pCR scheint ein geeigneter Wert zu sein, um eine Unterscheidung zwischen verschiedenen Patientinnengruppen vorzunehmen.

Key words

breast cancer - pathological complete response (pCR) - neoadjuvant - chemotherapy

Schlüsselwörter

Brustkrebs - pathologische Komplettremission (pCR) - neoadjuvant - Chemotherapie

• References

• 1 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: 164-172
• 2 von Minckwitz G, Untch M, Blohmer JU. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30: 1796-1804
• 3 US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research. Guidance for Industry Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. 2014 Online: https://wwwfdagov/downloads/drugs/guidances/ucm305501pdf%202014 last access: 28.02.2018
• 4 Cortazar P, Geyer jr. CE. Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 2015; 22: 1441-1446
• 5 European Medicines Agency. The role of the pathological Complete Response as an endpoint in neoadjuvant breast cancer studies (2014). Online: http://wwwemaeuropaeu/docs/en_GB/document_library/Scientific_guideline/2014/04/WC500165781pdf last access: 28.02.2018
• 6 Fasching PA, Heusinger K, Haeberle L. et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011; 11: 486
• 7 Taran FA, Schneeweiss A, Lux MP. et al. Update Breast Cancer 2018 (Part 1) – Primary Breast Cancer and Biomarkers. Geburtsh Frauenheilk 2018; 78: 237-245
• 8 Lux MP, Janni W, Hartkopf AD. et al. Update Breast Cancer 2017 – Implementation of Novel Therapies. Geburtsh Frauenheilk 2017; 77: 1281-1290
• 9 Untch M, Huober J, Jackisch C. et al. Initial Treatment of Patients with Primary Breast Cancer: Evidence, Controversies, Consensus: Spectrum of Opinion of German Specialists at the 15th International St. Gallen Breast Cancer Conference (Vienna 2017). Geburtsh Frauenheilk 2017; 77: 633-644
• 10 Schmidt M, Fasching PA, Beckmann MW. et al. Biomarkers in Breast Cancer – An Update. Geburtsh Frauenheilk 2012; 72: 819-832
• 11 Sestak I, Buus R, Cuzick J. et al. Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2018; 4: 545-553
• 12 Cardoso F, vanʼt Veer LJ, Bogaerts J. et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016; 375: 717-729
• 13 Sparano JA, Gray RJ, Makower DF. et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014
• 14 Sparano JA, Gray RJ, Makower DF. et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018; DOI: 10.1056/NEJMoa1804710.
• 15 Untch M, Fasching PA, Konecny GE. et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011; 29: 3351-3357
• 16 Huober J, von Minckwitz G, Denkert C. et al. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 2010; 124: 133-140
• 17 von Minckwitz G, Blohmer JU, Raab G. et al. In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study. Ann Oncol 2005; 16: 56-63
• 18 Lips EH, Mulder L, de Ronde JJ. et al. Breast cancer subtyping by immunohistochemistry and histological grade outperforms breast cancer intrinsic subtypes in predicting neoadjuvant chemotherapy response. Breast Cancer Res Treat 2013; 140: 63-71
• 19 Kim KI, Lee KH, Kim TR. et al. Ki-67 as a predictor of response to neoadjuvant chemotherapy in breast cancer patients. J Breast Cancer 2014; 17: 40-46
• 20 Goldhirsch A, Wood WC, Gelber RD. et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003; 21: 3357-3365
• 21 Goldhirsch A, Glick JH, Gelber RD. et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16: 1569-1583
• 22 Hammond ME, Hayes DF, Wolff AC. Clinical Notice for American Society of Clinical Oncology-College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol 2011; 29: e458
• 23 Goldhirsch A, Ingle JN, Gelber RD. et al. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 2009; 20: 1319-1329
• 24 Gass P, Fasching PA, Fehm T. et al. Factors Influencing Decision-Making for or against Adjuvant and Neoadjuvant Chemotherapy in Postmenopausal Hormone Receptor-Positive Breast Cancer Patients in the EvAluate-TM Study. Breast Care (Basel) 2016; 11: 315-322
• 25 Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol 2018; 19: 27-39
• 26 Paluch-Shimon S, Friedman E, Berger R. et al. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 2016; 157: 157-165
• 27 Fasching PA, Loibl S, Hu C. et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study. J Clin Oncol 2018; DOI: 10.1200/JCO.2017.77.2285.
• 28 Wunderle M, Gass P, Haberle L. et al. BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat 2018; DOI: 10.1007/s10549-018-4797-8.
• 29 Hahnen E, Lederer B, Hauke J. et al. Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol 2017; 3: 1378-1385
• 30 Schneeweiss A, Jackisch C, Schmatloch S. et al. Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline/cyclophosphamide for patients with early breast cancer-GBG69. Cancer Research 2018; DOI: 10.1158/1538-7445.SABCS17-GS3-05.
• 31 Tamirisa NP, Vernia H, Thomas SM. et al. The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 587
• 32 Buus R, Sestak I, Kronenwett R. et al. Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy. J Natl Cancer Inst 2016; DOI: 10.1093/jnci/djw149.
• 33 Cuzick J, Dowsett M, Pineda S. et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 2011; 29: 4273-4278
• 34 Dowsett M, Sestak I, Lopez-Knowles E. et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013; 31: 2783-2790
• 35 Ravdin PM, Siminoff LA, Davis GJ. et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001; 19: 980-991
• 36 Wishart GC, Bajdik CD, Dicks E. et al. PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2. Br J Cancer 2012; 107: 800-807
• 37 Thiel FC, Schrauder MG, Fasching PA. et al. Shared decision-making in breast cancer: discrepancy between the treatment efficacy required by patients and by physicians. Breast Cancer Res Treat 2012; 135: 811-820
• 38 Lux MP, Bayer CM, Loehberg CR. et al. Shared decision-making in metastatic breast cancer: discrepancy between the expected prolongation of life and treatment efficacy between patients and physicians, and influencing factors. Breast Cancer Res Treat 2013; 139: 429-440