The guideline development group (GDG) prioritized about 90 clinical questions (Schünemann 2020). Recommendations were informed by systematic reviews and GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision (EtD) frameworks were used to structure the process and minimize the influence of competing interests by enhancing transparency (Schünemann 2019). The use of the EtDs allow for adoption, adaptation or creation of new contextual recommendations (Schünemann - Adolopment). among these recommendations, one regarded the use of multigene tests to guide decisions about chemotherapy in women with Hormone receptor (HoR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer.
HoR-positive (i.e. oestrogen and /or progesterone receptor positive), HER-2 negative breast cancer represents about 70% of those diagnosed in western countries (Howlader 2014). At diagnosis, around 60% of this type of cancer has not spread to llymph nodes, and approximately 15% of these women will develop a recurrence within 10 years if treated with adjuvant endocrine therapy alone (EBCTCG 2005, 2011). The risk of recurrence could be reduced by adding chemotherapy (EBCTCG 2011). However, given the relatively low risk of recurrence and the partial effectiveness of chemotherapy in these women, most would be over-treated if all received chemotherapy.
In the last 15 years, different tests try to stratify patients with early breast cancer into different recurrence risk groups by analysing the activity of various genes. Although they use diverse techniques (RT-PCR, microarray, and others) and diverse target gene combinations, they all focus on genes involved in cell proliferation. Some tests, 12-gene molecular score (12-MS) and the PAM50 risk of recurrence score (PAM50-RORS), provide additional information to clinical-pathological features. Based on the MINDACT trial6 results, the application of the 70-gene signature (70-GS) also takes into account clinical prognostic characteristics, while the 21-gene recurrence score (21-RS) has been proposed to substitute clinical risk-based treatment decisions.
The systematic review supporting the ECIBC recommendation retrieved 5 eligible studies (2 marker-based design randomized controlled trials (RCTs), two treatment interaction design RCTs and 1 pooled individual data analysis from observational studies). As no eligible studies on PAM50-RORS or 12-MS were identified, due topredictive search strategy used,the GDG did not formulate recommendations for them. Treatment interaction analyses of previous RCTs, as well the pooled analysis of observational studies, had limited statistical power, while marker-based RCTs were designed in a way that did neither allow evaluation of the exact impact on outcomes of using multigene tests for deciding to use chemotherapy, nor determining which women would most benefit from testing. Therefore, the GDG created a simple and transparent model considering the outcomes of different scenarios in which decisions about chemotherapy were taken: 1) according to clinical variables only; 2) multigene test results only; or 3) sequential use of clinical characteristics and, in a subgroup, multigene test results.
Based on the evidence about health benefits and harms, women’s values, costs, acceptability and feasibility and considerations on impact on equity, summarized in the EtD, the ECIBC GDG suggests the use of the 21-RS for lymph node negative women (conditional recommendation, very low certainty of evidence). In doing so, the ECIBC GDG recognized that, in addition to greater health benefits than harms, the desirable consequences outweigh the undesirable consequences in women at high risk of recurrence based on clinical characteristics. Similarly, the ECIBC GDG suggests the use of the 70-GS for women at high clinical risk (conditional recommendation, low certainty of evidence), and recommends not using 70-GS in women at low clinical risk (strong recommendation, low certainty of evidence).
- European Cancer Information System From https://ecis.jrc.ec.europa.eu, accessed on 20/July/2019. 2018.
- Schünemann HJ, Lerda D, Dimitrova N, et al. Methods for Development of the European Commission Initiative on Breast Cancer Guidelines: Recommendations in the Era of Guideline Transparency. Ann Intern Med. 2019 Aug 20;171(4):273-280. doi: 10.7326/M18-3445. Epub 2019 Jul 23. PMID: 31330534.
- Schünemann HJ, Lerda D, Quinn C, et al. Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines. Ann Intern Med. 2020 Jan 7;172(1):46-56. doi: 10.7326/M19-2125. Epub 2019 Nov 26. PMID: 31766052.
- Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 28:106, 2014.
- Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687-717, 2005.
- Early Breast Cancer Trialists' Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378:771-84, 2011.
- Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 375:717-29, 2016.
- Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 379:111-121, 2018.
- Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726-34, 2006.
- Albain KS, Barlow WE, Shak S, et al. Breast Cancer Intergroup of North America. Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in a Randomized Trial of Chemotherapy for Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer. Lancet Oncol 11:55-65, 2010.
- Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 120:655-61, 2010.