St Gallen International Consensus Guidelines in early breast cancer: experts to prevent patients’ overtreatment and breaking the bank?

In this issue of Annals, Burstein et al. [1.Burstein H.J. Curigliano G. Loibl S. et al.Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019.Ann Oncol. 2019; 30: 1541-1557Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar] report the conclusions reached by a panel of experts from 23 countries from the 16th St Gallen International Breast Conference, focusing on therapy recommendation and treatment optimization for early breast cancer. We applaud the authors for being able to reach consensus with such contextual differences from different countries and with the added challenge that these guidelines provide advice to clinicians for their routine practice. Breast cancer remains one of the most common cancers worldwide [2.Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (31890) Google Scholar]. However, differences in mortality among countries reflect uneven social, economic and public health investments that particularly affect the epidemiology and the curability of early-stage disease. During the last decades, a major international effort has been made to first improve the management of cancers and then optimize it according to prognostic and predictive criteria that are increasingly better defined. These rapid advances require the updating of knowledge and the prioritization of therapeutic strategies, which is the goal of the guidelines already provided by international and national societies like ESMO [3.Cardoso F. Kyriakides S. Ohno S. et al.Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 1194-1220Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar], ASCO [4.Andre F. Ismaila N. Henry N.L. et al.Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update—integration of results from TAILORx.J Clin Oncol. 2019; 37: 1956-1964Crossref PubMed Scopus (69) Google Scholar, 5.Henry N.L. Somerfield M.R. Abramson V.G. et al.Role of patient and disease factors in adjuvant systemic therapy decision making for early-stage, operable breast cancer: update of the ASCO Endorsement of the Cancer Care Ontario Guideline.J Clin Oncol. 2019; 37: 1965-1977Crossref PubMed Scopus (21) Google Scholar] or NCCN [6.Goetz M.P. Gradishar W.J. Anderson B.O. et al.NCCN Guidelines Insights: breast cancer, version 3.J Natl Compr Canc Netw. 2019; 17: 118-126Crossref PubMed Scopus (87) Google Scholar]. However, making decisions on individual patients might be one of the most difficult situations for oncologists. This is why expertise and shared decision-making with patients are the criteria that turn guidelines into practice and fully justify expert meetings like St Gallen. Umberto Veronesi summed this up by saying that we were moving from the maximum tolerable treatments to the minimum effective treatments [7.Veronesi U. Stafyla V. Luini A. Veronesi P. Breast cancer: from “maximum tolerable” to “minimum effective”.Front Oncol. 2012; 2: 125Crossref PubMed Google Scholar]. The conclusions from the 2019 St Gallen panelists clearly illustrate this. On one hand, minimum effective treatments are becoming the new reference with the use prognostic and predictive prospectively validated genomic assays for determining whether to recommend or not adjuvant chemotherapy in patients with HR+/HER2−, T1-T2N0, T3 N0 and TxN1 (one to three positive LN) tumors [8.Sparano J.A. Gray R.J. Makower D.F. et al.Prospective validation of a 21-gene expression assay in breast cancer.N Engl J Med. 2015; 373: 2005-2014Crossref PubMed Scopus (765) Google Scholar, 9.Sparano J.A. Gray R.J. Makower D.F. et al.Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer.N Engl J Med. 2018; 379: 111-121Crossref PubMed Scopus (745) Google Scholar, 10.Nitz U. Gluz O. Christgen M. et al.Correction to: reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.Breast Cancer Res Treat. 2019; 175: 265-266Crossref PubMed Scopus (2) Google Scholar, 11.Cardoso F. van't Veer L.J. Bogaerts J. et al.70-Gene signature as an aid to treatment decisions in early-stage breast cancer.N Engl J Med. 2016; 375: 717-729Crossref PubMed Scopus (800) Google Scholar]. In addition, the de-escalation of axillary dissection, even in the neoadjuvant approach [12.Giuliano A.E. Ballman K.V. McCall L. et al.Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial.JAMA. 2017; 318: 918-926Crossref PubMed Scopus (456) Google Scholar, 13.Donker M. van Tienhoven G. Straver M.E. et al.Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.Lancet Oncol. 2014; 15: 1303-1310Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar], and the use of hypofractionated [14.Whelan T.J. Pignol J.P. Levine M.N. et al.Long-term results of hypofractionated 696 radiation therapy for breast cancer.N Engl J Med. 2010; 362: 513-520Crossref PubMed Scopus (1077) Google Scholar] and accelerated breast irradiation treatment schedules are recommended [15.Whelan T. Julian J. Levine M. et al.Abstract GS4-03: RAPID: a randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiotherapy (3D-699 CRT).Cancer Res. 2019; 79 (GS4-03)Google Scholar, 16.Vicini F.A. Cecchini R.S. White J.R. et al.Abstract GS4-04: primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer.Cancer Res. 2019; 79 (GS4.04)Google Scholar]. On the other hand, selecting treatment escalation or modulation using the evaluation of residual disease after neoadjuvant treatment seems to be the actual best approach for high-risk HER2-positive and triple-negative breast cancer (TNBC) with the recommendation of (neo)adjuvant pertuzumab for high-risk HER2+ tumors [17.von Minckwitz G. Procter M. de Azambuja E. et al.Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med. 2017; 377: 122-131Crossref PubMed Scopus (588) Google Scholar] or trastuzumab-emtansine in the presence of residual disease after neoadjuvant trastuzumab treatment [18.von Minckwitz G. Huang C.S. Mano M.S. et al.Trastuzumab emtansine for residual invasive HER2-positive breast cancer.N Engl J Med. 2019; 380: 617-628Crossref PubMed Scopus (580) Google Scholar] as well as adjuvant capecitabine in TNBC patients with residual disease after neoadjuvant chemotherapy [19.Masuda N. Lee S.J. Ohtani S. et al.Adjuvant capecitabine for breast cancer after preoperative chemotherapy.N Engl J Med. 2017; 376: 2147-2159Crossref PubMed Scopus (472) Google Scholar]. While there is no debate about the clinical gain associated with these proposals, there is still the question of their feasibility based on the cost of these strategies, especially in countries with limited resources and investment in their public healthcare system. Moreover, how health authorities interpret these data differs not only from their evaluation by clinicians but also varies depending on individual countries. The key message from St Gallen 2019 is that risks and benefits must be disclosed and discussed with patients; the potential downside is perhaps cost. Expenses in health care have been rising in Western European countries; by 2016, they represented ∼11% of their gross domestic product in Germany, UK and France, with costs up to 338 billion euros in Germany [20.World Health OrganisationGlobal health expenditure database.http://apps.who.int/nha/databaseGoogle Scholar]. Increases in the price for new drugs, reaching a peak in 2017, led to the European Commission to release an expert panel’s recommendations on high drug prices [21.European Commission: Innovative Payment Models for High-Cost Innovative Medicines. 2019; https://ec.europa.eu/health/expert_panel/sites/expertpanel/files/docsdir/opinion_innovative_medicines_en.pdfGoogle Scholar] to examine new ways of paying for new and costly medicines to find solutions for their ever-increasing prices. This is particularly important in countries with public social insurance trying to offer treatments equally for all patients. These propositions were echoed in the recommendations of the UN High-Level Panel on Access to Medicines and Innovation [22.The United Nations secretary-general's high-level panel on access to medicines report. 2019; http://www.unsgaccessmeds.org/final-reportGoogle Scholar] and the Lancet Commission on Essential Medicines Policies [23.Wirtz V.J. Hogerzeil H.V. Gray A.L. et al.Essential medicines for universal health coverage.Lancet. 2017; 389: 403-476Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar] as well as numerous reports by the World Health Organization [24.World Health OrganisationPublic health, innovation, intellectual property and trade.https://www.who.int/phi/cewg_report/en/Google Scholar]. Two recommendations from the St Gallen 2019 consensus could illustrate the economical implication of these guidelines. The economic impact of the use of genomic signatures in early breast cancer is still not clear despite numerous publications with high variability among their conclusions, likely due to methodologic biases (reviewed in [25.Wang S.Y. Dang W. Richman I. et al.Cost-effectiveness analyses of the 21-gene assay in breast cancer: systematic review and critical appraisal.J Clin Oncol. 2018; 36: 1619-1627Crossref PubMed Scopus (30) Google Scholar]). A recent study, retrospectively assessing the real-world impact of genomic testing with respect to chemotherapy costs in the USA using the SEER-Medicare database, reported than in a review of around 30 000 patients, genomic testing was able to lower costs only in clinically high-risk patients (i.e. node-positive). In contrast, no impact was observed when genomic testing was carried out in clinically low- or intermediate-risk patients [26.Dinan M.A. Wilson L.E. Reed S.D. Chemotherapy costs and 21-gene recurrence score genomic testing among medicare beneficiaries with early-stage breast cancer, 2005 to 2011.J Natl Compr Canc Netw. 2019; 17: 245-254Crossref PubMed Scopus (5) Google Scholar]. Interestingly, the National Institute for Health and Care Excellence (NICE) in the UK [27.National Institute For Health And Care ExcellenceTumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer.https://www.nice.org.uk/guidance/dg34/chapter/1-RecommendationsGoogle Scholar] have approved the use of Endopredict®, Oncotype DX® Breast recurrence score and Prosigna® (although not Mammaprint®) for ER+/HER2− LN− early breast cancer if they have an intermediate risk of recurrence using a validated clinical risk assessment tool (like PREDICT UK). Whereas the HAS (Haut Authorité Santé) in France do not currently recommend routine use of a genomic signature, they approve temporary and conditional funding only in the specific case of pT1c-2 N0 grade II HR+/HER2− early breast cancer [28.Haute Authorité de SantéClinical utility of genomic signatures in early-stage breast cancer - INAHTA Brief.https://www.has-sante.fr/jcms/c_2748998/en/clinical-utility-of-genomic-signatures-in-early-stage-breastcancer-inahta-briefGoogle Scholar]. The German Federal Joint Committee (G-BA) exclusively reimburse Oncotype DX® [29.German Federal Joint Committee (G-BA)Richtlinie Methoden vertragsärztliche Versorgung: Biomarkerbasierte Tests zur Entscheidung für oder gegen eine adjuvante systemische Chemotherapie beim primären Mammakarzinom.https://www.g-ba.de/beschluesse/3809/Google Scholar]. For patients with HER2+ breast cancer, studies analyzing the cost−benefit of adding pertuzumab in adjuvant treatment are even scarcer. In a recent report analyzing the use of adjuvant pertuzumab in the USA, the projected mean costs were higher with pertuzumab ($361 234) compared with trastuzumab alone ($294 588) but the projected mean outcomes were better with pertuzumab in the LN-positive population with 17.97 life-year (LYs) and 14.98 quality-adjusted life-year (QALYs) versus 17.11 LYs and 14.22 QALYs for trastuzumab alone [30.Garrison Jr, L.P. Babigumira J. Tournier C. et al.Cost-effectiveness analysis of pertuzumab with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy in the adjuvant treatment of HER2-positive breast cancer in the United States.Value Health. 2019; 22: 408-415Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Moreover, NICE initially refused any reimbursement for pertuzumab in the adjuvant setting in their first evaluation in June 2018 because the cost-effectiveness estimates were interpreted by the committee as implausible [31.National Institute For Health And Care ExcellenceAppraisal consultation document Pertuzumab for adjuvant treatment of early HER2-positive breast cancer.https://www.nice.org.uk/guidance/ta569/documents/appraisal-consultation-documentGoogle Scholar]. Subsequently, after discussions between NICE and the drug company including (among others) a revised economic model based on treatment only in LN-positive patients, more conservative estimates of how long the treatment benefit with pertuzumab will last and decreased expenses with the introduction of trastuzumab biosimilars, NICE finally approved the use of pertuzumab in this population [32.National Institute For Health And Care ExcellencePertuzumab for adjuvant treatment of HER2-positive early stage breast cancer.https://www.nice.org.uk/guidance/TA569/chapter/1-RecommendationsGoogle Scholar]. On the other hand, these same data have been interpreted by the French HAS as still insufficient to justify reimbursement of this drug in early breast cancer, even in the neoadjuvant setting [33.Haute Authorité de SantéPerjeta. Avis sur les médicaments. Extension d’indication.https://www.has-sante.fr/jcms/p_3067188/fr/perjetaGoogle Scholar]. There is certainly need for a stronger collaboration to approach the views and the expectancies from oncologists (and patients) to those from the health authorities (and within them) to provide rapid (and equal) access to new therapies to prevent these guidelines become more of a ‘wish list’ than a reality. This might get worse with the next consensus guidelines in 2 years’ time when results from neoadjuvant immunotherapy use in TNBC and the adjuvant use of CDK4/6 inhibitors in HR+ breast cancer patients become available. We hope these initiatives might serve not only to standardize patients’ care but also to put pressure on health authorities for more rapid approval of new treatments for patients’ benefit and also on drug companies to better define the value of innovative treatments. None declared.

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