Pathological grade-independent prediction of chemosensitivity by CINSARC should rehabilitate adjuvant chemotherapy in soft tissue sarcomas of any grade

In a recent issue of Annals of Oncology [1.Valentin T. Lesluyes T. Le Guellec S. Chibon F. Chemotherapy in localized soft tissue sarcoma: will we soon have to treat grade 1 tumours? Update on CINSARC performances.Ann Oncol. 2019; 30: 153-155Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar], Valentin et al. confirmed the prognostic value of the CINSARC signature [2.Chibon F. Lagarde P. Salas S. et al.Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity.Nat Med. 2010; 16: 781-787Crossref PubMed Scopus (322) Google Scholar] in a pooled series of 600 early-stage soft tissue sarcomas (STS). ‘High-risk’ patients displayed shorter metastasis-free survival than ‘low-risk’ patients in each pathological (Federation Francaise des Centres de Lutte Contre le Cancer) FNCLCC grade, notably in grade 1, leading to the provocative conclusion that adjuvant chemotherapy might become a standard treatment for patients with grade 1 ‘high-risk’ STS. Fifty percent of adult patients operated for an early-stage STS die of metastatic relapse. The use of adjuvant chemotherapy, based on an anthracycline/ifosfamide combination, remains controversial [3.Casali P.G. Abecassis N. Bauer S. et al.Soft tissue and visceral sarcomas: eSMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv51-iv67Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar]. The absence of accurate prognostic features and predictors of response to chemotherapy explain in part the difficulty to prove its eventual benefit. Pathological grade, the best prognostic factor of STS, is also predictive for response to chemotherapy but remains imperfect to solve STS heterogeneity. Thus, CINSARC, which outperforms pathological grade in prognostic term, could revive the interest of adjuvant chemotherapy in STS. However, it must also be determined whether the CINSARC ‘high-risk’ patients, potential candidate for chemotherapy, are more sensitive to chemotherapy than ‘low-risk’ patients, notably in each grade category including the classically chemoresistant grade 1. No STS series in the literature combines gene expression data and response to chemotherapy. Thus, to start addressing this question and because CINSARC has prognostic value in breast cancer (BC) [4.Lesluyes T. Delespaul L. Coindre J.M. Chibon F. The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms.Sci Rep. 2017; 7: 5480Crossref PubMed Scopus (23) Google Scholar], we studied the relationship between CINSARC and response to chemotherapy in our expression database of 1203 BC samples treated with neo-adjuvant chemotherapy based on anthracycline and cyclophosphamide, an alkylating agent close to ifosfamide, followed by mastectomy and assessment of the pathological response [5.Bertucci F. Finetti P. Simeone I. et al.The Immunologic Constant of Rejection classification (ICR) refines the prognostic value of conventional prognostic signatures in breast cancer.Br J Cancer. 2018; 119: 1383-1391Crossref PubMed Scopus (33) Google Scholar]. Pathological complete response (pCR) was defined as no evidence of cancer cell within breast and axillary lymph nodes. Pathological grade was associated with pCR achievement (P = 8.83E−17), with an odds ratio (OR) of 3.3 [95% confidence interval (CI) 0.99–11] between grades 2 (12% pCR) and 1 (4% pCR), and 12 (95% CI 3.6–39) between grades 3 (31% pCR) and 1 (Table 1). Similarly, CINSARC ‘high-risk’ patients (N = 580) exhibited more pCR than ‘low-risk’ patients (N = 623; OR = 2.7, 95% CI 2.05–3.66, P = 5.68E−13), suggesting higher sensitivity to chemotherapy. Importantly, CINSARC predicted the response to chemotherapy independently from the pathological grade (P = 5.77E−06): indeed in each category, the pCR rate was higher in the ‘high-risk’ class than in the ‘low-risk’ class (Fisher’s exact test) not only in grades 2 (20% versus 8%, respectively, P = 2.31E−03) and 3 (36% versus 24%, respectively, P = 2.27E−03) but also in grade 1, with 40% versus 0%, respectively (P = 7.26E−03). Obviously, such predictive value of CINSARC must be confirmed in STS. But yet, given the similarities between pathological grade in BC and STS and between chemotherapy regimens, our results give additional support to the idea that adjuvant chemotherapy might be beneficial in all patients with CINSARC ‘high-risk’ STS, regardless of the pathological grade. Pending the results of future CINSARC-based prospective trials of the French Sarcoma Group, such hypothesis can be tested retrospectively for the grade 2/3 STS enrolled in the previous randomized prospective trials of adjuvant chemotherapy [6.Le Cesne A. Ouali M. Leahy M.G. et al.Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials.Ann Oncol. 2014; 25: 2425-2432Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. But since these later did not enroll grades 1, only one of the future prospective trials will provide opportunity to answer this provocative question in this category.Table 1Uni- and multivariate analyses for pathological complete response to neoadjuvant chemotherapyUnivariateMultivariatenOR (95% CI)P value*nOR (95% CI)P valueaAnalysis of variance.Pathological grade 2 versus 110973.3 (0.99–11)8.83E−1710972.9 (0.85–9.60)8.83E−17 3 versus 1109712 (3.60–39)10978.0 (2.40–27.0)CINSARC class, ‘high risk’ versus ‘low risk’12032.7 (2.2–3.5)5.68E−1310972.0 (1.60–2.70)5.77E−06OR, odds ratio.a Analysis of variance. Open table in a new tab OR, odds ratio. This work was supported by Inserm, Institut Paoli-Calmettes, and grants from Ligue Nationale Contre le Cancer (EL2016.LNCC/DaB) and Fondation Groupe EDF (no grant number applies).