Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.

BACKGROUND: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. METHODS: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FINDINGS: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). INTERPRETATION: RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. FUNDING: National Cancer Institute at the US National Institutes of Health.

[How to improve the surgical trials quality in daily practice]. / Comment améliorer la qualité méthodologique et l'adoption en routine des résultats des essais chirurgicaux ?

Surgical studies have specific issues, such as quality assurance on procedures, standardization of techniques, surgeon effect, timing of randomization, blinding respect or choice of the reference arm. All these difficulties conducted to criticism many trials, and lack of results implementation. Indeed, adherence to methodological guidelines is often poor. Twelve recommendations were recently issued by the JAMA surgery revue for good practice in surgical studies to improve the quality of surgical trials in general and surgical oncology. We detail here the main issues of surgical trials in gynaecological oncology surgery, as well as possibilities of improvement for future studies.

Impact of the Area of Residence of Ovarian Cancer Patients on Overall Survival.

Survival disparities persist in ovarian cancer and may be linked to the environments in which patients live. The main objective of this study was to analyze the global impact of the area of residence of ovarian cancer patients on overall survival. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. We included all the patients with epithelial ovarian cancers diagnosed between 2010 and 2016. The areas of residence were analyzed by the hierarchical clustering of the principal components to group similar counties. A multivariable Cox proportional hazards model was then fitted to evaluate the independent effect of each predictor on overall survival. We included a total of 16,806 patients. The clustering algorithm assigned the 607 counties to four clusters, with cluster 1 being the most disadvantaged and cluster 4 having the highest socioeconomic status and best access to care. The area of residence cluster remained a statistically significant independent predictor of overall survival in the multivariable analysis. The patients living in cluster 1 had a risk of death more than 25% higher than that of the patients living in cluster 4. This study highlights the importance of considering the sociodemographic factors within the patient's area of residence when developing a care plan and follow-up.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial.

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS). Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response. Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence. Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery. Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR. Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS. Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS. Trial Registration: ClinicalTrials.gov Identifier NCT01042379.

Breast Magnetic Resonance Image Analysis for Surgeons Using Virtual Reality: A Comparative Study.

PURPOSE: The treatment of breast cancer, the leading cause of cancer and cancer mortality among women worldwide, is mainly on the basis of surgery. In this study, we describe the use of a medical image visualization tool on the basis of virtual reality (VR), entitled DIVA, in the context of breast cancer tumor localization among surgeons. The aim of this study was to evaluate the speed and accuracy of surgeons using DIVA for medical image analysis of breast magnetic resonance image (MRI) scans relative to standard image slice-based visualization tools. MATERIALS AND METHODS: In our study, residents and practicing surgeons used two breast MRI reading modalities: the common slice-based radiology interface and the DIVA system in its VR mode. Metrics measured were compared in relation to postoperative anatomical-pathologic reports. RESULTS: Eighteen breast surgeons from the Institut Curie performed all the analysis presented. The MRI analysis time was significantly lower with the DIVA system than with the slice-based visualization for residents, practitioners, and subsequently the entire group (P < .001). The accuracy of determination of which breast contained the lesion significantly increased with DIVA for residents (P = .003) and practitioners (P = .04). There was little difference between the DIVA and slice-based visualization for the determination of the number of lesions. The accuracy of quadrant determination was significantly improved by DIVA for practicing surgeons (P = .01) but not significantly for residents (P = .49). CONCLUSION: This study indicates that the VR visualization of medical images systematically improves surgeons' analysis of preoperative breast MRI scans across several different metrics irrespective of surgeon seniority.

Adjuvant chemotherapy for breast cancer after preoperative chemotherapy: A propensity score matched analysis.

Although identified to be at a higher risk of relapse, no consensus exists on the treatment of breast cancer (BC) patients with no pathological complete response after neoadjuvant chemotherapy (NAC). The benefit of adjuvant chemotherapy (ADJ) in this context has scarcely been studied. We evaluated the benefit of administrating adjuvant chemotherapy in a real life cohort of BC patients with invasive residual disease after NAC. 1199 female BC patients with T1-3NxM0 invasive tumors receiving NAC at Institut Curie from 2002 to 2012 were included in the analysis. 1061 had been treated by NAC only, whereas 138 had received additional adjuvant chemotherapy after NAC (FUN protocol: 5-FU-Vinorelbine). We compared disease-free survival (DFS) and overall survival (OS) rates between patients having received NAC only and patients having received NAC+ADJ. To ensure comparability of our populations, we used a propensity score (which defines the probability of treatment assignment conditional on observed baseline covariates) and matched each patient having received NAC+ADJ (n = 138) with a patient having received NAC only that had a similar propensity score value. Before propensity score matching, DFS and OS rates were significantly lower in the NAC+ADJ group compared to NAC only, after 3 years, 5 years and 10 years follow-up (p<0.01). After one-to-one PS matching, the two groups were comparable (n = 276 patients; 138 patients in each group). No significant difference was found regarding DFS (p = 0.87) or OS (p = 0.59) rates, neither in global population, nor by pathological subtype. Although our study did not show a benefit of administrating ADJ with FUN protocol (5-Florouracil- Vinorelbine) to BC patients with residual disease after NAC, further studies are warranted to determine the impact of other adjuvant regimens. Thereby, patients with little chance of responding to particular regimens could avoid the toxicity of futile therapy, and be study participants in evaluations of novel treatment strategies.

Prognostic value of the Residual Cancer Burden index according to breast cancer subtype: Validation on a cohort of BC patients treated by neoadjuvant chemotherapy.

INTRODUCTION: The Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)). METHODS: We retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes. RESULTS: 717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR = 3.25 CI [2.1-5.1] p<0.001; RCB-III versus RCB-0: HR = 5.6 CI [3.5-8.9] p<0.001). The prognostic impact of RCB index was significant for TNBC and HER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8-62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months. CONCLUSION: RCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies.

Text Mining in Electronic Medical Records Enables Quick and Efficient Identification of Pregnancy Cases Occurring After Breast Cancer.

PURPOSE: To apply text mining (TM) technology on electronic medical records (EMRs) of patients with breast cancer (BC) to retrieve the occurrence of a pregnancy after BC diagnosis and compare its performance to manual curation. MATERIALS AND METHODS: The training cohort (Cohort A) comprised 344 patients with BC age ≤ 40 years old treated at Institut Curie between 2005 and 2007. Manual curation consisted in manually reviewing each EMR to retrieve pregnancies. TM consisted of first applying a keyword filter ("accouch*" or "enceinte," French terms for "deliver*" and "pregnant," respectively) to select a subset of EMRs, and, second, checking manually EMRs to confirm the pregnancy. Then, we applied our TM algorithm on an independent cohort of patients with BC treated between 2008 and 2012 (Cohort B). RESULTS: In Cohort A, 36 pregnancies were identified among 344 patients (10.5%; 2,829 person-years of EMR). Thirty were identified by manual review versus 35 by TM. TM resulted in a lower percentage of manual checking (26.7% v 100%, respectively) and substantial time gains (time to identify a pregnancy: 13 minutes for TM v 244 minutes for manual curation, respectively). Presence of any of the two TM filters showed excellent sensitivity (97%) and negative predictive value (100%). In Cohort B, 67 pregnancies were identified among 1,226 patients (5.5%; 7,349 person-years of EMR). Similarly, for Cohort B, TM spared 904 (73.7%) EMRs from manual review and quickly generated a cohort of 67 pregnancies after BC. Incidence rate of pregnancy after BC was 0.01 pregnancy per person-year of EMR in both cohorts. CONCLUSION: TM is highly efficient to quickly identify rare events and is a promising tool to improve rapidity, efficiency, and costs of medical research.