To compare RCB (Residual Cancer Burden) and Neo-Bioscore in terms of prognostic performance and see if adding pathological variables improve these scores.
We analysed 750 female patients with ...invasive breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) at Institut Curie between 2002 and 2012. Scores were compared in global population and by BC subtype using Akaike information criterion (AIC), C-Index (concordance index), calibration curves and after adding lymphovascular invasion (LVI) and pre-/post-NAC TILs levels.
RCB and Neo-Bioscore were significantly associated to disease-free and overall survival in global population and for triple-negative BC. RCB had the lowest AICs in every BC subtype, corresponding to a better prognostic performance. In global population, C-Index values were poor for RCB (0.66; CI 0.61-0.71) and fair for Neo-Bioscore (0.70; CI 0.65-0.75). Scores were well calibrated in global population, but RCB yielded better prognostic performances in each BC subtype. Concordance between the two scores was poor. Adding LVI and TILs improved the performance of both scores.
Although RCB and Neo-Bioscore had similar prognostic performances, RCB showed better performance in BC subtypes, especially in luminal and TNBC. By generating fewer prognostic categories, RCB enables an easier use in everyday clinical practice.
Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly
pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant ...chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to
status.
Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline
pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.
Among 1199 BC patients: 46 were
-deficient and 221
proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in
deficient BC (
0.001), and this association remained statistically significant only in the luminal BC subtype (
0.006). The interaction test between BC subtype and
status was nearly significant (
= 0.056). Pre and post-NAC TILs were not significantly different between
deficient and
proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in
deficient BC. Survival analysis were not different between
carriers and non-carriers.
mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC.
-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.
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)). 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. 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 (P.sub.interaction = 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. 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.
Abstract
Background
High levels of stromal tumor-infiltrating lymphocytes (sTIL) are associated with increased pathological complete response (pCR) rate and longer survival after neoadjuvant ...chemotherapy in triple-negative breast cancer (TNBC) patients. Here, we evaluated the value of sTIL in predicting pCR and explored prognosis in TNBC patients treated with neoadjuvant chemotherapy according to body mass index (BMI).
Methods
sTIL were scored centrally on pretreatment biopsies from 2 retrospective series of nonunderweight TNBC patients (n = 445). sTIL and BMI were considered as binary (sTIL: <30.0% vs ≥30.0%; BMI: lean vs overweight and obese) and continuous variables. Associations with pCR (ypT0/isN0) were assessed using logistic regression, and associations with event-free survival and overall survival were assessed using Cox regressions.
Results
236 (53.0%) patients were lean and 209 (47.0%) overweight and obese. pCR was achieved in 181 of 445 (41.7%) patients. Median sTIL was 11.0%, and 99 of 445 (22.2%) tumors had high sTIL. A statistically significant interaction between sTIL and BMI, considered as categorical or continuous variables, for predicting pCR was observed in the multivariable analysis (Pinteraction = .03 and .04, respectively). High sTIL were statistically significantly associated with pCR in lean (odds ratio OR = 4.24, 95% confidence interval CI = 2.10 to 8.56; P < .001) but not in heavier patients (OR = 1.48, 95% CI = 0.75 to 2.91; P = .26) in the multivariable analysis. High sTIL were further associated with increased event-free survival in lean (hazard ratio HR = 0.22, 95% CI = 0.08 to 0.62; P = .004) but not in heavier patients (HR = 0.53, 95% CI = 0.26 to 1.08; P = .08). Similar results were obtained for overall survival.
Conclusion
BMI is modifying the effect of sTIL on pCR and prognosis in TNBC patients treated with neoadjuvant chemotherapy.
Tobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response (pCR) rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocyte ...(TIL) levels and is associated with a better long-term survival outcome. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients. We retrospectively evaluated pre- and post-NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and according to BC subtype. Nine hundred and fifty-six BC patients with available smoking status information were included in our analysis (current smokers, n = 179 (18.7%); ever smokers, n = 154 (16.1%) and never smokers, n = 623 (65.2%)). Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor in any BC subtype group. With a median follow-up of 101.4 months, relapse-free survival (RFS) and overall survival (OS) were not significantly different by smoking status. We did not find any significant effect of tobacco use on pre- and post-NAC TILs nor response to NAC. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.
Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant ...chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2
+
BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.
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.
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.
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).
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.
National Cancer Institute at the US National Institutes of Health.
Breast cancer involves various types of tumors. The objective of this review was to provide a summary of the main methods currently available in clinical practice to characterize breast cancers at a ...molecular level and to discuss their prognostic and predictive values. Hormonal receptors expression and the HER2 status are prognostic markers and can also predict the response to targeted therapies. Their analysis through immunohistochemistry is systematical. Ki67 is an effective prognostic marker, but its reliability is debated because of its low reproducibility between laboratories and between pathologists. Commercial genomic signatures are all considered valid prognostic tools and may guide physicians to make therapeutic choices. These signatures are costly and should therefore be restricted to situations in which the use of chemotherapy remains equivocal.
Fish embryo models are widely used as screening tools to assess the efficacy and/or toxicity of chemicals. This assessment involves the analysis of embryo morphological abnormalities. In this ...article, we propose a multi-scale pipeline to allow automated classification of fish embryos (Medaka: Oryzias latipes) based on the presence or absence of spine malformations. The proposed pipeline relies on the acquisition of fish embryo 2D images, on feature extraction based on mathematical morphology operators and on machine learning classification. After image acquisition, segmentation tools are used to detect the embryo before analysing several morphological features. An approach based on machine learning is then applied to these features to automatically classify embryos according to the presence of axial malformations. We built and validated our learning model on 1459 images with a 10-fold cross-validation by comparison with the gold standard of 3D observations performed under a microscope by a trained operator. Our pipeline results in correct classification in 85% of the cases included in the database. This percentage is similar to the percentage of success of a trained human operator working on 2D images. The key benefit of our approach is the low computational cost of our image analysis pipeline, which guarantees optimal throughput analysis.
Display omitted
•An automated method to detect the presence or absence of spine malformations is fish embryos 2D images is proposed.•The method is based on features extraction due to mathematical morphology and on machine learning classification.•We assess the inter-expert subjectivity and the rate of information loss between microscope 3D observations and 2D images.•We achieve a success rate of 85% on 1459 images, which is similar to the one of a human operator working on 2D images.
PDF
