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.
We studied the relationship between time to ipsilateral breast tumor recurrence (IBTR) and distant metastasis-free survival (DMFS) in patients with breast cancer treated by neoadjuvant chemotherapy ...(NAC).
Between 2002 and 2012, 1199 patients with primary breast cancer were treated with NAC. Clinical, radiological and pathological data were retrieved from medical records. Multivariate analysis was performed with the random survival forest (RSF) method, to evaluate the relationship between time to local recurrence and DMFS.
Time to IBTR, local recurrence and molecular subtype were the factors most strongly associated with DMFS. In the total population, DMFS increased linearly with recurrence time, up to 50 months. For recurrences after 50 months, DMFS was similar for all times to recurrence. Considering molecular subtypes separately, the threshold was similar for the TNBC subtype (50 months), but appeared to occur later for the luminal and HER2-positive subtypes (75 months).
A threshold of 50 months seems to differentiate between early and late recurrences and could be used to guide the medical management of local breast tumour recurrences.
Recent retrospective studies suggest potential large patient’s benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, ...neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex.
A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied.
361 patients were investigated (80% non-small cell lung cancer patients, mean SD age: 63 11 years, 39% of women, 83% PS0–1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 1.17-2.1, p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 1.10-2.12, p = 0.011; PS2–3 patients, HR=0.50 0.25–0.97, p = 0.042). Morning PS0–1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1–3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 12:48–14:23, and in early morning was equal to 4.8 (2.3-10.1, p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4).
Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0–1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.
•Early morning Immune Checkpoint Blockade (ICB) was associated with increased survival and response.•All ICB timing differences were observed in patients with PS0-1 but not with PS2-3.•Best vs Worst ICB timing resulted in a-4.8-fold difference in patient mortality risk.•ICB toxicities were highly timing-dependent in women and not in men.
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.
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.
Purpose
Few studies evaluated the prognostic value of the presence of lymphovascular invasion (LVI) after neoadjuvant chemotherapy (NAC) for breast cancer (BC).
Methods
The association between LVI ...and survival was evaluated in a cohort of BC patients treated by NAC between 2002 and 2011. Five post-NAC prognostic scores (ypAJCC, RCB, CPS, CPS + EG and Neo-Bioscore) were evaluated and compared with or without the addition of LVI.
Results
Out of 1033 tumors, LVI was present on surgical specimens in 29.2% and absent in 70.8% of the cases. Post-NAC LVI was associated with impaired disease-free survival (DFS) (HR 2.54; 95% CI 1.96–3.31;
P
< 0.001), and the magnitude of this effect depended on BC subtype (
P
interaction
= 0.003), (luminal BC: HR 1.83;
P
= 0.003; triple negative BC: HR 3.73;
P
< 0.001;
HER2
-positive BC: HR 6.21;
P
< 0.001). Post-NAC LVI was an independent predictor of local relapse, distant metastasis, and overall survival; and increased the accuracy of all five post-NAC prognostic scoring systems.
Conclusions
Post-NAC LVI is a strong independent prognostic factor that: (i) should be systematically reported in pathology reports; (ii) should be used as stratification factor after NAC to propose inclusion in second-line trials or adjuvant treatment; (iii) should be included in post-NAC scoring systems.
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.
Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors ...for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment.
We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed.
pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12).
Major pCR and DFS gains in HER2-positive BC were observed since 'trastuzumab' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.
Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a ...selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications. In the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables. In conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.
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