Biomarker Dynamics and Long-Term Treatment Outcomes in Breast Cancer Patients with Residual Cancer Burden after Neoadjuvant Therapy.
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ABSTRACT:
SUBMITTER: Holanek M
PROVIDER: S-EPMC9318288 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-Pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists. The size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-Pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among pathologists was 0.931 (95% confidence interval (CI) 0.908-0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% CI 0.539-0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient=0.980; 95% CI 0.954-0.992), than the primary component (overall concordance correlation coefficient=0.795; 95% CI 0.716-0.853). At a median follow-up of 12 years residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient=0.995; 95% CI 0.989-0.998). Residual cancer burden assessment is highly reproducible, with reproducible long-term prognostic significance.
| S-EPMC4830087 | biostudies-literature
Project description:BackgroundAssessing the residual cancer burden (RCB) predictive performance, the potential subgroup effects, and time-dependent impact on breast cancer patients who underwent neoadjuvant therapy in a developer's independent cohort is essential for its usage in clinical routine.MethodsBetween 2011 and 2016, the RCB scores of 184 female breast cancer patients were prospectively collected, and subsequent clinicopathological and follow-up data were obtained retrospectively. Recurrence-free survival (RFS), overall survival (OS), as well as subgroup analysis, and time-dependent variables were calculated with multivariate, complex, or linear statistical models.ResultsA total of 184 patients (HER2 33%, TNBC 27%), with a mean follow-up time of 4 years, treated with neoadjuvant systemic therapy (92% anthracycline-taxane based) were analyzed revealing 43 events (38 recurrences, 28 deaths). High RCB scores were associated with recurrence (median index: 2.34 vs. 1.39 points, rank-sum p < 0.0001), decreased RFS (hazard ratio [HR] = 1.80, 95% confidence interval [CI] 1.44-2.24, p < 0.0001) and reduced OS (HR 1.96, 95% CI 1.49-2.59, p < 0.0001). The RCB score showed proportionality of hazards (interaction HR with linear follow-up time = 1.00, p = 0.896) and good discriminating power (Harrell's c index 0.7).ConclusionsOur results confirm the RCB score as externally valid prognostic marker and being independent of molecular subtype for RFS and OS in a clinical setting.
| S-EPMC6864028 | biostudies-literature
Project description:BACKGROUND:The integration of residual cancer burden (RCB) and post-treatment Ki67 as residual proliferative cancer burden (RPCB) has been proposed as a stronger predictor of long-term outcome in unselected patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT), as compared with RCB. However, no specific analysis in hormone-receptor-positive (HR+) human epidermal growth receptor 2-negative (HER2-) BC is available so far. MATERIALS AND METHODS:A cohort of 130 patients with HR+/HER2- BC who underwent NACT between 2000 and 2014 was included. Archival surgical specimens were evaluated for RCB. RPCB was calculated by combining RCB and Ki67 as previously described. Patients were categorized in four RCB and RPCB categories (pathological complete response and tertiles). Disease-free survival (DFS) and overall survival (OS) estimates were determined by Kaplan-Meier analysis and compared using the log-rank test. Overall change of ?2 and c-indexes were used to compare the performance of the prognostic models. RESULTS:RPCB was calculated for 85 patients. After a median follow up of 8.5?years, RCB was associated with OS (p = .048) but not with DFS (p = .152); RPCB was instead significantly associated with both DFS and OS (p = .034 and p < .001, respectively). In terms of OS, RPCB provided a significant amount of prognostic information beyond RCB (??2 5.73, p < .001). In addition, c-index for OS prediction was significantly higher for RPCB as compared with RCB (0.79 vs. 0.61, p = .03). CONCLUSION:This is the first study evaluating RPCB in patients with HR+/HER2- BC treated with NACT. In this independent cohort, RPCB was a strong predictor of DFS and OS. The better performance of RPCB versus RCB was in part due to the ability of RPCB to discriminate a subgroup of patients with a particularly worse prognosis after NACT, who may be candidates for clinical trials evaluating novel adjuvant strategies. IMPLICATIONS FOR PRACTICE:The present work validated residual proliferative cancer burden (RPCB) as a strong predictor of long-term outcome in patients with hormone receptor-positive human epidermal growth receptor 2-negative (HR+/HER2-) breast cancer (BC) treated with neoadjuvant chemotherapy. In addition, results from the present study suggest RPCB as a promising tool to identify patients with HR+/HER2- BC who might potentially benefit from the inclusion in clinical trials evaluating novel or escalated postneoadjuvant treatment strategies because it allowed to discriminate a subgroup of patients with particularly poor prognosis despite having received subsequent endocrine therapy in the adjuvant setting.
| S-EPMC7485331 | biostudies-literature
Project description:PurposeWe aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL).Experimental designHER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure.ResultsA total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs.ConclusionsWe have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.
| S-EPMC10472099 | biostudies-literature
Project description:BackgroundThis follow-up analysis of a Swedish prospective multicentre trial had the primary aim to determine invasive disease-free (IDFS), breast cancer-specific (BCSS) and overall survival (OS) rates, and their association with axillary staging results before and after neoadjuvant systemic therapy for breast cancer.MethodsWomen who underwent neoadjuvant systemic therapy for clinically node-positive (cN+) or -negative (cN0) primary breast cancer between 2010 and 2015 were included. Patients had a sentinel lymph node biopsy before and/or after neoadjuvant systemic therapy, and all underwent completion axillary lymph node dissection. Follow-up was until February 2019. The main outcome measures were IDFS, BCSS and OS. Univariable and multivariable Cox regression analyses were used to identify independent factors associated with survival.ResultsThe study included a total of 417 women. Median follow-up was 48 (range 7-114) months. Nodal status after neoadjuvant systemic therapy, but not before, was significantly associated with crude survival: residual nodal disease (ypN+) resulted in a significantly shorter 5-year OS compared with a complete nodal response (ypN0) (83·3 versus 91·0 per cent; P = 0·017). The agreement between breast (ypT) and nodal (ypN) status after neoadjuvant systemic therapy was high, and more so in patients with cN0 tumours (64 of 66, 97 per cent) than those with cN+ disease (49 of 60, 82 per cent) (P = 0·005). In multivariable analysis, ypN0 (hazard ratio 0·41, 95 per cent c.i. 0·22 to 0·74; P = 0·003) and local radiotherapy (hazard ratio 0·23, 0·08 to 0·64; P = 0·005) were associated with improved IDFS, and triple-negative molecular subtype with worse IDFS.ConclusionThe present findings underline the prognostic significance of nodal status after neoadjuvant systemic therapy. This confirms the clinical value of surgical axillary staging after neoadjuvant systemic therapy.
| S-EPMC10364852 | biostudies-literature
Project description:The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy dose reduction and RCB scores. In this extended validation study, 367 breast cancer patients with available RCB scores were followed up for recurrence-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). We also computed standardized cumulative doses of anthracyclines and taxanes (A/Ts) to investigate a potential interaction between neoadjuvant chemotherapy dose reduction and RCB scores. Higher RCB scores were consistently associated with adverse clinical outcomes across different molecular subtypes (HR for RFS = 1.60, 95% CI 1.33-1.93, p < 0.0001; HR for DDFS = 1.70, 95% CI 1.39-2.05, p < 0.0001; HR for OS = 1.67, 95% CI 1.34-2.08, p < 0.0001). The adverse impact prevailed throughout 5 years of follow-up, with a peak for relapse risk between 1-2 years after surgery. Clinical outcomes of patients with RCB class 1 did not differ substantially at 5 years compared to RCB class 0. A total of 180 patients (49.1%) underwent dose reduction of neoadjuvant A/T chemotherapy. We observed a statistically significant interaction between dose reduction and higher RCB scores (interaction p-value = 0.042). Our results confirm RCB score as a prognostic marker for RFS, DDFS, and OS independent of the molecular subtype. Importantly, we show that lower doses of cumulative neoadjuvant A/T were associated with higher RCB scores in patients who required a dose reduction.
| S-EPMC8161089 | biostudies-literature
Project description:PurposeTo examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT).Patients and methodsWe identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.ResultsOf 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range: 7.9 × 10 -7 to 4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12.ConclusionNAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.
| S-EPMC10029037 | biostudies-literature
Project description:IntroductionPathologic complete response (pCR) after neoadjuvant chemotherapy has a demonstrated survival advantage; however, outcomes for non-pCR by receptor status are less understood. We sought to evaluate survival and distant recurrence by receptor status for patients with residual stage II/III breast cancer.MethodsA stage-stratified random sample of 11,366 patients with stage II-III breast cancer in 2006-2007 was selected from 1217 facilities in the National Cancer Database for a Commission on Cancer Special Study. We identified patients with residual pathologic stage II/III cancer who received standard of care therapy based on receptor status. Distant recurrence and 5-year survival were abstracted and Kaplan-Meier curves were generated by receptor status. Multivariable Cox regression was used to estimate hazard ratios for death and distant recurrence.ResultsA total of 734 patients had residual disease; 58%, 28%, and 14% were ER or PR+/Her2neu-, ER and PR-/Her2neu-, and Her2neu+ (any ER/PR), respectively. ER and PR-/Her2neu- cancers had the poorest 5-year overall (52% vs. 82% for Her2neu+ and ER or PR+/Her2neu-, p?<?0.0001) and distant recurrence-free survival (57% vs. 72% Her2neu+ and 77% ER or PR+/Her2neu, p?<?0.0001). Cox regression models demonstrated a higher likelihood of distant recurrence and death for patients with ER and PR-/Her2neu- disease (HR 2.25, 95% CI 1.56-3.24 and HR 3.19, 95% CI 2.20-4.64 respectively) compared with ER or PR+/Her2neu-.ConclusionsPatients with residual ER and PR-/Her2neu- cancer have a significant risk of distant recurrence and mortality compared with other breast cancer types, supporting the consideration for additional adjuvant therapy and novel clinical trials in this cohort. Trial registry number ClinicalTrials.gov identifier NCT02171078.
| S-EPMC7590230 | biostudies-literature
Project description:To avoid unnecessary neoadjuvant chemotherapy in case anticipating a poor therapy response, it is essential to find the pathological parameters that would predict pathological complete response or at least a decrease in tumor burden following neoadjuvant chemotherapy. The purpose of this study is to investigate the hypothesis that tumor infiltrating lymphocytes can predict the efficacy of neoadjuvant chemotherapy and to find the Ki67 cutoff value that best predicts the benefit of chemotherapy. 153 cases of breast cancer were chosen, based on their molecular subtype: triple negative subtype (77) and luminal, HER2-ve subtype (76). Histopathological assessment of pretherapy core biopsies was conducted to assess variable pathological parameters including TILs rates with the aid of immunohistochemical staining for CD20 and CD3. Moreover, core biopsies were stained for Ki67, and the findings were compared to the residual cancer burden following neoadjuvant chemotherapy. On analyzing and contrasting the two groups, a significant association between molecular subtype and pathological complete response was confirmed, while tumor-infiltrating lymphocytes in either group had no effect on therapy response. We used receiver operating characteristic curve analysis to determine that a cutoff of 36% for Ki67 is the most accurate value to predict complete therapy response.
| S-EPMC9484975 | biostudies-literature
Project description:Compared with surgery alone, postoperative adjuvant radiotherapy (RT) improves relapse-free survival of patients with early-stage breast cancer. We evaluated the long-term overall and disease-free survival rates of neoadjuvant (presurgical) versus adjuvant RT in early-stage breast cancer patients.We used the Surveillance, Epidemiology, and End Results (SEER) database provided by the National Institutes of Health to derive an analytic dataset of 250,195 female patients with early-stage breast cancer who received RT before (n?=?2554; 1.02%) or after (n?=?247,641; 98.98%) surgery. Disease-free survival, defined as time to diagnosis of a second primary tumor at any location, was calculated from automated patient identification matching of all SEER records.Partial and complete mastectomies were performed in 94.4% and 5.6% of patients, respectively. In the largest cohort of estrogen receptor-positive women who underwent partial mastectomy, the HR of developing a second primary tumor after neoadjuvant compared with adjuvant RT was 0.64 (95% CI 0.55-0.75; P?<?0.0001). Overall survival was independent of radiation sequence (HR 1; P?=?0.95). Neoadjuvant RT also resulted in a lower HR for second primary cancer among estrogen receptor-positive patients who underwent mastectomy compared with those who received adjuvant RT (HR 0.48, 95% CI 0.26-0.87; P?=?0.0162).Neoadjuvant RT may significantly improve disease-free survival without reducing overall survival, especially for estrogen receptor-positive patients with early-stage breast cancer. This finding warrants further exploration of potential long-term benefits of neoadjuvant radiotherapy for early-stage breast cancer in a controlled, prospective clinical trial setting, with correlative studies done to identify potential mechanisms of superiority.
| S-EPMC5493088 | biostudies-literature