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Background: This multicenter and retrospective study investigated the additive value of tumor morphologic features derived from the functional tumor volume (FTV) tumor mask at pre-treatment (T0) and the early treatment time point (T1) in the prediction of pathologic outcomes for breast cancer patients undergoing neoadjuvant chemotherapy. Methods: A total of 910 patients enrolled in the multicenter I-SPY 2 trial were included. FTV and tumor morphologic features were calculated from the dynamic contrast-enhanced (DCE) MRI. A poor response was defined as a residual cancer burden (RCB) class III (RCB-III) at surgical excision. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance. The analysis was performed in the full cohort and in individual sub-cohorts stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Results: In the full cohort, the AUCs for the use of the FTV ratio and clinicopathologic data were 0.64 ± 0.03 (mean ± SD [standard deviation]). With morphologic features, the AUC increased significantly to 0.76 ± 0.04 (p < 0.001). The ratio of the surface area to volume ratio between T0 and T1 was found to be the most contributing feature. All top contributing features were from T1. An improvement was also observed in the HR+/HER2- and triple-negative sub-cohorts. The AUC increased significantly from 0.56 ± 0.05 to 0.70 ± 0.06 (p < 0.001) and from 0.65 ± 0.06 to 0.73 ± 0.06 (p < 0.001), respectively, when adding morphologic features. Conclusion: Tumor morphologic features can improve the prediction of RCB-III compared to using FTV only at the early treatment time point. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most commonly diagnosed malignant tumor in women. The disease and its subsequent treatment pose a serious burden on the quality of life of patients. Neoadjuvant chemotherapy (NAC) has become one of the crucial strategies for the management of BC. Since the identification of the vitamin D receptor (VDR) in mammary tissues, extensive mechanistic research has been conducted on its function. The expression of VDR in BC cells and the tumor microenvironment could be a new prognostic factor for BC after NAC. Patients and Methods: This observational, single-center study compared data from clinical and histopathological records of 111 female subjects with the expression of VDR in different cellular and tissue components of breast specimens obtained from surgery after NAC. VDR expression was evaluated using an immunoreactive score assigned after immunohistochemistry. Intergroup comparisons and logistic regression were used to identify associations between VDR expression and clinicopathological features of BC. Results: We found that the expression of VDR is associated with various clinical features (i.e., age, menopausal status, and NAC cycle number) and characteristics of prognostic significance, such as residual cancer burden class. Logistic regression analysis revealed that the expression of VDR in the nuclei and cytoplasm of surrounding normal mammary cells predicted vascular invasion and lymph node involvement. Conclusions: The expression of VDR in tumor cells and their microenvironment is related to the clinicopathological characteristics of BC after NAC. [ABSTRACT FROM AUTHOR]

Background: This multicenter and retrospective study investigated the additive value of tumor morphologic features derived from the functional tumor volume (FTV) tumor mask at pre-treatment (T0) and the early treatment time point (T1) in the prediction of pathologic outcomes for breast cancer patients undergoing neoadjuvant chemotherapy. Methods: A total of 910 patients enrolled in the multicenter I-SPY 2 trial were included. FTV and tumor morphologic features were calculated from the dynamic contrast-enhanced (DCE) MRI. A poor response was defined as a residual cancer burden (RCB) class III (RCB-III) at surgical excision. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance. The analysis was performed in the full cohort and in individual sub-cohorts stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Results: In the full cohort, the AUCs for the use of the FTV ratio and clinicopathologic data were 0.64 ± 0.03 (mean ± SD [standard deviation]). With morphologic features, the AUC increased significantly to 0.76 ± 0.04 (p < 0.001). The ratio of the surface area to volume ratio between T0 and T1 was found to be the most contributing feature. All top contributing features were from T1. An improvement was also observed in the HR+/HER2- and triple-negative sub-cohorts. The AUC increased significantly from 0.56 ± 0.05 to 0.70 ± 0.06 (p < 0.001) and from 0.65 ± 0.06 to 0.73 ± 0.06 (p < 0.001), respectively, when adding morphologic features. Conclusion: Tumor morphologic features can improve the prediction of RCB-III compared to using FTV only at the early treatment time point.

BackgroundBreast cancer (BC) is the most commonly diagnosed malignant tumor in women. The disease and its subsequent treatment pose a serious burden on the quality of life of patients. Neoadjuvant chemotherapy (NAC) has become one of the crucial strategies for the management of BC. Since the identification of the vitamin D receptor (VDR) in mammary tissues, extensive mechanistic research has been conducted on its function. The expression of VDR in BC cells and the tumor microenvironment could be a new prognostic factor for BC after NAC.Patients and MethodsThis observational, single-center study compared data from clinical and histopathological records of 111 female subjects with the expression of VDR in different cellular and tissue components of breast specimens obtained from surgery after NAC. VDR expression was evaluated using an immunoreactive score assigned after immunohistochemistry. Intergroup comparisons and logistic regression were used to identify associations between VDR expression and clinicopathological features of BC.ResultsWe found that the expression of VDR is associated with various clinical features (i.e., age, menopausal status, and NAC cycle number) and characteristics of prognostic significance, such as residual cancer burden class. Logistic regression analysis revealed that the expression of VDR in the nuclei and cytoplasm of surrounding normal mammary cells predicted vascular invasion and lymph node involvement.ConclusionsThe expression of VDR in tumor cells and their microenvironment is related to the clinicopathological characteristics of BC after NAC.

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis.

PURPOSE: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. METHODS: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. RESULTS: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years). CONCLUSION: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Background: Neoadjuvant therapy (NAT) is an important tool for the treatment of patients with breast cancer. The aim of NAT is to make it operable for patients with locally advanced breast cancer, to shrink early-stage tumors – thus allowing for breast conservation. Pathological complete response achieved by post-chemotherapy is an independent factor in the long-term survival of patients. Thus, the histopathological components of post-chemotherapy changes such as cellularity and lymph node (LN) tumor deposits, when combined, help to assess residual carcinoma burden. Aims and Objectives: This study aims to analyze various histopathological changes in the breast after neoadjuvant chemotherapy with the objective of evaluating post-chemotherapy response and residual cancer burden. Materials and Methods: A total of 34 cases of post-chemotherapy modified radical mastectomy specimens were analyzed for pathological response (pCR) and residual cancer burden were evaluated. Tumor cellularity, stromal changes, lymphovascular invasion, and LN involvement were noted. Results: The age group of presentation of 34 cases ranged from 30 to 75 years of age with the mean age being 43.5 years. The most common histomorphological finding was fibrosis/elastosis and vacuolation with 26 (76.5%) and 24 (70.6%) cases, respectively. The number of cases that showed partial pCR was 30 (88.2%) and 1 (2.9%) case showed a pathological complete response which belonged to Stage 0, pathological no response was shown by 3 (8.8%) cases which belonged to Stage II and Stage IV. Conclusion: Post-chemotherapy response of neoadjuvant chemotherapy in breast carcinoma is important for prognosis and predictive information for disease relapse.

KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR. • KEYNOTE-522 evaluated neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab versus neoadjuvant chemotherapy alone in early TNBC. • Neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab significantly improved pCR/EFS versus neoadjuvant chemotherapy alone. • We explored the effect of adding pembrolizumab to chemotherapy on outcomes by RCB category. • Pembrolizumab not only increased pCR rates, but also improved EFS among many patients who do not have a pCR. • Findings support neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab as a standard of care treatment in early TNBC. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant therapy (NAT) is an important tool for the treatment of patients with breast cancer. The aim of NAT is to make it operable for patients with locally advanced breast cancer, to shrink early-stage tumors - thus allowing for breast conservation. Pathological complete response achieved by post-chemotherapy is an independent factor in the long-term survival of patients. Thus, the histopathological components of post-chemotherapy changes such as cellularity and lymph node (LN) tumor deposits, when combined, help to assess residual carcinoma burden. Aims and Objectives: This study aims to analyze various histopathological changes in the breast after neoadjuvant chemotherapy with the objective of evaluating post-chemotherapy response and residual cancer burden. Materials and Methods: A total of 34 cases of post-chemotherapy modified radical mastectomy specimens were analyzed for pathological response (pCR) and residual cancer burden were evaluated. Tumor cellularity, stromal changes, lymphovascular invasion, and LN involvement were noted. Results: The age group of presentation of 34 cases ranged from 30 to 75 years of age with the mean age being 43.5 years. The most common histomorphological finding was fibrosis/elastosis and vacuolation with 26 (76.5%) and 24 (70.6%) cases, respectively. The number of cases that showed partial pCR was 30 (88.2%) and 1 (2.9%) case showed a pathological complete response which belonged to Stage 0, pathological no response was shown by 3 (8.8%) cases which belonged to Stage II and Stage IV. Conclusion: Post-chemotherapy response of neoadjuvant chemotherapy in breast carcinoma is important for prognosis and predictive information for disease relapse. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. Methods: This retrospective study consecutively included previously untreated patients with stage I–III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. Results: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). Conclusion: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment. [ABSTRACT FROM AUTHOR]

Abstract Purpose The residual cancer burden index (RCB) was proposed as a response evaluation criterion in breast cancer patients treated with Neoadjuvant Chemotherapy (NAC). This study evaluated the relevance of RCB with replase-free survival (RFS). Methods The clinical data of 254 breast cancer patients who received NAC between 2016 and 2020 were retrospectively collected. The relationship between clinicopathologic factors and RFS was evaluated using Cox proportional hazards regression models. RFS estimates were determined by Kaplan–Meier(K-M) analysis and compared using the log-rank test. Multivariate logistic regression analysis was used to evaluate the risk factors associated with RCB. Receiver operating characteristic (ROC) curves showed the potential of the RCB and MP grading systems as biomarkers for RFS. Results At a median follow-up of 52 months, 59 patients(23.23%) developed relapse. Multivariate Cox regression showed that older age (P = 0.022), high Pathologic T stage after NAC (P = 0.023) and a high RCB score(P = 0.003) were risk factors for relapse. The outcomes of the multivariate logistic analysis indicated that RCB 0 (pathologic complete response [pCR]) was associated with HER2-positive patients (P = 0.002) and triple-negative breast cancer (TNBC) patients (P = 0.013). In addition, the RCB and MP scoring systems served as prognostic markers for patients who received NAC, and their area under curves (AUCs) were 0.691 and 0.342, respectively. Conclusion These data suggest that RCB can be equally applied to predict RFS in Chinese patients with NAC. The application of RCB may help guide the selection of treatment strategies.

Purpose: Few studies have reported on patient prognosis according to residual cancer burden after neoadjuvant chemotherapy (NAC). Herein, we evaluated the survival of patients based on residual disease after NAC to identify subpopulations with distinct prognoses. Methods: We retrospectively reviewed 728 patients treated with NAC from 2010 to 2017. Patients were divided into four subgroups depending on post-surgical residual disease according to the staging system: pathological complete response (pCR) (ypT0/TisN0), minimal residual disease (MRD) (ypT1mi/T1aN0 or ypT0/Tis ypN0i+/N1mic), node-only pCR (≥ ypT1b ypN0), and breast-only pCR (ypT0/Tis ≥ ypN1a). Clinicopathological characteristics and survival outcomes were analyzed by adjusting for factors affecting survival. Results: Overall, 50.4% (n = 367) of patients achieved pCR, with the MRD group accounting for 16.5% (n = 120). Although age and clinical stage were not different among the study groups, histologic grade, subtypes, chemotherapy response, and local treatment showed differences. Event-free survival (EFS) and overall survival (OS) demonstrated no significant difference between the pCR and MRD groups. In the multivariate analysis, pCR status was the only significant factor in EFS, and no statistical difference was noted between the pCR and MRD groups. However, clinical stage, pCR status, and subtype significantly affected the OS. MRD showed favorable outcomes in terms of both EFS and OS in all subtypes, except for those with triple-negative breast cancer (TNBC). Conclusion: Patients with MRD showed outcomes comparable to those of patients who achieved pCR and may be candidates for de-escalation of post-NAC treatment, except for those with a TNBC subtype. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NAC) is widely used as a standard treatment for early-stage triple-negative breast cancer (TNBC). While patients who achieve pathologic complete response (pCR) have a highly favorable outcome, patients who do not achieve pCR have variable prognoses. It is important to identify patients who are most likely to have poor survival outcomes to identify candidates for more aggressive therapeutic approaches after NAC. Many studies have demonstrated that cytokines and growth factors packaged into extracellular vesicles (EVs) have an essential role in tumor progression and drug resistance. In this study, we examined the role of serum-derived EV-associated cytokines as prognostic biomarkers for long-term outcomes in patients who underwent anthracycline–taxane-based NAC. We isolated extracellular vesicles from the serum of 190 TNBC patients who underwent NAC between 2015 and 2018 at Samsung Medical Center. EV-associated cytokine concentrations were measured with ProcartaPlex Immune Monitoring 65-plex panels. The prognostic value of EV-associated cytokines was studied. We found that patients with high EV_APRIL, EV_CXCL13, and EV_VEGF-A levels had shorter overall survival (OS). We further evaluated the role of these selected biomarkers as prognostic factors in patients with residual disease (RD) after NAC. Even in patients with RD, high levels of EV_APRIL, EV_CXCL13, and EV_VEGF-A were correlated with poor OS. In all subgroup analyses, EV_CXCL13 overexpression was significantly associated with poor overall survival. Moreover, multivariate analysis indicated that a high level of EV_CXCL13 was an independent predictor of poor OS. Correlation analysis between biomarker levels in EVs and serum showed that EV_VEGF-A positively correlated with soluble VEGF-A but not CXCL13. An elevated level of soluble VEGF-A was also associated with poor OS. These findings suggest that EV_APRIL, EV_CXCL13, and EV_VEGF-A may be useful in identifying TNBC patients at risk of poor survival outcomes after NAC. [ABSTRACT FROM AUTHOR]

Abstract Introduction The use of neoadjuvant therapy (NAT) has been showing an incraesing tendency in the treatment of locally advanced breast cancer. The evaluation of residual cancer could be performed by Residual Cancer Burden (RCB) calculator. The prognostic system takes the two largest diameters of the tumor, the cellularity, the amount of in situ carcinoma, the number of metastatic lymph nodes, and the size of the largest metastatic deposit into account. The aim of our study was to examine the reproducibility of RCB in NAT treated patients. Methods Patients who were treated with NAT and had resection specimens between 2018 and 2021 were selected. Histological examination was performed by five pathologists. After assessment of the examined variables, RCB points and RCB classes were defined. For statistical analysis, interclass correlation was used (SPSS Statistics V.22.0 software). Results Altogether 100 patients were included in our retrospective, cohort study (average age: 57 years). In two‐thirds of the cases, third generation chemotherapy was used, and mastectomy was performed. Significant concordance was found in the two largest diameters of the tumor (coefficients, 0.984 and 0.973), the cellularity (coefficient, 0.970), and the largest metastatic deposit (coefficient, 0.998). Although the amount of in situ carcinoma proved to be the least reproducible factor, it resulted in almost 90% of agreement (coefficient, 0.873). Regarding RCB points and classes, similar results were observed (coefficients, 0.989 and 0.960). Conclusions Significant agreement was observed between examiners based on almost all RCB parameters, points, and classes, reflecting the optimal reproducibility of RCB. Therefore, we recommend the use of the calculator in routine histopathological reports in NAT cases.

Neoadjuvant chemotherapy is widely used in the therapy of stage II–III breast cancers and pathologic complete response (pCR; ypT0/is, ypN0) predicts excellent long-term survival. However, the correlation between improvement in pCR rate and survival is highly variable across trials. A major limitation of pCR is that it does not capture downstaging in patients with residual disease. We previously introduced the residual cancer burden score that measures pathologic response on a continuous scale. Comparison of residual cancer burden score distributions between trial arms reflects treatment efficacy more accurately than differences in pCR rate. We developed the treatment efficacy score as a new statistical metric that appears to be a better surrogate for trial arm-level survival improvement than pCR rate difference. [ABSTRACT FROM AUTHOR]

Aims: The 8th Edition of the American Joint Committee on Cancer Staging System (yAJCC) excludes treatment‐related fibrosis from the measurement of residual tumour after neoadjuvant chemotherapy (NAC) for breast cancer. The impact of the 8th Ed. yAJCC on post‐NAC pathologic staging was examined in 188 breast cancer specimens from 183 patients with measurable residual tumour. Methods: Tumour size, ypT, and ypN categories were reassessed with the current yACC criteria and compared to the original pathology reports. Histological patterns of response in the breast were categorised as concentric or scattered. Results: The reassessed breast tumour size or ypT category differed from the original report in 101 (53.7%) cases. Changes in the ypT and/or ypN category resulted in downstaging of 45/185 (24.3%). A smaller reassessed tumour size or lower ypT category occurred more often in hormone receptor‐positive/HER2‐negative (HR+/HER2−) (68.3%) and HER2‐positive (HER2+) tumours (74.0%) than triple‐negative breast cancer (TNBC) (37.5%) (P < 0.001). A scattered pattern of response was more frequent in HR+/HER2− (54.9%) and HER2+ (66.0%) tumours than TNBC (35.7%) (P = 0.006). Changes in size, ypT, or multifocality based on the 8th Ed. yAJCC criteria were more frequent in tumours with a scattered pattern of response (P < 0.001). Conclusion: Strict adherence to yAJCC criteria for measurement of the residual breast tumour after NAC resulted in smaller tumour size, lower ypT category, lower yAJCC stage, and more frequent classification of residual tumour as multifocal. Downstaging based on 8th Ed. yAJCC criteria was associated with tumour subtype and histological pattern of response. [ABSTRACT FROM AUTHOR]

Breast cancer patients undergoing neoadjuvant chemotherapy (NAC) require precise and accurate evaluation of treatment response. Residual cancer burden (RCB) is a prognostic tool widely used to estimate survival outcomes in breast cancer. In this study, we introduced a machine-learning-based optical biosensor called the Opti-scan probe to assess residual cancer burden in breast cancer patients undergoing NAC. The Opti-scan probe data were acquired from 15 patients (mean age: 61.8 years) before and after each cycle of NAC. Using regression analysis with k-fold cross-validation, we calculated the optical properties of healthy and unhealthy breast tissues. The ML predictive model was trained on the optical parameter values and breast cancer imaging features obtained from the Opti-scan probe data to calculate RCB values. The results show that the ML model achieved a high accuracy of 0.98 in predicting RCB number/class based on the changes in optical properties measured by the Opti-scan probe. These findings suggest that our ML-based Opti-scan probe has considerable potential as a valuable tool for the assessment of breast cancer response after NAC and to guide treatment decisions. Therefore, it could be a promising, non-invasive, and accurate method for monitoring breast cancer patient's response to NAC. [ABSTRACT FROM AUTHOR]

In high-risk prostate cancer patients, neoadjuvant degarelix plus apalutamide prior to radical prostatectomy results in a significantly improved pathological response compared with degarelix alone. However, it is yet unclear whether this superior pathological response will result in an improved oncological outcome. High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP). To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo. ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP. Patients were randomly assigned at a 1:1 ratio to degarelix (240–80–80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed. The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored. Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5–11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET–estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET–estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001). In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy. In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The use of neoadjuvant therapy (NAT) has been showing an incraesing tendency in the treatment of locally advanced breast cancer. The evaluation of residual cancer could be performed by Residual Cancer Burden (RCB) calculator. The prognostic system takes the two largest diameters of the tumor, the cellularity, the amount of in situ carcinoma, the number of metastatic lymph nodes, and the size of the largest metastatic deposit into account. The aim of our study was to examine the reproducibility of RCB in NAT treated patients. Methods: Patients who were treated with NAT and had resection specimens between 2018 and 2021 were selected. Histological examination was performed by five pathologists. After assessment of the examined variables, RCB points and RCB classes were defined. For statistical analysis, interclass correlation was used (SPSS Statistics V.22.0 software). Results: Altogether 100 patients were included in our retrospective, cohort study (average age: 57 years). In two‐thirds of the cases, third generation chemotherapy was used, and mastectomy was performed. Significant concordance was found in the two largest diameters of the tumor (coefficients, 0.984 and 0.973), the cellularity (coefficient, 0.970), and the largest metastatic deposit (coefficient, 0.998). Although the amount of in situ carcinoma proved to be the least reproducible factor, it resulted in almost 90% of agreement (coefficient, 0.873). Regarding RCB points and classes, similar results were observed (coefficients, 0.989 and 0.960). Conclusions: Significant agreement was observed between examiners based on almost all RCB parameters, points, and classes, reflecting the optimal reproducibility of RCB. Therefore, we recommend the use of the calculator in routine histopathological reports in NAT cases. [ABSTRACT FROM AUTHOR]

Purpose: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45− cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. Methods: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45− cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45− cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. Results: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45− cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years). Conclusion: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery. [ABSTRACT FROM AUTHOR]

Keywords: Triple-negative breast cancer; tumor infiltrating lymphocytes; prognosis; disease burden; residual cancer burden EN Triple-negative breast cancer tumor infiltrating lymphocytes prognosis disease burden residual cancer burden 1045 1047 3 10/31/23 20231001 NES 231001 1. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. [Extracted from the article]

This study aims to investigate the change of Ki67 value pre- and post-neoadjuvant therapy (NAT) and evaluate its potential value in predicting survival outcomes in different molecular subtypes of breast cancer. A total of 257 breast cancer patients who underwent NAT at Renmin Hospital of Wuhan University from July 2019 to Sep 2023 were included in this study. The Ki67 index of the patients was re-interpreted by two attending physicians, and the changes of Ki67 value pre- and post-NAT were compared. Chi-square test (χ2) and logistic regression were conducted to examine the correlation between various characteristics and the efficacy of NAT. Disease-free survival (DFS) was calculated using the Kaplan-Meier curve and compared using the log-rank test. Patients with higher histological grade, negative expression of estrogen receptor (ER) or progesterone receptor (PR), positive expression of human epidermal growth receptor 2 (HER2), higher pretreatment Ki67 index, absence of lymph node metastasis, and those with HER2 positive and triple-negative breast cancer were associated with improved efficacy of NAT. Our study identified that the optimal cut-off value for the changes in Ki67 index pre- and post-NAT related to the effectiveness of NAT was "-88.19 %" in whole chort, which was related to the aforementioned clinical characteristics. Besides, the optimal cut-off values for the luminal, HER2-enriched and triple-negative subtypes were "-91.83 %", "-46.12 %" and "-81.67 %", respectively. Survival analysis demonstrated that the changes in Ki67 value were significantly associated with DFS in the HER2-enriched and triple-negative subtype, but not in the luminal subtype. Preoperative clinicopathological features and changes in Ki67 value pre-and post-NAT can contribute to providing patients with a more accurate prognosis. [ABSTRACT FROM AUTHOR]

Background: This multicenter and retrospective study investigated the additive value of tumor morphologic features derived from the functional tumor volume (FTV) tumor mask at pre-treatment (T0) and the early treatment time point (T1) in the prediction of pathologic outcomes for breast cancer patients undergoing neoadjuvant chemotherapy., Methods: A total of 910 patients enrolled in the multicenter I-SPY 2 trial were included. FTV and tumor morphologic features were calculated from the dynamic contrast-enhanced (DCE) MRI. A poor response was defined as a residual cancer burden (RCB) class III (RCB-III) at surgical excision. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance. The analysis was performed in the full cohort and in individual sub-cohorts stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status., Results: In the full cohort, the AUCs for the use of the FTV ratio and clinicopathologic data were 0.64 ± 0.03 (mean ± SD [standard deviation]). With morphologic features, the AUC increased significantly to 0.76 ± 0.04 ( p < 0.001). The ratio of the surface area to volume ratio between T0 and T1 was found to be the most contributing feature. All top contributing features were from T1. An improvement was also observed in the HR+/HER2- and triple-negative sub-cohorts. The AUC increased significantly from 0.56 ± 0.05 to 0.70 ± 0.06 ( p < 0.001) and from 0.65 ± 0.06 to 0.73 ± 0.06 ( p < 0.001), respectively, when adding morphologic features., Conclusion: Tumor morphologic features can improve the prediction of RCB-III compared to using FTV only at the early treatment time point.

Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov–Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov–Smirnov, Mann–Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone. • We developed a statistical tool to compare two RCB distributions giving a single metric named Treatment Efficacy Score (TES). • TES identifies a regimen with a higher pCR rate and also captures the downstaging effects of treatment on residual cancer. • TES correlates with event-free and distant recurrence-free survival better than pCR rate difference. • TES could serve as a better early surrogate for trial arm level survival than pCR rate difference. • We created a free web tool (http://dssoftware.aei.polsl.pl/TES/TES/) to plot RCB distributions and calculate TES statistic. [ABSTRACT FROM AUTHOR]

A residual cancer burden after neoadjuvant therapy (NAT) for breast cancer (BC) is associated with worse treatment outcomes compared to patients who achieved pathologic complete remission. This single-institutional retrospective study of 767 consecutive patients, including 468 patients with assessable residual cancer burden (aRCB) after NAT, with a median follow-up of 36 months, evaluated the biomarkers assessed before NAT from a biopsy and after NAT from a surgical specimen, their dynamics, and effect on long-term outcomes in specific breast cancer subtypes. The leading focus was on proliferation index Ki-67, which was significantly altered by NAT in all BC subtypes (p < 0.001 for HER2 positive and luminal A/B HER2 negative and p = 0.001 for TNBC). Multivariable analysis showed pre-NAT and post-NAT Ki-67 as independent predictors of survival outcomes for luminal A/B HER2 negative subtype. For TNBC, post-NAT Ki-67 was significant alone, and, for HER2 positive, the only borderline association of pre-NAT Ki-67 was observed in relation to the overall survival. Steroid and HER2 receptors were re-assessed just in a portion of the patients with aRCB. The concordance of both assessments was 92.9% for ER status, 80.1% for PR, and 92.2% for HER2. In conclusion, these real-world data of a consecutive cohort confirmed the importance of biomarkers assessment in patients with aRCB, and the need to consider specific BC subtypes when interpreting their influence on prognosis. [ABSTRACT FROM AUTHOR]

PurposeSeveral pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined.MethodsUsing data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation.ResultsAmong 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies.ConclusionsThese data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

Breast cancer patients undergoing neoadjuvant chemotherapy (NAC) require precise and accurate evaluation of treatment response. Residual cancer burden (RCB) is a prognostic tool widely used to estimate survival outcomes in breast cancer. In this study, we introduced a machine-learning-based optical biosensor called the Opti-scan probe to assess residual cancer burden in breast cancer patients undergoing NAC. The Opti-scan probe data were acquired from 15 patients (mean age: 61.8 years) before and after each cycle of NAC. Using regression analysis with k-fold cross-validation, we calculated the optical properties of healthy and unhealthy breast tissues. The ML predictive model was trained on the optical parameter values and breast cancer imaging features obtained from the Opti-scan probe data to calculate RCB values. The results show that the ML model achieved a high accuracy of 0.98 in predicting RCB number/class based on the changes in optical properties measured by the Opti-scan probe. These findings suggest that our ML-based Opti-scan probe has considerable potential as a valuable tool for the assessment of breast cancer response after NAC and to guide treatment decisions. Therefore, it could be a promising, non-invasive, and accurate method for monitoring breast cancer patient’s response to NAC.

We developed a model for improving the prediction of survival outcome using postoperative Ki-67 value in combination with residual cancer burden (RCB) in patients with breast cancer (BC) who underwent neoadjuvant chemotherapy (NAC). We analyzed the data from BC patients who underwent NAC between 2010 and 2019 at Samsung Medical Center and developed our residual proliferative cancer burden (RPCB) model using semi-quantitative Ki-67 value and RCB class. The Cox proportional hazard model was used to develop our RPCB model according to disease free survival (DFS) and overall survival (OS). In total, 1,959 patients were included in this analysis. Of 1,959 patients, 905 patients were excluded due to RCB class 0, and 32 were due to a lack of Ki-67 data. Finally, an RPCB model was developed using data from 1,022 patients. The RPCB score was calculated for DFS and OS outcomes, respectively (RPCB-DFS and RPCB-OS). For further survival analysis, we divided the population into 3 classes according to the RPCB score. In the prediction of DFS, C-indices were 0.751 vs 0.670 and time-dependent areas under the receiver operating characteristic curves (AUCs) at 3-year were 0.740 vs 0.669 for RPCB-DFS and RCB models, respectively. In the prediction of OS, C-indices were 0.819 vs 0.720 and time-dependent AUCs at 3-year were 0.875 vs 0.747 for RPCB-OS and RCB models, respectively. The RPCB model developed using RCB class and semi-quantitative Ki-67 had superior predictive value for DFS and OS compared with that of RCB class. This prediction model could provide the basis to decide risk-stratified treatment plan for BC patients who had residual disease after NAC. [ABSTRACT FROM AUTHOR]

Investigamos la correlación entre los índices de PET/TC con 18F-FDG y la respuesta patológica en el cáncer de mama tratado con quimioterapia neoadyuvante (QNA), que se puntuó con el sistema de carga de cáncer residual (RCB) después de la cirugía. Nuestro objetivo es detectar antes una carga extensa de cáncer residual mediante el uso de los índices de PET/TC. Se recuperaron las características de las pacientes de forma retrospectiva. Se calculó el valor máximo de captación estándar (SUVmáx), el volumen metabólico del tumor (MTV) y los índices de glucólisis total de la lesión (TLG), así como la tasa de reducción (RR) entre la línea de base y la evaluación intermedia, con la exploración FDG PET/TC. Todos los pacientes fueron evaluados según las puntuaciones RCB después de la cirugía. Las respuestas patológicas y los resultados de las mediciones de PET/TC se analizaron con parámetros demográficos y clínicos. Un total de 95 pacientes fueron incluidos en el estudio. Según las respuestas patológicas, la distribución de RCB-0, -1, -2, -3 fue de 13 (13,7%), 11 (11,6%), 30 (31,6%) y 41 (43,2%), respectivamente. La supervivencia libre de enfermedad fue significativamente menor en el grupo RCB-3 en comparación con el grupo de respuesta patológica (p = 0,01). Según el análisis multivariante, se determinó que el RR del SUVmáx era una variable independiente que predecía la RCB extensa con un valor de corte óptimo del 86% (p < 0,05). Determinamos el RR de SUVmáx como un factor independiente para predecir la carga tumoral residual extensa. Creemos que el RR de SUVmáx es suficiente para predecir la respuesta patológica en la práctica diaria. Además, las mediciones de MTV y TLG no contribuyen adicionalmente al SUVmáx por sí solas y pueden causar una pérdida de trabajo innecesaria. We investigated the correlation between 18F-FDG PET/CT indices and pathological response in breast cancer treated with neoadjuvant chemotherapy (NACT) which was scored with Residual Cancer Burden (RCB) system after surgery. Our aim is to detect extensive residual cancer burden earlier by using PET/CT indices. Characteristics of patients were retrieved retrospectively. Baseline maximum Standart Uptake Value (SUVmax), Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) indices and reduction rate (RR) between baseline and interim evaluation were calculated with FDG PET/CT scan. All patients were evaluated according to RCB scores after surgery. Pathological responses and PET/CT measurement results were analyzed with demographic and clinical parameters. A total of 95 patients were included in the study. According to pathological responses, the distribution of RCB-0, -1, -2, -3 were 13 (13.7%), 11 (11.6%), 30 (31.6%), 41 (43.2%), respectively. Disease-free survival was significantly lower in the RCB-3 group compared to the pathological responder group (P =.01). According to multivariate analysis, RR of SUVmax was determined as an independent variable predicting extensive residual cancer burden with an optimal cut-off value of 86% (P <.05). We determined RR of SUVmax as an independent factor for predicting extensive residual tumor burden. We believe that RR of SUVmax is sufficient to predict pathological response in daily practice. In addition, MTV and TLG measurements do not contribute additionally to SUVmax alone and can cause unnecessary labor loss. [ABSTRACT FROM AUTHOR]

We developed a model for improving the prediction of survival outcome using postoperative Ki-67 value in combination with residual cancer burden (RCB) in patients with breast cancer (BC) who underwent neoadjuvant chemotherapy (NAC). We analyzed the data from BC patients who underwent NAC between 2010 and 2019 at Samsung Medical Center and developed our residual proliferative cancer burden (RPCB) model using semi-quantitative Ki-67 value and RCB class. The Cox proportional hazard model was used to develop our RPCB model according to disease free survival (DFS) and overall survival (OS). In total, 1,959 patients were included in this analysis. Of 1,959 patients, 905 patients were excluded due to RCB class 0, and 32 were due to a lack of Ki-67 data. Finally, an RPCB model was developed using data from 1,022 patients. The RPCB score was calculated for DFS and OS outcomes, respectively (RPCB-DFS and RPCB-OS). For further survival analysis, we divided the population into 3 classes according to the RPCB score. In the prediction of DFS, C-indices were 0.751 vs 0.670 and time-dependent areas under the receiver operating characteristic curves (AUCs) at 3-year were 0.740 vs 0.669 for RPCB-DFS and RCB models, respectively. In the prediction of OS, C-indices were 0.819 vs 0.720 and time-dependent AUCs at 3-year were 0.875 vs 0.747 for RPCB-OS and RCB models, respectively. The RPCB model developed using RCB class and semi-quantitative Ki-67 had superior predictive value for DFS and OS compared with that of RCB class. This prediction model could provide the basis to decide risk-stratified treatment plan for BC patients who had residual disease after NAC.

Rationale and Objectives: There are limited data on pretreatment imaging features that can predict response to neoadjuvant chemotherapy (NAC). To extract volumetric pretreatment MRI radiomics features and assess corresponding associations with breast cancer molecular subtypes, pathological complete response (pCR), and residual cancer burden (RCB) in patients treated with NAC.Materials and Methods: In this IRB-approved study, clinical and pretreatment MRI data from patients with biopsy-proven breast cancer who received NAC between September 2009 and July 2016 were retrospectively analyzed. Tumors were manually identified and semi-automatically segmented on first postcontrast images. Morphological and three-dimensional textural features were computed, including unfiltered and filtered image data, with spatial scaling factors (SSF) of 2, 4, and 6 mm. Wilcoxon rank-sum tests and area under the receiver operating characteristic curve were used for statistical analysis.Results: Two hundred and fifty nine patients with unilateral breast cancer, including 73 (28.2%) HER2+, 112 (43.2%) luminal, and 74 (28.6%) triple negative breast cancers (TNBC), were included. There was a significant difference in the median volume (p = 0.008), median longest axial tumor diameter (p = 0.009), and median longest volumetric diameter (p = 0.01) among tumor subtypes. There was also a significant difference in minimum signal intensity and entropy among the tumor subtypes with SSF = 4 mm (p = 0.009 and p = 0.02 respectively) and SSF = 6 mm (p = 0.007 and p < 0.001 respectively). Additionally, sphericity (p = 0.04) in HER2+ tumors and entropy with SSF = 2, 4, 6 mm (p = 0.004, 0.02, 0.047 respectively) in luminal tumors were significantly associated with pCR. Multiple features demonstrated significant association (p < 0.05) with pCR in TNBC and with RCB in luminal tumors and TNBC, with standard deviation of intensity with SSF = 6 mm achieving the highest AUC (AUC = 0.734) for pCR in TNBC.Conclusion: MRI radiomics features are associated with different molecular subtypes of breast cancer, pCR, and RCB. These features may be noninvasive imaging biomarkers to identify cancer subtype and predict response to NAC. [ABSTRACT FROM AUTHOR]

Aims and Objectives: We examined the prognostic value of Tumor stroma ratio (TSR) in breast tumor core biopsy (TCB) specimen to determine response to neoadjuvant therapy (NAT) prior to modified radical mastectomy (MRM). Methods: This was a retrospective analysis of patients with breast cancer who underwent TCB before NAT between August 2016 and July 2018. TSR in TCB was studied independently by 2 pathologists ( VM, VS) defined as stroma rich (TSR≤50%) or stroma poor (TSR>50%). MRM specimen of these patients were subsequently studied .Residual cancer burden (RCB) was calculated using the MD Anderson RCB calculator, categorized as complete (0), good (1) Partial (2) and no response (3). Statistical analysis was done to assess correlation of TSR to RCB. Results: A total of 62 patients were analyzed. Mean(SD) age was 48(11) years.Twenty eight (45%) and 34 (55%) patients were stroma rich and stroma poor respectively. Twenty six (42%) patients were responders and 36 (58%) non-responders to NAT. Among stroma rich patients, only 3 (10%) were responders (Class 0 &1)and 25 (90%) non-responders(Class2&3)to NAT, among stroma poor patients 23 (68%) responded well and 11 (32%) did not.TSR had a moderate negative correlation with RCB (-0.6). On univariate analysis, only TSR had a significant effect on RCB class (

Human Epidermal Growth Factor Receptor 2 (HER2), a routinely tested breast cancer marker, is associated with worse prognosis yet increased sensitivity to targeted neoadjuvant therapy (NAT) in breast cancer patients. The presence of HER2 in breast carcinoma can be detected with either immunohistochemistry (IHC) or in situ hybridization (ISH). In this study, we examine the relationship between clinicopathological features, HER2 detection method (IHC vs ISH), and prognostic outcomes in NAT‐treated HER2‐positive breast cancer patients. We included 99 HER2‐positive patients from three academic institutions following 2018 HER2 testing updates and conducted a retrospective correlational study. Seventy‐one (72%) were HER2‐positive by IHC and 28 (28%) were positive following reflexive ISH. Multivariate analysis showed biomarker status to be significantly associated with pathologic complete response (pCR) (p = 0.003), Residual Cancer Burden (RCB) (p = 0.007), and tumor size downstaging (p = 0.002) and HER2 detection method of IHC to be significantly associated with pCR (p = 0.05), RCB (p = 0.004), and nodal downstaging (p= 0.03). In conclusion, HER2 detection method and biomarker subtype allow for further prognostic stratification of HER2‐positive patients when 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline updates are applied. [ABSTRACT FROM AUTHOR]

A residual cancer burden after neoadjuvant therapy (NAT) for breast cancer (BC) is associated with worse treatment outcomes compared to patients who achieved pathologic complete remission. This single-institutional retrospective study of 767 consecutive patients, including 468 patients with assessable residual cancer burden (aRCB) after NAT, with a median follow-up of 36 months, evaluated the biomarkers assessed before NAT from a biopsy and after NAT from a surgical specimen, their dynamics, and effect on long-term outcomes in specific breast cancer subtypes. The leading focus was on proliferation index Ki-67, which was significantly altered by NAT in all BC subtypes (p < 0.001 for HER2 positive and luminal A/B HER2 negative and p = 0.001 for TNBC). Multivariable analysis showed pre-NAT and post-NAT Ki-67 as independent predictors of survival outcomes for luminal A/B HER2 negative subtype. For TNBC, post-NAT Ki-67 was significant alone, and, for HER2 positive, the only borderline association of pre-NAT Ki-67 was observed in relation to the overall survival. Steroid and HER2 receptors were re-assessed just in a portion of the patients with aRCB. The concordance of both assessments was 92.9% for ER status, 80.1% for PR, and 92.2% for HER2. In conclusion, these real-world data of a consecutive cohort confirmed the importance of biomarkers assessment in patients with aRCB, and the need to consider specific BC subtypes when interpreting their influence on prognosis.

This study aimed to compare the efficacy and safety of the EC-T (4 cycles of epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2, followed by 4 cycles of docetaxel 75 mg/m2) and TCb (6 cycles of docetaxel 75 mg/m2, intravenous drip (ID), day 1 + carboplatin AUC 6, ID, day 1) neoadjuvant regimens in patients with TOP2A-normal stage II-III breast cancer. This study analyzed 280 patients enrolled from three studies registered with ClinicalTrials.gov (NCT03140553, NCT03154749, NCT03507465) with early TOP2A-normal stage II-III breast cancer who received neoadjuvant chemotherapy, including 100 patients who received the EC-T regimen and 180 patients who received the TCb regimen. The primary endpoint was the ratio of RCB 0/1 (residual cancer burden 0/1) after neoadjuvant chemotherapy. The secondary endpoint was the safety of the two groups. There was no significant difference in the ratio of RCB 0/1 between the two groups (23% vs. 23.9%, p=0.614). Among the triple-negative breast cancer patients, the efficacy did not differ between the two groups (40% vs. 32%, p=0.52). Among the lymph node metastasis patients, the efficacy of the EC-T group was significantly better than that of the TCb group (14% vs. 2.6%, p=0.03). Regarding the side effects, the incidence of grade 3/4 anemia was higher in the EC-T group than in the TCb group (21.0% vs. 8.33%, p=0.002), while the incidence of grade 3/4 neutropenia was higher in the EC-T group than in the TCb group (17% vs. 14.44%, p=0.570), and the incidence of grade 3/4 thrombocytopenia was low in each group (EC-T group: 6% and TCb group: 7.22%, p=0.697). In the EC-T group, grade 3/4 nausea and vomiting occurred in 5 patients. The EC-T group showed a higher rate of grade 3/4 myalgia than the TCb group (7% and 4.44%, respectively, p=0.363). To conclude, the TCb regimen can be used as an alternative regimen for TOP2A-normal stage II-III breast cancer patients in neoadjuvant chemotherapy. However, in patients with node-positive tumors, EC-T is still recommended. Though no difference of grade 3/4 thrombocytopenia in two groups, grade 4 thrombocytopenia caused by the carboplatincontaining regimen should be taken seriously. [ABSTRACT FROM AUTHOR]

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 χ2 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 (∆χ2 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. This article reports on the prognostic value of the Residual Proliferative Cancer Burden index in a cohort of patients with HR‐positive HER2‐negative breast cancer undergoing neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Systemic therapy for breast cancer may be given before (neoadjuvant) or after (adjuvant) surgery. When neoadjuvant systemic therapy is given, response to treatment can be evaluated. However, some prognostic information (for example, pathologic tumor size pretreatment) is then lost and pathologic evaluation of breast specimens after neoadjuvant therapy is more difficult. Pathologic complete response (pCR), defined as no invasive disease in the breast (ypT0/is or ypT0) and no disease in all sampled lymph nodes (ypN0), identifies patients with a lower risk of recurrence or death compared to those with residual disease. Multidisciplinary collaboration, marking of the tumor site and any lymph node involvement pretreatment, and access to specimen imaging to facilitate correlation of gross and microscopic findings are critical for accurate determination of pCR. For HER2‐positive and triple negative tumors requiring systemic therapy, giving the treatment before surgery identifies a high‐risk group of patients that can receive additional adjuvant therapy after surgery if a pCR is not achieved. Recent clinical trials have demonstrated that this approach reduced recurrence risk. More than ever, pathologic evaluation of response to neoadjuvant systemic therapy directs treatment received after surgery. Using a single standardized protocol for sampling of the post‐neoadjuvant surgical specimen allows pathologists to ensure accurate determination of pCR or residual disease and quantify residual disease. Residual cancer burden (RCB) and AJCC stage provide complementary quantitative information about residual disease and prognosis. [ABSTRACT FROM AUTHOR]

Neoadjuvant therapy (NAT) is becoming a common approach to treat breast cancers. The most important advantage of NAT is the opportunity to evaluate the tumor response to treatment within few months after starting the medication. Pathology is the gold standard to determine the post therapy changes and response. An accurate and reproducible pathology report requires a multidisciplinary approach, a standard and appropriate handling of the gross specimen and recognizing the microscopic changes associated with a post NAT specimen. This review focuses on the standard approach for a post NAT breast specimen, based on the available guidelines and other related articles. [ABSTRACT FROM AUTHOR]

Prognostic scores such as Residual Cancer Burden (RCB), Clinical Pathological Score (CPS), and Neo-Bioscore have been introduced to categorize breast cancer patients into different prognostic risk groups after neoadjuvant chemotherapy (NAC). To evaluate the prognostic value of the residual cancer burden index in a large group of Vietnamese breast cancer patients treated with neoadjuvant chemotherapy in real-world settings. 126 patients diagnosed with stage III breast cancer received neoadjuvant chemotherapy according to the AP regimes. After operation of BC, pathologic complete response (pCR) and Residual cancer burden (RCB) were evaluated. All breast cancer patients' survival were analyzed by using Kaplan-Meier and Log-Rank models. The average overall survival (OS) time was 75 months, with 90 (71.4%) recurrence and 82 (65%) mortality. The Kaplan Meier curve between OS and DFS with subgroups RCB indicate that the groups with higher RCB had a lower probability of survival, with statistical significance. Adjusted Cox regression model for age, menstruation, side of breast, clinical respose and overall stage illustrate that patients in RCB group 3 had a 2.7 times higher risk of mortality (95% CI: 1.28–5.67) compared to RCB group 0, p = 0.01. Patients with higher RCB levels had a higher risk of mortality. Stage IIIC, RCB score and RCB group are the independent prognostic factors for predicting survival time of breast cancer patients receiving neoadjuvant treatment. [ABSTRACT FROM AUTHOR]

Abstract Background The tumor immune environment not only modulates the effects of immunotherapy, but also the effects of other anticancer drugs and treatment outcomes. These immune responses can be evaluated with tumor-infiltrating lymphocytes (TILs), which has frequently been verified clinically. On the other hand, residual cancer burden (RCB) evaluation has been shown to be a useful predictor of survival after neoadjuvant chemotherapy (NAC). In this study, RCB and TILs evaluations were combined to produce an indicator that we have termed “RCB-TILs”, and its clinical application to NAC for breast cancer was verified by subtype-stratified analysis. Methods A total of 177 patients with breast cancer were treated with NAC. The correlation between RCB and TILs evaluated according to the standard method, and prognosis, including the efficacy of NAC, was investigated retrospectively. The RCB and TILs evaluations were combined to create the “RCB-TILs”. Patients who were RCB-positive and had high TILs were considered RCB-TILs-positive, and all other combinations were RCB-TILs-negative. Results On multivariable analysis, being RCB-TILs-positive was an independent factor for recurrence after NAC in all patients (p < 0.001, hazard ratio = 0.048), triple-negative breast cancer (TNBC) patients (p = 0.018, hazard ratio = 0.041), HER2-positive breast cancer (HER2BC) patients (p = 0.036, hazard ratio = 0.134), and hormone receptor-positive breast cancer (HRBC) patients (p = 0.002, hazard ratio = 0.081). Conclusions The results of the present study suggest that RCB-TILs is a significant predictor for breast cancer recurrence after NAC and may be a more sensitive indicator than TILs alone.

Substantial advances have been made in the systemic treatment of breast cancer with residual disease following neoadjuvant therapy. We reviewed recent and ongoing studies informing the standard clinical management of residual disease by subtype: HER2+, TNBC, and HR+/HER2-, as well as strategies for BRCA+ disease. We conclude with a discussion of ongoing clinical trials and current controversies regarding the treatment of residual disease in breast cancer., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Abstract Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies. [ABSTRACT FROM AUTHOR]

Background. Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER1), human epidermal growth factor receptor 2-negative (HER2-) disease. Materials and Methods. Women with ER1, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab- Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. Results. Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 01I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009-0.689; p5.0216). Conclusion. Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 01I rate indicates a significant drug antitumor activity with low rates of grade 3-4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; Clinical- Trials.gov: NCT01565499). [ABSTRACT FROM AUTHOR]