Impact Of PCR Research Articles

Pathological Complete Response with Platinum Containing Neoadjuvant Chemotherapy in Triple-negative Breast Cancer: An Interventional Study

Introduction: Triple-negative Breast Cancer (TNBC) accounts for 20% of all breast cancer cases globally and responds well to cytotoxic chemotherapy. The standard Neoadjuvant Chemotherapy (NAC) regimen for TNBC includes 4+4 cycles of anthracycline, cyclophosphamide, and taxane. Integrating platinum agents into the NAC has gained attention as an effective treatment for TNBC. Aim: To estimate the proportion of pathological Complete Response (pCR) in TNBC patients receiving platinum-based NAC. Materials and Methods: This interventional study enrolled 73 non metastatic TNBC patients who attended the radiotherapy Outpatient Department (OPD) of Government Medical College Thiruvananthapuram Kerala, India from April 2022 to April 2023. All patients underwent a complete history, physical examination, and tumour histopathology with Oestrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) receptor status assessment. Patients were treated with the NAC regimen: Epirubicin 90 mg/m2 , Cyclophosphamide 600 mg/m2 intravenously every three weeks for four cycles followed by Paclitaxel 175 mg/ m2 , Carboplatin according to Area Under Curve (AUC)-5 by intravenous administration every three weeks for four cycles. Clinical response was evaluated after the completion of NAC using Response Evaluation Criteria in Solid Tumours (RECIST) criteria. pCR assessment was conducted postsurgery. Study variables were entered into Microsoft Excel, and the analysis was performed using Statistical Packages for Social Sciences (SPSS) version 24.0. Results: Out of 73 patients with a mean age of 54.4 years, 33 (45.2%) patients showed complete response on clinical examination after eight cycles of Carboplatin-containing NAC, and 23 (31.5%) patients achieved pCR. Total 30 (41.1%) patients experienced complications during chemotherapy, with neutropenia and peripheral neuropathy being the most common, each occurring in 22 (30.1%) patients. Conclusion: In present study, one-third of the patients achieved pCR with platinum-based NAC with an acceptable side-effect profile. It represents a beneficial treatment option for TNBC patients; however, the impact of pCR on survival requires further validation through long-term studies. Given the poor prognosis and limited treatment options for TNBC, the addition of affordable and available agents to the existing chemotherapy regimen could potentially revolutionize the treatment of these patients.

Impacts of HER2 immunohistochemical scores on response and outcomes of HER2-positive breast cancers after neoadjuvant therapy.

Neoadjuvant systemic therapy (NST) is conducted in increased number of patients with breast cancer overexpressing human epidermal growth factor receptor 2 (HER2). Whether the intensity of HER2 protein expression determines response to treatment is challenged. This study aims to analyze the impact of HER2 immunohistochemical (IHC) scores on NST response and survival outcome. We analyzed a total of 197 patients with HER2-positive breast cancer receiving NST and definite surgery from a prospectively collected database. The analyzed endpoints included pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). More patients with IHC 2+/ in situ hybridization (ISH)-positive tumors presented positive for hormonal receptors, compared with those with IHC 3+ tumors. No clinicopathological features except tumor necrosis were significantly associated with pCR. Both positive hormone receptors and IHC scores stood on the borderline in statistical analysis. IHC 3+ group tends to present a higher pCR rate than IHC 2+/ISH+ groups (52.5% vs. 34.3%). Patients who achieved pCR had better survival outcome than that of non-pCR group. The impact of pCR on survival reached the statistical significance in the IHC 3+ group both in DFS (90.9% vs. 76.5%; p = 0.004) and OS (97.4% vs. 83.2%; p = 0.002). Multivariate analysis demonstrated IHC scores as an independent predictor of survival outcome with the adjustment of tumor staging and pCR. HER2 IHC score is an independent predictor for outcome. IHC 3+ tumors presented a trend of higher pCR rate and better outcome in HER2-positive breast cancer patients who receive NST.

Integrative review of clinical trials and meta-analysis of the main studies of neoadjuvant chemotherapy in the treatment of breast cancer in the past 30 years

Neoadjuvant chemotherapy (NAC) has become a common treatment strategy for early-stage breast cancer. In this study, we conducted a systematic research in the PubMed database using the following terms: breast cancer, neoadjuvant chemotherapy, randomized clinical trials, complete pathological response, overall survival, and disease-free survival. The research has been limited to articles published in the past 30 years (1993–2023). We included only randomized clinical trials that evaluated the use of NAC in breast cancer and data on PCR rates and survival outcomes. Our research resulted in a total of 13 randomized clinical trials and two meta-analyses. The PCR rates ranged from 13% to 58%, with higher rates observed in patients with triple-negative breast cancer (TNBC) and human epidermal growth factor 2 (HER-2+) disease. Several trials reveal a significant association between PCR and better survival results, including overall survival and disease-free survival. However, the impact of PCR on survival results was less consistent in patients with hormone receptor-positive breast cancer. The use of taxanes in combination with anthracyclines has been the most common NAC scheme evaluated in these trials. The PCR rates have been associated with better survival outcomes, in patients with TNBC and HER-2+ disease. However, the impact of PCR on survival outcomes in patients with hormone receptorpositive breast cancer is less clear. Additional studies are needed to determine the optimal NAC regimen for each subtype of breast cancer and to identify biomarkers that can predict the NAC response.

Abstract ES1-1: Escalating and de-escalation - titrating the right regimen in early stage HER2 positive

Abstract In HER2+ early breast cancer (EBC), treatment concepts so far do not differ according to hormone receptor (HR) status except for adding adjuvant endocrine therapy (ET) in HR+. Nevertheless, preclinical research shows that molecular subtype distributions differ between HR+ and HR- HER2+ with HER2-enriched subtype being more frequent in HR-. In the context of anti-HER2 therapy the clinical impact of biomarkers such as PIK3CA mutations also differs between HR+ and HR-. Moreover, in the neoadjuvant setting, pCR rates differ between HR+ and HR- HER2+ EBC with lower rates in HR+. Yet, the prognostic impact of pCR on outcome in HR+ HER2+ is less pronounced than in HR- HER2+ tumors. Standard therapy for small tumors (pT1 pN0) includes primary surgery followed by adjuvant weekly paclitaxel and 1y trastuzumab, independent of HR status. In all larger node-negative and in node-positive tumors, neoadjuvant chemotherapy with dual HER2 blockade is recommend. Adjuvant therapy is then individualized based on pCR status with antibody therapy continued for 1y in case of pCR and 14 cycles of T-DM1 in case of non-pCR. Based on the ExteNET trial, 1y neratinib is approved as an extended adjuvant anti-HER2 therapy. In Europe, the approval is restricted to high-risk HR+ HER2+ EBC within 1y after trastuzumab therapy based on ExteNET subgroup analyses. Escalation of the endocrine component in high-risk HR+ HER2+ EBC is currently evaluated in eMonarcHER2 by adding abemaciclib to T-DM1 and ET after non-PCR. Regarding de-escalation, TBCRC0023, one of the first chemotherapy-free de-escalation studies in HER2+ EBC, looked at duration of neoadjuvant trastuzumab and lapatinib - in HR+ tumors together with letrozole (+ GNRH if premenopausal). Longer therapy duration led to higher in-breast pCR rates, particularly in the ER+ subgroup (33% after 24 vs. 9% after 12 weeks). WSG ADAPT was the first subtype-specific umbrella trial aiming at tumor-biology adapted therapy de-escalation in EBC; all neoadjuvant sub-trials evaluated 12 weeks of preoperative therapy and allowed patients with a pCR to omit further standard chemotherapy. For HR+/HER2+, there are two neoadjuvant trials, ADAPT TP (triple-positive) and TP II, so far. In ADAPT TP, 4x T-DM1 led to a total pCR (breast and nodes) of 41% - independent of concomitant ET, whereas trastuzumab + ET only rendered 15%. pCR was prognostic for outcome; in patients with pCR, further standard chemotherapy did not improve survival. In TP II, 12x weekly paclitaxel + trastuzumab + pertuzumab achieved a total pCR rate of 57%, whereas the antibodies alone + ET rendered 24%. Individualizing therapy by escalation or de-escalation holds great promise in HER2+ EBC, but the full potential of taking HR-status into account for such strategies has not yet been explored. We now know that a pCR achieved with a de-escalated regimen is clinically meaningful and that de-escalation trials are safe for participating patients in HR+ HER2+ EBC - provided patients and physicians have the option for therapy escalation if clinically needed. The neoadjuvant strategy offers an ideal setting for de-escalation and escalation concepts based on pCR status as well as on early response assessment by biomarkers and conventional or molecular imaging. Optimal endpoints in HR+ HER2+ disease differ according to molecular subtype. As demonstrated in ADAPT TP, HER2-enriched subtype is associated with high pCR rates after HER-targeting regimens whereas luminal A and B subtypes have lower pCR rates. In luminal tumors, survival endpoints may thus be more appropriate to fully evaluate de-escalated regimens.In clinical routine, individualized therapy concepts including therapy de-escalation and escalation should always be evidence-based in order not to jeopardize the already excellent survival rates we have achieved over the last decade in HR+ HER2+ EBC. Citation Format: Escalating and de-escalation - titrating the right regimen in early stage HER2 positive [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES1-1.

Real-world outcomes of neoadjuvant treatment for HER2 positive early-stage breast cancer.

e18791 Background: Patients with HER2 positive early-stage breast cancer (ESBC) with residual disease (RD) following neoadjuvant therapy derive benefit from treatment escalation. However, treatment modifications for patients who achieve a complete pathologic response (pCR) remains controversial. The Neo-Bioscore is a validated prognostic tool used for patients with ESBC treated neoadjuvantly. To understand the impact of pCR on outcomes in a real-world setting, and better refine patient selection for treatment escalation or de-escalation, we investigated the use of the Neo-Bioscore and/or other prognostic variables. Methods: Patients diagnosed from 2005 to 2014 with stage I-III HER2 positive breast cancer and treated with neoadjuvant systemic therapy were identified from the BC Cancer Breast Cancer Outcomes Unit database. Outcomes of interest included breast cancer specific survival (BCSS), overall survival (OS), distant disease- free survival (DRFS), and locoregional recurrence free survival (LRFS), and were assessed using the Kaplan-Meier method, comparing the pCR and RD groups. Multivariate analysis was used to assess clinical and pathologic prognostic factors beyond pCR. Results: Of the 417 patients meeting inclusion criteria, median age was 50, including 38.1% with clinical stage 2 and 58.3% with clinical stage 3 disease and 59.5% with hormone receptor (HR) positive tumors. 98.1% received chemotherapy and 92.6% received trastuzumab. Median follow-up was 9.6 years (9.2, 10.0). Overall, 193 patients (46.3%) achieved a pCR. Those with RD had higher clinical T stage (p < 0.01) and more HR positive disease (p < 0.01). Patients who achieved a pCR had significantly better 5-year BCSS (91.2% vs. 74.8%, p< 0.0001), OS (90.7% vs. 69.9%, p< 0.0001), DRFS (87.9% vs. 66.3%, p< 0.0001) and LRFS (98.9% vs. 92.5%, p= 0.007) in univariate analyses. In multivariate analyses, the neo-bioscore (1 vs 5: HR 0.05, 95% CI 0.003,0.666, p = 0.02), higher pathological T stage (ypT3 vs ypT0: HR 7.2, 95% CI 1.3, 40.9, p = 0.03) and pathological N stage (ypN1 vs ypN0: HR 2.2, 95% CI 1.1, 4.5, p = 0.03) were associated with BCSS, whereas patients’ age, ER status and baseline clinical T and N stage were not. Conclusions: In a real-world population, ESBC patients with HER2 positive tumors treated with neoadjuvant systemic therapy who achieved pCR derived significant improvements across all survival parameters compared to those with RD. However, distant relapses still occurred in 12% of patients who achieved pCR. Further analyses to identify patients with pCR who relapsed are underway to determine who may benefit from treatment escalation. The final pathological stage and neo-bioscore for patients with RD were prognostic in a real-world cohort and should be considered for adjuvant treatment decisions. Validation of these results in an independent cohort are also ongoing to better understand predictive and prognostic variables.

Pathologic Complete Response Following Neoadjuvant Therapy for Gastric Adenocarcinoma: A National Cancer Database Analysis on Incidence, Predictors, and Outcomes.

With advances in multimodal therapy, survival rates in gastric cancer have significantly improved over the last two decades. Neoadjuvant therapy increases the likelihood of achieving negative margins and may even lead to pathologic complete response (pCR). However, the impact of pCR on survival in gastric cancer has been poorly described. We analyzed the rate and predictors of pCR in patients receiving neoadjuvant therapy as well as impact of pCR on survival. We conducted a National Cancer Database (NCDB) analysis (2004-2016) of patients with gastric adenocarcinoma who received neoadjuvant chemotherapy followed by surgical resection. The pCR rate was 2.2%. Following adjustment, only neoadjuvant chemoradiation, non-signet histology, and tumor grade remained as significant factors predicting pCR. pCR was a statistically significant predictor of survival. In this NCDB study, pCR was a predictor of survival. Though chemoradiation rather than chemotherapy alone was a predictor of pCR, it was not a predictor of survival. Further studies are needed to elucidate the role of radiation in the neoadjuvant setting and to discern the impact of pCR on survival.

Abstract P2-16-25: Young age breast cancer who achieve pathologic complete response after neoadjuvant chemotherapy display excellent outcome than older age breast cancers

Abstract Introduction: Patients with pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) is known to have a good prognosis compared with patients with no residual disease necessitating additional adjuvant systemic therapy for some population. Also there are cases of recurrence and/or death among patients with pCR. We aimed to 1)analyze whether prognostic impact of pCR differ across subtypes and age groups and 2)investigate factors associated with outcome after achieving pCR. Methods: Among 1930 patients who underwent NCT at Asan Medical Center between 1890 to 2018, 1688 patients with clinico-pathological, follow-up data available were analyzed. 339 (20.1%) patients had pCR defined as ypT0/Tis with no residual nodes(N0) after NCT. Pathologic CR rate were 10.2% (102/1003), 40.0% (100/250) and 31.6% (137/434) in each HR positive, HRneg/HER2pos and triple negative tumors. Pathologic CR rate were 19.7% (232/1175) and 20.9% (107/513) in young age and old age group respectively. Results: Median follow up period was 62 months (6-129 months). Five-year disease free survival (5yr-DFS) of ‘total’ patients and patients with ‘no-pCR’ and ‘pCR’ were 81.7%, 79.1% and 92.4% respectively (p=<0.01). Pathologic complete response was significant favorable indicator across all subtypes and both in young/old age group (Cox regression analysis in each group, Table 1). Among patients with pCR, residual in-situ disease (p=<0.01, HR 3.889), tumor size>5cm (p=0.006, HR=1.45), and negative hormone receptor (p<0.01, HR=9.269) were independently associated with worse disease free survival. These prognostic factors were similar in patients with residual disease as well. Intriguingly, magnitude of impact affecting prognosis differed by age groups that younger patients (≤50) who achieved pCR displayed excellent outcome similar to older age group (HR=1.33, CI 0.57-3.12, p=0.51). On the other hand, young age patients who did not achieve pCR had the worst outcome with 5yr-DFS 77.3% indicating the necessity of additional systemic therapy. Also, while HR negative tumors are known to have worse outcome, HRneg/pCR group had longer 5yr-DFS than HRpos/no-pCR groups (90.6% vs 83.9%, p=0.009). The outcomes were similarly observed for overall survival analysis. Conclusion: Patients with pCR after NCT showed better DFS and OS across all subtypes. Achieving pathologic complete response was a good prognostic indicator especially in young age population. Younger patients with residual disease after NCT may be candidates for additional adjuvant systemic therapy after surgery. Table1. Cox regression analysis in each grouppCRNo-pCRHazard ratio (ref, pCR)95%CIP value5yr-DFS (%)5yr-DFS (%)SubtypesHR positive96.183.93.081.35-7.020.007HRneg/HER2pos89.672.02.431.13-5.220.023HRneg/HER2pos91.567.83.591.87-6.89<0.001AgeYoung age (≤50)93.377.34.502.53-8.08<0.001Old age (>50)90.183.42.251.06-4.750.033 Citation Format: Young Joo Lee, Yung Il Shin, Jisun Kim, Sae Byul Lee, Hee Jeoung Kim, Il Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei-Hyun Ahn. Young age breast cancer who achieve pathologic complete response after neoadjuvant chemotherapy display excellent outcome than older age breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-25.

Rapid Diagnostic Testing as a Tool for Guiding Treatment of Infectious Disease in Elite Athletes

PURPOSE: To describe the most common etiologies of upper respiratory tract infections (URI) in elite athletes presenting to an ambulatory sports medicine clinic as diagnosed with polymerase chain reaction rapid diagnostic testing (PCR). METHODS: Retrospective analysis of medical records from 42 patient-athletes who presented to a sports medicine clinic for evaluation of URI. Clinic care pathways identify a criterion for the implementing PCR testing of patient’s presenting with symptoms and objective signs of an URI. Descriptive statistics were used to describe the etiology of URI in this cohort. RESULTS: 42 URI cases met clinical criteria for PCR testing. 22 of these cases yielded positive identification of at least one pathogen. 21 of the 22 positive cases represented viral agents (95%). Influenza was the responsible agent in 50% of positive cases. Chlamydia pneumoniae was the sole bacterial pathogen identified. There were 3 cases of co-infection composed of multiple viral pathogens. CONCLUSION: Viral pathogens are the most common cause of URI in the elite athlete population. The identification of viral URI with PCR testing in athlete populations provides for the opportunity to implement evidence-based management. The significant number of negative PCR findings in patients with upper respiratory symptoms suggests there are additional unidentified etiologies for respiratory symptoms in athletes. The impact of PCR on the treatment strategies and outcomes of URI requires further investigation.

HSR19-106: Association Between Pathological Complete Responses and Long-Term Survival Outcomes Among Triple-Negative Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Objective: Pathological complete response (pCR) has been a commonly used endpoint in neoadjuvant trials for breast cancer (BC). A pooled analysis of 12 neoadjuvant BC trials by Cortazar et al (2014) reported a positive association between pCR and long-term survival outcomes among patients with general BC and certain subtypes including triple negative BC (TNBC). To update and extend the evidence to assess the association of pCR and survival outcomes in TNBC, this study reviewed and summarized cohort studies and recent clinical trials in the literature. Methods: English publications reporting association between pCR and survival outcomes among TNBC patients receiving neoadjuvant chemotherapy were searched in MEDLINE, EMBASE, Cochrane CENTRAL, and Northern Light Sciences Conference Abstracts. Full-text publications from all years and conference abstracts since year 2016 were identified. Relevant clinical trials, real-world evidence (RWE) studies, and meta-analyses were included for review and extraction. Results: Of total 1,880 publications retrieved, 35 reported association between pCR and survival outcomes for neoadjuvant TNBC (9 clinical trials, 21 RWE studies, and 5 pooled/meta-analyses). The sample size of TNBC patients varied between 25 and 1,645. Different pCR definitions were used across studies, of which absence of tumor in the breast and axillary nodes was most common (N=29). The prognostic impact of pCR was evaluated for multiple survival outcomes: overall survival (OS; N=19), disease-free survival (DFS; N=14), relapse-free survival (RFS; N=7), event-free survival (N=5), distant DFS (N = 4), and local RFS (N=2). Kaplan-Meier analysis was used to assess the association between pCR and these outcomes in 31 studies. Clear separation of survival curves in favor of pCR was observed in all the studies. Log-rank tests were conducted in 18 studies, and statistically significant association was reported in majority of them, except for 1 RWE study with small sample size (N=35) and 1 pooled analysis with a different pCR definition (absence of tumor in the breast) than most of the others. Cox proportional hazards model was used in 17 studies, wherein hazard ratios of survival outcomes comparing pCR vs non-pCR ranged from 0.08 to 0.53. Conclusions: Despite divergent study designs and pCR definitions, evidence from both clinical and real-world settings consistently suggest that pCR is a strong predictor of OS and other survival outcomes among TNBC patients.

Abstract P1-15-19: Carboplatin-addition in neoadjuvant treatment of women with triple negative breast cancer (TNBC): Prognostic value in real-world patients

Abstract Background The addition of carboplatin to an anthracycline/taxane-based chemotherapy(CT) in neoadjuvant setting has been suggested to improve pathological complete response(pCR) in TNBC. However, the impact of pCR in prognosis is unknown. We aim to study the value and feasibility of the addition of carboplatin in neoadjuvant setting. Methods Demographic and clinical data of TNBC patients treated with neoadjuvant CT in a comprehensive cancer center between 2010-2018 were retrospectively collected. Two cohorts were defined: one treated with Carboplatin/Paclitaxel followed by dose-dense Doxorrubicin/Cyclophosphamide(CP-AC) and other with AC followed by Docetaxel(AC-D). Median follow-up time was 3.1 and 6.9 years, respectively. pCR was defined as absence of residual invasive tumor in breast/axilla. Survival analysis using Kaplan-Meier method and Cox proportional-hazards model were applied. Statistical significance was set at p<0.05. Results One-hundred and sixty patients were enrolled: 78 CP-AC and 38 AC-D. Groups were balanced regarding patients and tumor characteristics with exception of pre-menopausal status, more frequent in CP-AC(68% vs 47%;p=.04). Age at diagnosis was 47(28-76)years, the majority had ECOG 0(92%) ductal carcinomas(82%), clinicalT2/3 stages(76%), grade 3(81%) with lymph node involvement(N+)(57%). 14% had Inflammatory breast cancer(IBC)(CP-AC 14%;AC-D 13%; p=.9). Neutropenia was the most prevalent adverse event(G3/4: CP-AC 61%;AC-D 16%;p=.02), 12% and 16% of febrile neutropenia(p=.8). G3/4 thrombocytopenia occurred only in CP-AC(6%). Hypersensitivity reactions were more prevalent in CP-AC(19% vs 2.7%;p=.02), majority to paclitaxel, all G1/2. Hospital admission occurred in 12%(CP-AC 13%;AC-D 9%; p=.8). There were no treatment-related deaths. Treatment schedule was complete in 89%(CP-AC 87%;AC-D 92%;p=.5), with 20% dose reductions(CP-AC 25%;AC-D 11%;p=0.9). pCR was achieved in 42%(CP-AC 50%;AC-D 28%;p=.03). 1- and 3-year disease-free survival(DFS) was 94%/85% for CP-AC and 72%/58% for AC-D(p=.3). Risk of recurrence was higher in IBC(HR 25.1;CI95% 7.7-81.3;p<.0001), N+ disease(HR 3.6;CI95% 1.2-10.5;p=.02) and non-pCR(HR 10.9;CI95% 2.3-52.3,p=.003). N+ disease was associated with higher recurrence only in AC-D(HR 11.7;CI95% 1.3-104;p=.03). Cancer-related deaths were 20%(CP-AC 10%;AC-D 40%;p=.001). 1- and 2-year overall survival (OS) was 99%/95% for CP-AC and 70%/61% for AC-D(p=.06). N+ disease was associated with higher risk of death in AC-D(HR 6.3;CI95% 1.1-24.6;p=.04). Risk of death was independently associated with IBC(HR 4.1;CI95% 2.1-18.7; p=.001) but not with N+ disease(HR 2.7;CI95% 0.8-9.5;p=.13) or pCR(HR 4.1;CI95% 0.9-19.7;p=.08) although pCR was statistically significant in univariate analysis (1- and 2-year OS 97% vs 92% and 94% vs 86% for pCR and non-PCR;p=.003). Conclusions Carboplatin addition clearly increased pCR with a trend to DFS and OS benefit. This regimen was associated with more, nevertheless manageable, adverse events with most of the patients able to tolerate and complete the full-dose regimen. Though we did not find a subgroup of patients that benefit with carboplatin regimen, we should consider avoiding AC-D at least in N+ disease. Citation Format: Coelho S, Abreu MH, Sales C, Lopes AR, Sousa MF, Couto R, Pousa I, Ferreira A, Ferreira M, Vieira C, Leal C, Castro F, Sousa S, Pereira D. Carboplatin-addition in neoadjuvant treatment of women with triple negative breast cancer (TNBC): Prognostic value in real-world patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-19.

Magnetic Resonance, Vendor-independent, Intensity Histogram Analysis Predicting Pathologic Complete Response After Radiochemotherapy of Rectal Cancer

The objective of this study is finding an intensity based histogram (IBH) signature to predict pathologic complete response (pCR) probability using only pre-treatment magnetic resonance (MR) and validate it externally in order to create a workflow for the external validation of an MR IBH signature and to apply the model out of the environment where it has been tuned. The impact of pCR and the final predictors on the survival outcome were also evaluated. Three centers using different MR scanners were involved in this retrospective study. The first center recruited 162 patients for model training, and the second and third centers provided 34 plus 25 patients for external validation. Patients provided written consent. Accrual period was from May 2008 to December 2014. After surgery pathologic response was defined. T2-weighted MR scans acquired before chemoradiation therapy (CRT) were used for analysis addressed on primary lesions. Images were pre-processed using Laplacian of Gaussian (LoG) filter with multiple σ, and first order intensity histogram-based features (kurtosis, skewness, and entropy) were extracted. Features selection was performed using Mann-Whitney test. Tumor staging (cT, cN) was added to build a logistic regression model and predict pCR. Model performance was evaluated with internal and external validation using area under the curve (AUC) of the receiver operator characteristic (ROC) and calibration with Hosmer-Lemeshow test. The linear cross-correlation matrix (Pearson's coefficient) and the variance inflation factor (VIF) were used to check the correlation and the co-linearity among the final predictors. The amount of the information added through the radiomics features was estimated by using the DeLong's test, and the impact of pCR and the final predictors on survival outcomes were evaluated through the Kaplan-Meier curves by using the log-rank test and the multivariate Cox model. Candidate-to-analysis features were skewness (σ=0.485, P value=.01) and entropy (σ=0.344, P value<.05). Logistic regression analysis showed as significant covariates cT (P value<.01), skewness-σ=0.485 (P value=.01), and entropy-σ=0.344 (P value<.05). Model AUCs were 0.73 (internal) and 0.75 (external). This MR-based, vendor-independent model can be helpful for predicting pCR probability in locally advanced rectal cancer (LARC) patients only using pre-treatment imaging.

Discrepancy of pathologic complete response and outcome between breast tumor and axillary node in HER2 positive breast cancer after neoadjuvant chemotherapy.

e12503 Background: The pathologic complete response (pCR) rate in primary tumor and axillary node after different chemotherapy regimens of neoadjuvant chemotherapy (NAC) in HER2 positive breast cancer (BC) is unknown, the impact of pCR on disease free survival (DFS) and overall survival (OS) is still controversial. Methods: A cohort of 350 HER2 positive BC (296 cytologically proved axillary node metastasis) received NAC with different regimens, antracyclin with taxotere (AT), docetaxel with transtuzumab (DT) and docetaxel with transtuzumab and pertuzumab( DTP) between 2005 and 2016 in a large medical center were analyzed retrospectively. The impact of pCR rates of breast and axillary node on DFS and OS were analyzed. Results: Of 350 women with HER2 positive BC received NAC, median age was 50 years(18~93), median tumor size was 4.3 cm, the pCR rates of breast and axillary node were 16.2% and 28.7% ( P= 0.018) in patients received AT( n= 130) , 47.6% and 66.9% ( P= 0.00028 ) in patients received DT( n= 191) ,65.5% and 77.8% ( P= 0.372 ) in patients received DTP( n= 29), respectively. The 5-year DFS were 79.3% and 66.0% ( p= 0.0023), 5-year OS were 89.5% and 76.6% ( P= 0.0201) in patients with breast pCR and non-pCR, respectively. The 5-year DFS were 75.7% and 58.4% ( P= 0.00037), 5-year OS were 85.7% and 72.6% ( P= 0.0024) in axillary pCR and non-pCR patients, respectively. The 5-year DFS were 79.3% and 75.7% ( P= 0.430), and 5-year OS were 89.5% and 85.7% ( P= 0.695) in breast and axillary pCR, respectively . The 5-year DFS in breast pCR whom received targeted therapy (DT and DTP groups) was significantly better than whom not received targeted therapy (AT groups), 85.3% and 65.0% ( P= 0.039), respectively Conclusions: Higher pCR rate in axillary node than breast was found in this cohort. Either pCR in axillary node or breast was associated with improved DFS and OS, but no difference of DFS and OS between breast and axillary pCR . The 5-year DFS in breast pCR received targeted therapy were significantly better than breast pCR patients received chemotherapy alone.

P03.25 Impact of PCR based molecular analysis in daily diagnosis for the patient with gliomas

P03.25 Impact of PCR based molecular analysis in daily diagnosis for the patient with gliomas

Abstract P5-16-02: Pathological complete response is associated with excellent outcomes in BRCA mutation associated triple negative breast cancer

Abstract Introduction: Pathological complete response (pCR) in unselected triple negative breast cancer (TNBC) is associated with excellent long-term survival. However, controversy remains as to whether pCR in BRCA mutation associated (BRCA[+]) TNBC is predictive of improved long-term outcome. A recent study suggests that pCR was not a surrogate for outcomes in BRCA1 associated TNBC. All of the patients in this study harbored an Ashkenazi Jewish founder BRCA1 mutation and the majority of mutation carriers underwent lumpectomy. Impact of pCR as it relates to BRCA status in a larger, heterogeneous TNBC cohort treated in a contemporary time frame is not known. Aim: Evaluate and compare the prognostic impact of pCR as it relates to the BRCA mutation status in patients enrolled in a prospective multisite TNBC registry. Methods: 453 patients with stage I-III TNBC were enrolled within a multisite registry between 2011- 2015, out of which 173 received neoadjuvant chemotherapy (NAC) and also underwent germline BRCA testing. pCR in the breast and axilla was evaluated and patients were followed for reoccurrence and survival. Recurrence free survival (RFS) was estimated according to the Kaplan-Meier method and compared among groups with log-rank statistic. Results: For the 173 eligible patients the median age was 49 years; African-American:14%; median tumor size:3 cm; 42%:Lymph node positive; and 18% (32/173) demonstrated BRCA mutation (BRCA1=28, BRCA2=4). All patients received anthracycline and/or taxane based NAC. pCR rates for BRCA[+] and wild type (BRCA[-]) patients was 72% and 46% respectively (p=0.01). 97% of BRCA[+] and 42% of BRCA[-] patients underwent bilateral mastectomy (p=0.001). The three year RFS was 92% and 81% in BRCA[+] and BRCA[-] patients, respectively (p=0.18). Attainment of pCR was associated with excellent 3 year RFS of 95% and 97% in BRCA[+] and BRCA[-] patients, respectively (p=0.85). Among BRCA[-] patients lack of pCR was associated with significantly worse 3 year RFS (70% RFS in patients without pCR, compared to 97% in patients with pCR; p=0.001). Among BRCA[+] patients lack of pCR was associated with numerically lower but not statistically significant worse 3 year RFS (83% RFS in patients without pCR, compared to 95% in patients with pCR; p=0.41). On multivariable Cox regression analysis, only stage III disease was associated with higher risk of relapse (p&amp;lt;0.001). Conclusions: Our observation of higher pCR in BRCA-carriers compared to wild-type TNBC patients is consistent with previously published literature. In this contemporary cohort of TNBC patients for whom the majority of BRCA[+] patients underwent bilateral mastectomy, attainment of pCR carried an excellent prognosis in both BRCA[+] and BRCA[-] patients. On the other hand, BRCA[+] patients who do not attain pCR may have better outcomes compared to BRCA[-] patients without pCR. Further research to explore the underlying biological mechanisms involved in tumor response and relapse in BRCA[+] and BRCA[-] TNBC patients is needed. Furthermore, given these observations, germline BRCA mutation status should be used as a stratification variable in studies evaluating pCR and long term outcomes with investigational therapies in TNBC. Citation Format: Prochaska LH, Godwin AK, Kimler BF, Lehn C, Klemp JR, O'Dea A, Elia M, Hoffmann MS, Crane G, McKittrick R, Sheehan M, Graff SL, Madhusudhana S, Khan QJ, Jensen RA, Sharma P. Pathological complete response is associated with excellent outcomes in BRCA mutation associated triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-02.

Abstract OT2-04-03: An intrinsic subtype-based platform of translational randomized phase II trials of response-guided neoadjuvant therapy in breast cancer (PREDIX)

Abstract Background: Pathologic complete response (pCR) after neoadjuvant therapy of breast cancer is associated with a better prognosis. The impact of pCR on outcome differs between intrinsic subtypes. Trial design: With the aim to improve treatment on an individual level, the PREDIX platform is designed as a compilation of randomized phase II studies based on functional "intrinsic subgroups" with the intention to direct treatment in relation to response. Four trials will be pursued: 1.Luminal A,N- (ER+ and/or PR+ without node metastases and age &amp;gt;40); 2.Luminal A,N+ (ER+ and/or PR+ with node metastases or age ≤40)/Luminal B (ER+ and high proliferation); 3.HER2 amplified (including HER2 positive luminal B tumors); 4.Triple-negative (this trial is currently in planning phase) The clinical management is accompanied by repeated core biopsies and blood sampling. Besides mammography and ultrasound, functional imaging with PET-CT, confined to the breast and regional lymph nodes is applied. Treatment plan: Trial 1. Eligible patients are treated with endocrine therapy (ET) for 4 weeks. A biopsy for Ki67 is obtained before start and after 2 weeks. If no decrease of Ki67 is observed, or no objective response (OR) is seen after 4 weeks of treatment, palbociclib is added to ET. Patients with decrease of Ki67/OR are randomized to continuous therapy with or without the addition of palbociclib for 12 weeks, followed by surgery. Trial 2. Patients are randomized to 12 weeks of palbociclib + ET or weekly paclitaxel, followed by switch to the other arm for additional 12 weeks before surgery. Trial 3. Patients are randomized to the combination of pertuzumab + trastuzumab + docetaxel or trastuzumab emtasine for 2 three-weekly cycles. If OR is documented, 4 additional cycles will be administered followed by surgery. Non-responding patients will switch to the opposite arm. In trials 2 and 3, additional anthracycline-based chemotherapy will be administered postoperatively. Adjuvant ET and radiotherapy will be used according to standard practice. Eligibility criteria: Patients &amp;gt;18y with primary breast cancer &amp;gt;2 cm or node metastases, with adequate performance status and organ function are eligible. Intrinsic subtype defined by immunohistochemistry or, preferably, by genomic profiling using RNA Seq. Specific aims: To evaluate the impact of response-guided treatment on objective response and long-term outcome and to identify tumor characteristics and treatment-related changes of tumor biology predictive of long-term prognosis. Statistical methods: The PREDIX trials are based on current knowledge of molecular characteristics of breast cancer and designed to find the distribution of objective response to primary medical treatment (primary endpoint) and to find predictors of response, disease-free and overall survival, and to evaluate toxicity and quality of life in the two treatment groups (secondary endpoints). Present accrual and target accrual: Present accrual (May 2015) in the HER2 positive trial is 14 patients. Trials 1 and 2 will open in July and September 2015. Target accrual is based on an explorative design and is between 180 to 200 patients in each trial. Citation Format: Foukakis T, Hellström M, Johansson H, Bergh J, Hatschek T. An intrinsic subtype-based platform of translational randomized phase II trials of response-guided neoadjuvant therapy in breast cancer (PREDIX). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-04-03.

The impact of PCR on Clostridium difficile detection and clinical outcomes.

PCR has increasingly replaced toxin A and B enzyme immunoassay (EIA) for the testing of Clostridium difficile infection (CDI). This study evaluated the clinical outcomes of CDI and disease epidemiology since the introduction of PCR. Clinical data and outcomes for patients admitted to a tertiary care centre during 2003 to 2012 were extracted using electronic medical records. Outcomes and incidence of disease were compared between types of CDI testing. In total, 15.6% of 108,092 patients admitted were tested for CDI. Among patients tested, 6.1% had positive results. The mean number of tests performed per 1000 admissions by EIA and PCR was 257.4 and 162.6, respectively. A total of 8.2% of PCR tests were positive compared to 5.0% of EIA tests (P < 0.001). The number of tests performed has decreased and the proportion of positive tests increased since PCR introduction. CDI incidence has remained constant. Only albumin (3.09 vs 3.24 g dl(-1), P 0.002) and inflammatory bowel disease (2.6 vs 7.0%, P < 0.001) status differed between the EIA and PCR groups. While hospital mortality did not differ, patients diagnosed by PCR had a shorter median length of stay (10 vs 8 days, P 0.004). Since PCR testing began, less CDI tests have been performed, but the proportion of positive results has increased. The incidence of CDI has remained constant, suggesting no change in disease epidemiology. The length of stay was shorter in the PCR group, reflective of either earlier detection and quicker onset of therapy or detection of less severe disease. Mortality did not change since the introduction of PCR.

Pathologic complete remission after preoperative high-dose-rate brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized multicenter study.

The role of preoperative intrauterine brachytherapy (BT) in the multidisciplinary treatment of early stage cervical carcinoma (ESCC) is controversial. In 2005, a prospective randomized multicenter study was initiated in Hungary in order to explore the potential advantages of preoperative high-dose-rate (HDR) BT. In this article we evaluate the efficiency of preoperative HDR BT by the rate of pathologic complete remission (pCR) in the first 185 patients enrolled in the study at the National Institute of Oncology and at the Uzsoki Municipal Cancer Center in collaboration with the 1st Department of Gynaecology and Obstetrics of Semmelweis University, Budapest, Hungary. In arm A, patients received 2x8Gy preoperative intracavitary HDR BT, while in arm B no preoperative treatment was given. In both arms patients underwent radical Wertheim (Piver III) hysterectomy. The pCR rate was 25.7% after preoperative HDR BT, while it was only 11.2% with surgery alone (p=0.03), in these cases the tumor was eliminated during the diagnostic excision or conisation. The rate of positive surgical margins was 1.5% after preoperative BT, while it was as high as 11.4% without preoperative RT (p=0.02). There was no significant difference in the local tumor control (LTC), distant metastases free survival (DMFS) and overall survival (OS) between the two arms. According to our preliminary results preoperative intracavitary HDR BT significantly increases the rate of pCR and decreases the rate of positive surgical margins in patients with ESCC. Longer follow-up is required to establish the possible impact of pCR on the ultimate LTC and OS.

Pathologic complete response after neoadjuvant chemotherapy in HER2-overexpressing breast cancer according to hormonal receptor status

ObjectiveFor patients with HER2-positive breast cancer, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is unclear when stratified by hormonal receptor (HR) status; however, the impact of pCR on survival when stratified by hormonal receptor (HR) status is uncertain. Patients and methodsThis multicenter retrospective study investigated the predictors of pCR and its prognostic value in Japanese patients 366 HER2-positive breast cancer who received NAC. pCR was defined as no invasive residual tumor in the breast or axilla. ResultsMedian follow-up was 55 months. Multivariate analysis revealed that HR status (OR, 0.37; p < 0.001) was one of the independent predictors of pCR. Five-year recurrence-free survival was higher in HR-negative patients with pCR (93%) than in those without pCR (68%), and pCR was independently prognostic (hazard ratio, 0.32; p = 0.005). However, 5-year recurrence-free survival was not different between HR-positive patients with pCR (94%) and those without pCR (84%), and pCR was not significantly prognostic (hazard ratio, 0.53; p = 0.39). In addition, 5-year overall survivals were high and similar (97% in pCR, 94% in non-pCR). Among 204 patients treated with neoadjuvant trastuzumab, pCR was not significantly prognostic in the HR-positive group (hazard ratio, 0.63; p = 0.56). ConclusionOur study suggested that the HER2-positive HR-positive patients had a good prognosis despite the lower achievement rate of pCR, whose prognostic impact was smaller than that in the HER2-positive HR-negative patients. The treatment strategy for HER2-positive breast cancer can be stratified by HR status.

Neoadjuvant single and dual HER2 blockade among patients with localized HER2-positive breast cancer.

147 Background: Dual neoadjuvant HER2 directed therapy is offered only in a clinical trial setting and is not standard of care, but emerging data suggests targeting multiple mechanisms may be more effective. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), and on pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, as well as the impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ breast cancer. Methods: MEDLINE, EMBASE, and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and p values were estimated for endpoints using the random effects statistical model. Results: We identified 36 trials (N = 4130). High pCR rates (&gt; 40%) were seen with anthracycline-based chemotherapy and trastuzumab alone, and non-anthracycline based dual HER2 blockade. The addition of trastuzumab to chemotherapy did not improve BCS rate (RR 1.40, p = 0.15), but significantly increased rates of pCR (RR 1.91, p = 0.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, p = 0.84), but significantly increased rates of pCR overall (RR 1.39, p &lt; 0.00001), in both ER+ (RR 1.72, p = 0.01) and ER- subsets (RR 1.91, p = 0.0001), with no increase in grade 3/4 toxicity (RR:1.13, p = 0.16). Dual HER-2 blockade without chemotherapy was associated with pCR in a subset (11.2% - 27%) with minimal toxicity (incidence of grade 3/4 toxicity:1-5%). Higher pCR was associated with improved DFS (RR 2.29, p = 0.006) and OS (RR 4.61, p = 0.009). Conclusions: Neither the addition of trastuzumab to chemotherapy, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS. However,both significantly improve rates of pCR, which is associated with improved DFS and OS. Dual HER2 blockade,with endocrine therapy for ER+, could potentially lessen or even obviate the use of chemotherapy.

Impact of single and dual neoadjuvant HER2-directed therapy on clinical outcomes among patients with HER2-positive breast cancer (BC).

647 Background: While the addition of trastuzumab to neoadjuvant chemotherapy (CTX) is well established for HER2+ BC, the use of dual agent HER2 blockade in the preoperative setting is not considered standard of care. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, and impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ BC. Methods: Based on QUORUM guidelines, MEDLINE and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for endpoints using the random effects model. Results: We identified 34 trials (N = 4064). High pCR rates (&gt; 40%) were seen with anthracycline-based CTX and trastuzumab, as well as taxane based CTX alone with dual HER2 blockade. The addition of trastuzumab to CTX did not improve BCS rate (RR 1.40, CI: 0.89-2.22, p=.15), but significantly increased rates of pCR (RR 1.91, CI: 1.38-2.64, p=.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, CI: 0.77-1.38, p=.84), but significantly increased rates of pCR overall (RR 1.38, CI: 1.24-1.53, p&lt;0.00001), in both ER+ (RR 1.72, CI: 1.14-2.61, p=.01) and ER- subsets (RR 1.91, CI: 1.38-2.64, p=.0001). Higher pCR was associated with improved DFS (RR 2.29, CI: 1.27-4.12, p=.006) and OS (RR 4.61, CI: 1.46-14.56, p=.009). Conclusions: Neither the addition of trastuzumab to CTX, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS, but both significantly improve rates of pCR, which is associated with improved DFS and OS. A subgroup of HER2+ BC patients can achieve pCR with dual HER2 blockade without dependence on anthracycline-based therapy. Predictive biomarkers are needed to improve patient selection and personalize the optimal regimen for HER2+ BC.