Pathologic Complete Response In Patients Research Articles

Prognostic significance of pathological complete response in non-small cell lung cancer following neoadjuvant treatment.

This study aims to investigate the factors associated with pathological complete response following neoadjuvant treatment and to examine the prognostic value of pathological complete response in patients with non-small cell lung cancer undergoing surgical resection. Between February 2009 and January 2016, a total of 112 patients (96 males, 16 females; mean age 60±8 years; range, 37 to 85 years) with the diagnosis of non-small cell lung cancer who underwent anatomical pulmonary resection after neoadjuvant treatment were retrospectively analyzed. Demographic, clinical, radiological, and pathological characteristics of the patients were recorded. The patients were classified as pathological complete response and nonpathological complete response according to the presence of tumors in the pathology reports. Predictive factors for pathological complete response and its prognostic significance were analyzed. The mean follow-up was 35±20 (range, 0 to 110) months. Of the patients, 30 (27%) achieved a pathological complete response. Reduction rate in tumor size was significantly higher in the responsive group (32.5±21.6% vs. 19.2±18.8%, respectively) and was a predictor of pathological complete response independent from the T and N factors (p=0.004). Survival of the responsive patients was significantly longer than unresponsive patients (75±9 vs. 30±4 months, respectively; p<0.001). During follow-up, tumor recurrence was seen in 30 patients. Recurrence was observed in only one patient in the responsive group, while 29 patients in the unresponsive group had recurrence or metastasis. Tumor shrinkage rate after neoadjuvant treatment in non-small cell lung cancer is a predictive factor for pathological complete response. Survival of patients with a pathological complete response is also significantly longer than unresponsive patients.

Predictive Value of FOLFOX-Based Regimen, Long Interval, Hemoglobin Levels and Clinical Negative Nodal Status, and Postchemoradiotherapy CEA Levels for Pathological Complete Response in Patients with Locally Advanced Rectal Cancer after Neoadjuvant Chemoradiotherapy.

We aimed to identify predictors of a pathological complete response (pCR) in patients with locally advanced rectal cancer (LARC) following a multimodality therapy. We retrospectively reviewed 236 patients with LARC treated with neoadjuvant chemoradiotherapy (CRT) followed by radical resection from January 2011 to December 2017. Patients were administered CRT, which comprised radiotherapy and chemotherapy with an oxaliplatin plus 5-fluorouracil- or fluoropyrimidine-based regimen. Clinical factors were correlated with treatment response. The multivariate logistic regression revealed that a negative nodal stage (odds ratio (OR) = 3.2, P=0.0135), a high hemoglobin level (>10 g/dL) during neoadjuvant CRT (OR = 3.067, P=0.0125), an oxaliplatin-containing neoadjuvant CRT (OR = 5.385, P=0.0044), a long interval (>8 weeks) between radiotherapy and surgery (OR = 1.135, P=0.0469), and a post-CRT CEA ≤2 ng/mL (OR = 2.891, P=0.0233) were the independent predictors of increased pCR rates. The prediction nomogram was developed according to the above independent variables. The concordance index was 0.74, and the calibration curve showed good agreement. In summary, negative nodal stages, high hemoglobin levels during treatment, oxaliplatin-containing neoadjuvant therapy, a long radiotherapy-surgery interval (>8 weeks), and post-CRT CEA levels ≤2 ng/mL were favorable predictors of a pCR. This prediction nomogram might be crucial for patients with LARC undergoing a multimodality therapy.

Evaluation of pathological complete response in patients with breast cancer submitted to neoadjuvant chemotherapy and surgery in hospital do câncer do mato grosso

This study aims at comparing the pathological complete response rate of women submitted to neoadjuvant chemotherapy for breast cancer in the world with the community from Hospital do Câncer do Mato Grosso, to verify which histological subtypes have higher chances of reaching the pathological complete response. Therefore, we will analyze the medical records of the patients who underwent neoadjuvant chemotherapy followed by surgery. Besides the initial clinical staging from I to III between 2014 to 209. The criteria in RECIST 1.1 were used (Response Evaluation Criteria in Solid Tumors) to define pathological complete response for the breast and the axilla. We concluded that the benefit of neoadjuvant chemotherapy is mostly seen in patients with negative hormone receptors and positive HER2, and they have higher chances of reaching pathological complete response. In the triple negative subtype, neoadjuvant chemotherapy with the objective of reaching pCR is, until this moment, the best strategy for higher survival rates in these patients, according to data from the global literature.

Subcutaneous Trastuzumab: A Review in HER2-Positive Breast Cancer.

A subcutaneous (SC) formulation of trastuzumab, a potent humanized anti-Human Epidermal growth factor Receptor 2 (HER2) receptor monoclonal antibody, with a recombinant hyaluronidase (Herceptin Hylecta™; Herceptin®) is indicated in the USA and EU for the treatment of HER2-positive breast cancer. In the phase III pivotal HannaH trial, SC trastuzumab was noninferior to the standard intravenous (IV) formulation of trastuzumab with respect to trough drug concentrations and pathological complete response in patients with HER2-positive early breast cancer. Other clinical outcomes, including event-free survival and overall survival rates, were generally similar between the formulation groups. SC trastuzumab had a manageable tolerability profile in patients with HER2-positive early or metastatic breast cancer, with the safety profile being generally similar to that of the IV formulation. In the phase III PrefHER and MetaspHER trials, more patients preferred SC over IV trastuzumab and more healthcare professionals expressed satisfaction with the SC formulation. Relative to IV trastuzumab, SC trastuzumab offers a quicker and more convenient dosage regimen, thereby potentially improving patient convenience, providing economic benefit and optimizing the use of medical resources. Thus, given the high preference for SC trastuzumab and its generally similar efficacy and tolerability profile to that of the IV formulation, SC trastuzumab is the preferred treatment of choice in patients receiving trastuzumab for the treatment of HER2-positive early or metastatic breast cancer.

Evaluation of the Accuracy of Percutaneous Biopsy by Vacuum-assisted Biopsy (VAB) to Assess Pathological Complete Response in Patients With Clinical and Radiological Complete Response After Neoadjuvant Chemotherapy (NeoVAB)

Evaluation of the Accuracy of Percutaneous Biopsy by Vacuum-assisted Biopsy (VAB) to Assess Pathological Complete Response in Patients With Clinical and Radiological Complete Response After Neoadjuvant Chemotherapy (NeoVAB)

How to Achieve a Higher Pathologic Complete Response in Patients With Locally Advanced Rectal Cancer Who Receive Preoperative Chemoradiation Therapy.

The current standard of care for treating patients with locally advanced rectal cancer includes preoperative chemoradiation therapy (PCRT) followed by a total mesorectal excision and postoperative adjuvant chemotherapy. A subset of these patients has achieved a pathologic complete response (pCR) and they have shown improved disease-free and overall survival compared to non-pCR patients. Thus, many efforts have been made to achieve a higher pCR through PCRT. In this review, results from various ongoing and recently completed clinical trials that are being or have been conducted with an aim to improve tumor response by modifying therapy will be discussed.

Abstract P3-06-09: BRCA mutations and not type 1 tandem duplicator phenotypes are associated with pathological complete response in patients with triple negative breast cancer undergoing neoadjuvant carboplatin/nab-paclitaxel

Abstract Background. We recently described six distinct genomic configurations characterized by large numbers of distributed somatic tandem duplications (TDs) known as Tandem Duplicator Phenotypes (TDPs). Different TDPs feature TDs of different span sizes, and are enriched in TNBC, ovarian, and uterine cancers. Type 1 TDPs (i.e. groups 1, 1/2mix and 1/3mix) feature short span TDs (˜11Kb in size), invariably show abrogation of BRCA1 (via mutation or methylation) and of TP53, and affect ˜40% of TNBCs. We had observed, in limited in vitro and preclinical PDX models, that TDP status correlates with platinum sensitivity (1). Here, we assess TDP status across a cohort of 42 TNBC patients (pts) undergoing neoadjuvant carboplatin and NAB-paclitaxel to test the hypothesis that type 1 TDP status may be predictive of optimal response to platinum-based therapy. Methods. 42 pts with TNBC were enrolled in a phase II study of neoadjuvant carboplatin/nab-paclitaxel at the City of Hope National Medical Center (NCT01525966).Pathological complete response (pCR) was achieved in 50% of pts (21/42). WGS was performed using standard Illumina protocols. Structural variants were called using Crest, Delly and BreakDancer, and high confidence breakpoints were selected when called by at least two tools and by requiring split-read support. TDP status was ascertained as recently described (2). BRCA1 methylation was determined by methylation-specific PCR. Results. 45% of the tumors classified as TDP (19/42). Consistent with our previous observation, the vast majority were type 1 TDPs with short span TDs (n=17) and were strongly associated with BRCA1 mutation or methylation (16/17, P= 1.4E-8). However, there was no correlation between TDP status and pCR (OR=1.1, NS). In a more detailed analysis, we found that BRCA1 mutation correlated with pCR rate (6/7 pCR, P=0.01), whereas promoter methylation did not (4/11 pCR, NS). Moreover, both pts with mutant BRCA2 achieved pCR. Thus, as a group, pts with BRCA1/2 mutations (but not BRCA1 methylation) were more likely to achieve pCR than those with wild type BRCA1/2 (OR=11.9, P=1.7E-2). Results were unchanged when using RCB 0 and 1 vs. RCB 2 and 3 as the response criteria. Conclusions. This study confirmed that reduction of BRCA1 activity via either mutation or methylation robustly associates with type 1 TDPs in TNBC. However, TDP status did not predict good response, suggesting the separation of BRCA effects on genomic instability and platinum sensitivity. This indicates that genomic signature assessments, such as TDP and HRD, may not be sufficient in predicting pCR in TNBC. Importantly, we found that BRCA1/2 mutated TNBC pts were more likely to experience pCR (8/9) compared with pts with either BRCA1 methylation (4/11) or wild type BRCA1/2 (8/21). The exact genetic underpinnings of response in non-BRCA pts are currently under investigation. References. 1) Menghi et al, The Tandem Duplicator Phenotype is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations, Cancer Cell (2018). 2) Menghi et al, The tandem duplicator phenotype as a distinct genomic configuration in cancer, Proc Natl Acad Sci (2016). Citation Format: Menghi F, Yuan Y, Somlo G, Liu ET. BRCA mutations and not type 1 tandem duplicator phenotypes are associated with pathological complete response in patients with triple negative breast cancer undergoing neoadjuvant carboplatin/nab-paclitaxel [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 P3-06-09.

Correction: HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2

Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR.

Accuracy of breast magnetic resonance imaging in evaluating the response to neoadjuvant chemotherapy: a study of 310 cases at a cancer center.

ObjectiveTo evaluate the accuracy of magnetic resonance imaging (MRI) of the breasts in the identification of a pathological complete response in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC).Materials and MethodsThis was a single-center, retrospective, observational study designed to validate a diagnostic test. The following variables were evaluated: age; results of the histological and immunohistochemical analysis of the biopsy; post-NAC MRI findings; and results of the histological analysis of the surgical specimen, using the residual cancer burden index. The radiological response, as assessed by MRI, was compared with the pathological response, as assessed by histological analysis of the surgical specimen (the gold standard method).ResultsWe evaluated 310 tumors in 308 patients. The mean age of the patients was 47 years (range, 27-85 years). For identifying a pathological complete response, breast MRI had an overall accuracy of 79%, with a sensitivity of 75%, specificity of 83%, positive predictive value of 75%, and negative predictive value of 83%. When that accuracy was stratified by molecular subtype, it was best for the HER2 subtype, with a sensitivity and specificity of 82% and 89%, respectively, followed by the triple-negative subtype, with a sensitivity and specificity of 78% and 83%, respectively.ConclusionBreast MRI showed good accuracy in the prediction of a pathological complete response after NAC. The sensitivity and positive predictive value were highest for the HER2 and triple-negative subtypes.

Patterns and risk of recurrence in patients with esophageal cancer with a pathologic complete response after chemoradiotherapy followed by surgery

ObjectivesA pathologic complete response in patients with locally advanced esophageal cancer after chemoradiotherapy and surgery is associated with improved overall and disease-free survival. Nevertheless, approximately one third of patients with a pathologic complete response still have a recurrence. The aim of this study was to evaluate risk factors and patterns of recurrence in patients with locally advanced esophageal cancer who achieved a pathologic complete response after chemoradiotherapy and surgery. MethodsWe performed a retrospective review of a single-institution database of 233 patients with stage II and III esophageal cancer with a pathologic complete response after chemoradiotherapy and surgery between 1997 and 2017. A multivariable competing risk-regression model was used to identify predictors of recurrence. ResultsA total of 61 patients exhibited recurrence in this cohort, 43 with adenocarcinoma and 18 with squamous cell carcinoma. Five-year cumulative incidence of recurrence did not vary by histology. Univariable analysis revealed that poor tumor differentiation (hazard ratio, 2.28; P = .022) and advanced clinical stage (hazard ratio, 1.89; P = .042) are predictors of recurrence in the esophageal adenocarcinoma subgroup, whereas poor tumor differentiation remained the only independent predictor on multivariable analysis in the entire cohort (hazard ratio, 2.28; P = .009). Patients with esophageal adenocarcinoma had a higher incidence of distant recurrences, and patients with esophageal squamous cell carcinoma demonstrated a higher incidence of loco-regional recurrence (P = .039). ConclusionsPoor tumor differentiation is an independent risk factor for recurrence in patients with esophageal cancer with a pathologic complete response. Although there is no difference in the cumulative incidence of recurrence between esophageal adenocarcinoma and esophageal squamous cell carcinoma, patterns of recurrence appear to differ. Thus, treatment and surveillance strategies may be tailored appropriately.

Role of epidermal growth factor receptor in breast cancer: An analysis of biomolecular receptor study and its clinicopathological correlation

&lt;p&gt;&lt;strong&gt;Introduction:&lt;/strong&gt; Epidermal growth factor receptor (EGFR) is member of human epidermal receptor is frequently expressed in diverse forms of cancer. Many studies have studied the relation of EGFR positivity in breast cancer and its prognostic value, but yet no conclusions have yet been drawn.We attempt to study the receptor positivity in our patient and its correlation with various clinic-pathological prognostic predictors and outcomes. &lt;strong&gt;Materials and Methods:&lt;/strong&gt; Data of 355 patients of breast cancer registered in our department between November 2014 and November 2016 and followed up until December 2016 was collected and reviewed for epidemiological and clinical features. Results: &lt;strong&gt;Results&lt;/strong&gt; of total 355 patients analyzed, TNBC group, were most common (n = 152) (43%) followed by luminal A (25%). Median age at disease presentation was 45.3 years (24–73 years). The EGFR-positivity rate was 30.3%. EGFR-negative patients presented as early breast cancer significantly more than EGFR-positive patients (47.36% vs. 27.10% P = 0.046). Significantly, higher proportion of EGFR-positive patients presented with Grade 3 cancers (44.10% vs. 19.16% P = 0.049). Nodal involvement was significantly more in EGFR-positive patients (66.6% vs. 37.5% P = 0.0364). Pathological complete response (CR) was significantly associated with EGFR positivity (16.1% vs. 12.5% P = 0.0349). There were more recurrences in a surgically treated group with EGFR positivity than negative group, but this difference did not reach significance (18.1% vs. 5.2% P = 0.061). &lt;strong&gt;Conclusion:&lt;/strong&gt; We found that our breast cancer was quite young with the median age almost two decades earlier than that of the west with very high number of patients presenting as an advanced stage and triple negative phenotypes. We found that EFGFR receptor positivity in almost one-third of the patients. This could be subgroup of patients which could be targeed by anti-EGFR therapy. This EGFR positivity also acted as surrogate for an aggressive disease which was shown by significantly larger proportion of advanced stage, high grade and node-positive disease present in receptor-positive patients. This subset showed a higher rate of pathological CR in patients subjected to neoadjuvant chemotherapy. There was trend of worse outcomes in surgically treated EGFR-positive patients which may be due to short follow-up period in our study. As we continue this study, EGFR positivity may emerge as a true prognostic marker of breast cancer.&lt;/p&gt;

Impact of Chemoradiotherapy Intensity on Pathological Complete Response in Patients with Esophageal Cancer Receiving Trimodality Therapy

Despite the current standard of neoadjuvant chemoradiation therapy followed by radical surgery improving outcomes in patients with operable esophageal carcinoma (EC), there are still limited reports of clinical and treatment-related features that might predict pathological complete response (pathCR), which indicated superior survival outcome in many series. The purpose of this study is to evaluate if chemoradiotherapy intensity and other clinical or treatment-related features might predict pathCR and acute toxicity in patients with esophageal cancer who received trimodality therapy. We retrospectively analyzed clinical and treatment-related features of 127 consecutive patients with EC who received trimodality therapy in two tertiary centers between January 2010 and December 2015. Either primary or nodal specimens with no residual carcinoma were defined as pathCR. We applied logistic regressions to identify independent clinical or treatment related features, especially chemoradiotherapy intensity, associated with pathCR and acute toxicity. The receiver-operating characteristic (ROC) curve was also generated to obtain the best cut-off point. With a majority of squamous cell histology (N=124, 97.6%) and male gender (N= 121, 95.3%), all patients received neoadjuvant therapy with cisplatin and fluorouracil chemotherapy and radiotherapy. A pathCR was achieved in 47 (37%) of 127 patients. Low-grade tumors (odds ratio [OR]: 32.279; p < .0001) and cumulative cisplatin dose (mg/m2) during radiotherapy (OR: 1.031; p < .0001, cut-off point: 128.5 mg/m2) significantly predicted higher pathCR rates in multivariate logistic regression models. A lower pathCR rate was observed in patients with greater body weight loss (by percentage) during neoadjuvant therapy (OR: 0.865, p= .010, cut-off point: 8.85%). Meanwhile, the higher radiation dose to gross tumors was not associated with pathCR (OR: 1.000, p= .374), but was the only independent factor that significantly predicted severe (≥ grade 3) acute hematologic toxicity (OR: 1.002, p< .001, cut-off point: 5200 cGy). Low-grade tumors and cumulative cisplatin dose during radiotherapy were predictive of a higher possibility of pathCR. Greater body weight lost during neoadjuvant therapy was a negative predictor for pathCR. Increasing radiation dose did not contribute to pathCR, but did increase the severity of acute hematologic toxicity. Interventions that improve treatment tolerance as per protocol and nutrition status during neoadjuvant therapy are needed to achieve higher pathCR rates and potentially better outcomes.

633P - The role of comprehensive evaluation for clinical complete response in predicting pathologic complete response in patients treated with neoadjuvant chemoradiation for esophageal squamous cell carcinoma (ESCC)

633P - The role of comprehensive evaluation for clinical complete response in predicting pathologic complete response in patients treated with neoadjuvant chemoradiation for esophageal squamous cell carcinoma (ESCC)

Quantitative contrast-enhanced ultrasound evaluation of pathological complete response in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy

PurposeTo clarify whether the quantitative parameters of contrast-enhanced ultrasound (CEUS) can be used to predict pathological complete response (pCR) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NAC). Material and methodsFifty-one patients with histologically proved locally advanced breast cancer scheduled for NAC were enrolled. The quantitative data for CEUS and the tumor diameter were collected at baseline and before surgery, and compared with the pathological response. Multiple logistic regression analysis was performed to examine quantitative parameters at CEUS and the tumor diameter to predict the pCR, and receiver operating characteristic (ROC) curve analysis was used as a summary statistic. ResultsMultiple logistic regression analysis revealed that PEAK (the maximum intensity of the time-intensity curve during bolus transit), PEAK%, TTP% (time to peak), and diameter% were significant independent predictors of pCR, and the area under the ROC curve was 0.932(Az1), and the sensitivity and specificity to predict pCR were 93.7% and 80.0%. The area under the ROC curve for the quantitative parameters was 0.927(Az2), and the sensitivity and specificity to predict pCR were 81.2% and 94.3%. For diameter%, the area under the ROC curve was 0.786 (Az3), and the sensitivity and specificity to predict pCR were 93.8% and 54.3%. The values of Az1 and Az2 were significantly higher than that of Az3 (P = 0.027 and P = 0.034, respectively). However, there was no significant difference between the values of Az1 and Az2 (P = 0.825). ConclusionQuantitative analysis of tumor blood perfusion with CEUS is superior to diameter% to predict pCR, and can be used as a functional technique to evaluate tumor response to NAC.

395 (PB-028) - Predictive Factors to Achieve Pathologic Complete Response in Patients with Locally Advanced Breast Cancer in Decision Making for more Conservative Management

395 (PB-028) - Predictive Factors to Achieve Pathologic Complete Response in Patients with Locally Advanced Breast Cancer in Decision Making for more Conservative Management

Prediction of Response to Neoadjuvant Chemotherapy and Radiation Therapy with Baseline and Restaging 18F-FDG PET Imaging Biomarkers in Patients with Esophageal Cancer.

Purpose To assess the value of baseline and restaging fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) radiomics in predicting pathologic complete response to neoadjuvant chemotherapy and radiation therapy (NCRT) in patients with locally advanced esophageal cancer. Materials and Methods In this retrospective study, 73 patients with histologic analysis-confirmed T1/N1-3/M0 or T2-4a/N0-3/M0 esophageal cancer were treated with NCRT followed by surgery (Chemoradiotherapy for Esophageal Cancer followed by Surgery Study regimen) between October 2014 and August 2017. Clinical variables and radiomic features from baseline and restaging 18F-FDG PET were selected by univariable logistic regression and least absolute shrinkage and selection operator. The selected variables were used to fit a multivariable logistic regression model, which was internally validated by using bootstrap resampling with 20 000 replicates. The performance of this model was compared with reference prediction models composed of maximum standardized uptake value metrics, clinical variables, and maximum standardized uptake value at baseline NCRT radiomic features. Outcome was defined as complete versus incomplete pathologic response (tumor regression grade 1 vs 2-5 according to the Mandard classification). Results Pathologic response was complete in 16 patients (21.9%) and incomplete in 57 patients (78.1%). A prediction model combining clinical T-stage and restaging NCRT (post-NCRT) joint maximum (quantifying image orderliness) yielded an optimism-corrected area under the receiver operating characteristics curve of 0.81. Post-NCRT joint maximum was replaceable with five other redundant post-NCRT radiomic features that provided equal model performance. All reference prediction models exhibited substantially lower discriminatory accuracy. Conclusion The combination of clinical T-staging and quantitative assessment of post-NCRT 18F-FDG PET orderliness (joint maximum) provided high discriminatory accuracy in predicting pathologic complete response in patients with esophageal cancer. © RSNA, 2018 Online supplemental material is available for this article.

The importance of stromal and intratumoral tumor lymphocyte infiltration for pathologic complete response in patients with locally advanced breast cancer.

Increased tumor-infiltrating lymphocytes (TILs) in breast carcinoma tissues is an independent predictive factor for pathologic complete response (pCR). The increased intratumoral and stromal TILs (sTILs) in breast cancer (BC) have significant prognostic effects. In this study, we evaluated whether pCR rates to neoadjuvant chemotherapy (NACT) are higher in tumors with increased number of TILs in the pretreatment biopsy. We retrospectively evaluated the number of TILs in intratumoral TILs (iTILs) and sTILs compartments from pretreatment full-face hematoxylin and eosin-stained sections of 62 patients with locally advanced BC (LABC) who received NACT. The capacity of sTILs and iTILs in predicting pCR to NACT in LABC analyzed using receiver operating characteristic (ROC) curve analysis. According to ROC curve analysis, the optimum sTILs and iTILs cut-off points (the number of positive cells per square millimeter of tissue) for patients with LABC patients with pCR (+) were 19 (area under the curve (AUC): 0.668, 95% confidence interval [CI] [0.501-0.835],P = 0.064) and 4 (AUC: 0.786, 95%CI [0.666-0.907],P = 0.002), respectively. Of the 62 patients, 26 had sTILs >19 and 25 had iTILs >4. The patients were divided into two according to percent of sTILs (sTILs >19 and sTILs ≤19 groups) and iTILs (iTILs >4 and iTILs ≤4 groups). Both sTILs >19 and iTILs >4 patients were associated with development higher pCR. While pCR was significantly higher in iTILs >4 patients (P = 0.002), it was not significantly in sTILs >19 patients (P = 0.107). There is significantly an association between pCR and increased number of intratumoral TILs (>4 cells/mm 2 of tissue) in BC who received NACT.

Pathological complete response in patients with esophageal cancer after the trimodality approach: The association with baseline variables and survival-The University of Texas MD Anderson Cancer Center experience.

Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence-free survival (RFS), and patterns of recurrence in a large cohort from a single institution. The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log-rank testing and Cox models to determine the association between a pathCR and the time-to-event outcomes (OS and RFS). Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A lower pathCR rate was observed for 1) older patients (>60 years), 2) patients with poorly differentiated tumors, 3) patients with signet ring cells (SRCs), and 4) patients with a higher T stage. Patients with a pathCR had longer OS and RFS than those without a pathCR (P = .0021 and P = .0011, respectively). Recurrences occurred more in non-pathCR patients. Distant metastases were the most common type of recurrence. PathCR patients developed brain metastases at a marginally higher rate than non-pathCR patients (P = .051). In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. © 2017 American Cancer Society.

HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.

Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR.

EarlyR genomic signature to predict pathological complete response following neoadjuvant anthracycline-taxane chemotherapy in estrogen-receptor positive (ER+) breast cancer.

579 Background: EarlyR is a prognostic signature computed from expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR that stratifies ER+ breast cancer (BC) into EarlyRLow, EarlyRInt, and EarlyRHigh risk strata. Here, we show that EarlyR is also predictive of pathological complete response (pCR) following neoadjuvant anthracycline-taxane (AT) based chemotherapy. Methods: The ability of EarlyR gene signature to predict pCR was assessed in Affymetrix microarrays datasets (GSE25065, GSE25066, GSE20194, GSE20271; n = 541, pCR = 42 (7.8%) collectively labeled as Cohort A) derived from patients with ER+ breast cancer treated with neoadjuvant TFAC or FEC. For 2 of these datasets (GSE25065, GSE25066 (n = 291)) distant metastasis-free survival (DMFS) results were also available. The DMFS data in cohort A were compared to that of BC patients not treated with chemotherapy (denoted Cohort B, n = 1269) derived from ER+ samples from 7 GEO datasets (GSE3494, GSE7390, GSE12093, GSE6532, GSE2034, GSE11121, GSE17705). Results: In cohort A, EarlyR is a significant predictor of pCR (p = 1.0 x 10-6) (EarlyRLow, n = 273, pCR = 5, 1.8%; EarlyRInt, n = 11, pCR = 1, 9.1% and EarlyRHigh, n = 256, pCR = 36, 14.1%). Notably, 86% of the 42 cases with pCR have EarlyRHigh. Of the 291 patients with 8-year DMFS data from Cohort A, who had received chemotherapy, the survival of EarlyRHigh [0.79 (95%CI 0.70-0.89)] was nearly the same as that of EarlyRLow [0.82 (95%CI 0.74-0.90)]. In contrast, in cohort B, who were not treated with chemotherapy, 8-year DMFS is significantly (p = 5 x 10-15) lower in EarlyRHigh [0.57 (95%CI 0.51-0.64)] than in EarlyRLow[0.81 (95%CI 0.78-0.84)]. Conclusions: EarlyR is a strong predictor of pathological complete response in patients treated with TFAC or FEC. In addition, EarlyR also predicts poor DMFS outcomes for patients in EarlyRHigh not receiving chemotherapy. More importantly, neoadjuvant chemotherapy dramatically improved survival of patients in EarlyRHigh. These results document that EarlyR identifies a set of patients, EarlyRHigh, with a high risk of distant metastasis, who are also likely to respond favorably to chemotherapy.