Pathologic Response In Patients Research Articles

Vitamin D Deficiency and Tumor Response Failure in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy at a Medical Center in Mexico

Background: Vitamin D deficiency has been associated with not achieving a complete pathological response in patients with breast cancer after neoadjuvant chemotherapy. The objective of this study was to determine whether vitamin D deficiency is associated with tumor response failure in patients with breast cancer operated and who received neoadjuvant chemotherapy. Materials and Methods: This was a prospective, cross-sectional, analytical and observational study. Vitamin D was measured in patients with breast cancer who had received neoadjuvant chemotherapy and its association with tumor response was determined. For the inferential analysis, the Student’s t-test, chi-square test, and Fisher’s exact test were used. A p value <0.05 was considered statistically significant. Results: Thirty-six patients were included. There was tumor response failure to treatment in 69.3% and vitamin D deficiency occurred in 58.3%. No association was found between vitamin D deficiency and tumor response failure (p = 0.729), histological type (p = 0.691), molecular profile (p = 0.969), clinical stage (p = 0.468) or menopause status (p = 0.701). Conclusion: Vitamin D deficiency is not associated with tumor response failure in breast cancer patients who received neoadjuvant chemotherapy.

Dosimetric Parameters Associated With Pathologic Response in Patients Undergoing Preoperative Spatially Fractionated Radiotherapy (GRID) for Soft Tissue Sarcoma

<h3>Purpose/Objective(s)</h3> Spatially fractionated radiotherapy, or GRID radiotherapy, is a technique utilizing multiple beamlets of high dose radiotherapy in a heterogeneous grid pattern to treat tumor non-uniformly with megavoltage X-rays while maintaining normal tissue tolerance. We sought to characterize associations between GRID dosimetric parameters and pathologic response in patients undergoing preoperative GRID radiotherapy for high grade soft tissue sarcoma. <h3>Materials/Methods</h3> We analyzed 26 patients with high grade soft tissue sarcomas undergoing GRID radiotherapy. Dosimetric parameters included mean dose to GTV, maximum dose to 0.01 cc, maximum dose to 0.03 cc, D5, D10, D20, D50, D90, D100, V5, V10, V20, V50, V90, V100, total area under the curve, maximum tumor length, maximum tumor width, tumor volume, equivalent uniform dose to GTV, minimum surface to tumor distance, maximum surface to tumor distance, maximum tumor depth, maximum dose outside GTV, maximum dose to skin, number of beamlets, peak to valley ratio, and peak to peak distance. <h3>Results</h3> The dosimetric parameters most closely associated with pathologic response were maximum dose to 0.01 cc and maximum dose to 0.03 cc (Spearman coefficient of 0.685, <i>P</i>-value of 0.01). Mean dose to GTV, V90, and V100 showed weak associations that weaker associations that were not significant (Spearman coefficient of 0.442, 0.510, and 0.504 with <i>P</i>-values of 0.08, 0.09, 0.09). <h3>Conclusion</h3> This study showed an association between the dosimetric parameters maximum dose to 0.01 cc and maximum dose to 0.03 cc and pathologic response in patients undergoing preoperative GRID radiotherapy for high grade soft tissue sarcoma.

Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy.

Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non-small cell lung cancer (NSCLC). In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897-1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.

Development of a model to predict pathologic response to chemotherapy in patients with colorectal liver metastases.

Preoperative chemotherapy has widely been used in colorectal cancer liver metastasis (CRLM). Pathological response to chemotherapy is very important in evaluating tumor biology. However, there is still a lack of a non-invasive and accurate method to evaluate pathological response before surgery. We retrospectively analyzed the clinicopathologic data of patients with CRLM who underwent liver resection after preoperative chemotherapy between January 2006 and December 2018. Pathological responses were defined as minor when there are ≥50% remnant viable cells and as major when 0-49% remnant viable cells exist. A total of 482 patients were included and randomly divided into training (n=241) and validation (n=241) cohorts. The proportion of major pathologic response was similar between the two groups (51.5% and 48.5%). Multivariate analysis determined the disease-free interval (DFI), tumor size, tumor number, and RAS status as independent predictors of major pathologic response to preoperative chemotherapy. The nomogram incorporating these variables showed good concordance statistics in the training cohort (0.746, 95% CI: 0.685-0.807) and validation cohort (0.764, 95% CI: 0.704-0.823). In addition, the nomogram showed good applicability in patients with different characteristics. The established nomogram model performed well in predicting pathological response in patients with CRLM.

Ki-67 and Its Relation With Complete Pathological Response in Patients With Breast Cancer.

IntroductionKi-67 is a nuclear antigen present in the synthesis phase of the cell cycle. Studies have shown that a high value of Ki-67 results in greater response to chemotherapy with higher incidence of complete pathological response, which ultimately results in improved overall survival.Methods and materialsThe objective of the study was to determine the frequency of high Ki-67 levels in breast cancer patients and to find the correlation of complete pathological response in breast cancer with Ki-67 levels. It is a descriptive case series with a correlational study design done at Fauji Foundation Hospital Rawalpindi. Eighty patients with locally advanced breast cancer who underwent neoadjuvant chemotherapy followed by surgery were recruited. Their Ki-67 levels were determined on trucut biopsy. Pathological response in the post-op sample was correlated with Ki-67 levels.ResultsThe results showed 27 (33%) patients out of the 80 had high Ki-67 values. Among them 17 (63%) had complete pathological response, seven (26%) showed partial pathological response whereas three (11%) had disease progression. In contrast, out of the 53 patients having low Ki-67 values, only nine (17%) had complete pathological response, 31 (58%) showed partial pathological response and 13 (25%) had progressive disease. A Chi-square test was applied which showed significant correlation between Ki-67 and complete pathological response, with a p value of 0.00018.ConclusionTherefore high Ki-67 values in patients with breast cancer correlated well with attainment of complete pathological response. We can incorporate Ki-67 in the initial clinical assessment of breast cancer patients to help predict effectiveness as well as response to chemotherapy.

Combination of tumor markers predicts progression and pathological response in patients with locally advanced gastric cancer after neoadjuvant chemotherapy treatment

BackgroundThe prognostic values of preoperative tumor markers (TMs) remain elusive in patients with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy treatment (NACT). This study aimed to assess and establish a novel scoring system incorporating carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4) to enhance prognostic accuracy for progression-free survival (PFS) and pathological response (pCR).MethodsPatients' data were retrospectively analyzed from December 2006 to December 2017 in our center. The cutoff value of TMs was determined using the time-dependent receiver operating test characteristics method. These three TMs were allocated 1 point each for the post neoadjuvant chemotherapy combination of tumor markers (post-NACT CTM) scores. The training group comprised 533 patients, responsible for full analysis, and the validation group comprised 137 patients based on the selection protocol.ResultsOf 533 enrolled patients, 138, 233, 117, and 45 patients scored 0, 1, 2, 3 respectively. The 3-year PFS rate Multivariate analysis revealed that post-NACT CTM score was an independent predictor of PFS (0 vs. 1, HR: 1.34, 95% CI: 0.92–1.96, P = 0.128; 0 vs. 2, HR: 2.03, 95% CI: 1.35–3.05, P = 0.001; 0 vs. 3, HR: 2.98, 95% CI: 1.83–4.86, P < 0.001). The time-dependent area under curve (AUC) revealed a consistent highest level for post-NACT CTM than other three single TMs. Lower post-NACT CTM score significantly correlated with higher pCR rate based on multivariate logistic regression (2/3 vs. 1, OR: 2.77, 95% CI: 0.90–8.53, P = 0.077; 2/3 vs. 0, OR: 4.33, 95% CI: 1.38–13.61, P = 0.012). A nomogram was formed with both internal and external validation.ConclusionsThe post-NACT CTM score system served as a strong independent predictor for PFS and pCR in LAGC patients who received NACT. Further population-based studies are required to confirm our results.

Abstract 538: Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer

Abstract We examined the utility of serial liquid biopsies to monitor clonal dynamics and predict pathologic response in patients with esophageal/gastroesophageal junction (E/GEJ) cancer undergoing treatment with neoadjuvant immunotherapy and concurrent chemoradiation (CA209-906; NCT03044613). Methods: Using Targeted Error Correction sequencing (TEC-Seq), we performed high-depth next generation sequencing on 79 serial plasma samples from 16 patients with operable stage II/III E/GEJ cancer undergoing treatment with neoadjuvant nivolumab, followed by nivolumab plus chemo-radiation and surgery as part of the CA209-906 trial. Liquid biopsies were evaluated pre-treatment, after each of two cycles of neoadjuvant nivolumab, and after concurrent nivolumab and chemoradiation immediately prior to surgery, for an average of 4 time points per patient. Deep sequencing of matched leukocyte DNA and whole exome sequencing (WES) of pre-treatment tumors was performed. The origin of plasma variants was determined by comparison to tumor WES (tumor-derived) and leukocyte TEC-Seq (clonal hematopoiesis (CH)-derived or germline) and their clonal dynamics over time were evaluated. Resected tumors were reviewed by central pathology and percent residual tumor was estimated. Patients were followed for an average of 2 years post-surgery. Results: Eight of 16 patients had detectable circulating tumor-derived DNA (ctDNA) at any time point. Additionally, 13 CH-derived mutations were detected in plasma of 8 patients. The number of CH-derived mutations was correlated with increasing patient age. Identification and removal of CH-derived mutations via comparison to matched leukocyte sequencing allowed for accurate assessment of kinetics of bona fide tumor-derived mutations in plasma. Tumor mutation burden as determined by tumor WES was not associated with pathological response (mean baseline mutations per exome 90 vs 81 for patients with residual disease &amp;gt;20% and &amp;lt;20% respectively). Detectable ctDNA at the last pre-surgery time point was found in 3 patients and was associated with residual tumor &amp;gt;20% (50% vs 23% with or without detectable ctDNA respectively). ctDNA clearance, defined as detectable ctDNA at one or more earlier time points that subsequently becomes undetectable before surgery, occurred in 5 patients and was associated with improved pathologic response (80% of patients with ctDNA clearance had residual tumor &amp;lt;=20% and no evidence of disease progression). Furthermore, of the three patients who did not have ctDNA clearance, two subsequently developed disease progression. Conclusion: Comprehensive analyses of ctDNA from E/GEJ patients undergoing neoadjuvant immunotherapy with concurrent chemoradiation revealed ctDNA dynamics that were associated with pathologic response and disease recurrence. These approaches may be used to identify patients at high risk for disease progression. Citation Format: Jenna VanLiere Canzoniero, Vincent Lam, Zineb Belcaid, Mara Lanis, Lamia Rhymee, Blair Landon, Archana Balan, Kristen Marrone, Patrick Forde, Benjamin Levy, David Ettinger, Heather Schneider, Hanika Rodavia, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Blair Jobe, Ali Zaidi, Elizabeth Thompson, Julie Brahmer, Victor Velculescu, Ronan Kelly, Josephine Feliciano, Valsamo Anagnostou. Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 538.

Temporal determinants of tumour response to neoadjuvant rectal radiotherapy.

IntroductionIn locally advanced rectal cancer, longer delay to surgery after neoadjuvant radiotherapy increases the likelihood of histopathological tumour response. Chronomodulated radiotherapy in rectal cancer has recently been reported as a factor increasing tumour response to neoadjuvant treatment in patients having earlier surgery, with patients receiving a larger proportion of afternoon treatments showing improved response. This paper aims to replicate this work by exploring the impact of these two temporal factors, independently and in combination, on histopathological tumour response in rectal cancer patients.MethodsA retrospective review of all patients with rectal adenocarcinoma who received long course (≥24 fractions) neoadjuvant radiotherapy with or without chemotherapy at a tertiary referral centre was conducted. Delay to surgery and radiotherapy treatment time were correlated to clinicopathologic characteristics with a particular focus on tumour regression grade. A review of the literature and meta-analysis were also conducted to ascertain the impact of time to surgery from preoperative radiotherapy on tumour regression.ResultsFrom a cohort of 367 patients, 197 patients met the inclusion criteria. Complete pathologic response (AJCC regression grade 0) was seen in 46 (23%) patients with a further 44 patients (22%) having at most small groups of residual cells (AJCC regression grade 1). Median time to surgery was 63 days, and no statistically significant difference was seen in tumour regression between patients having early or late surgery. There was a non-significant trend towards a larger proportion of morning treatments in patients with grade 0 or 1 regression (p = 0.077). There was no difference in tumour regression when composite groups of the two temporal variables were analysed. Visualisation of data from 39 reviewed papers (describing 27379 patients) demonstrated a plateau of response to neoadjuvant radiotherapy after approximately 60 days, and a meta-analysis found improved complete pathologic response in patients having later surgery.ConclusionsThere was no observed benefit of chronomodulated radiotherapy in our cohort of rectal cancer patients. Review of the literature and meta-analysis confirms the benefit of delayed surgery, with a plateau in complete response rates at approximately 60-days between completion of radiotherapy and surgery. In our cohort, time to surgery for the majority of our patients lay along this plateau and this may be a more dominant factor in determining response to neoadjuvant therapy, obscuring any effects of chronomodulation on tumour response. We would recommend surgery be performed between 8 and 11 weeks after completion of neoadjuvant radiotherapy in patients with locally advanced rectal cancer.

Impact of a ketogenic diet intervention during radiotherapy on body composition: IV. Final results of the KETOCOMP study for rectal cancer patients

Obesity and low muscle mass are associated with worse outcomes of colorectal cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in rectal cancer patients undergoing radiotherapy. Patients with non-metastasized rectal cancer were allocated to either the KD (N=24) or the SD (N=25) group during radiotherapy. Body composition was measured weekly by bioimpedance analysis and analyzed using linear mixed effects models. Pathologic response in patients undergoing neoadjuvant treatment was evaluated at the time of surgery. A total of 18 KD and 23 SD patients completed the study and were eligible for analysis. The SD group experienced no noteworthy changes in any body composition parameter. In contrast, patients in the KD group lost significant amounts of body weight and fat mass, averaging 0.5 and 0.65kg/week (p<0.0001). There was a rapid loss of intracellular water consistent with initial intramuscular glycogen and water depletion, but skeletal muscle tissue was conserved. Pathological tumor responses were somewhat greater in the KD group, with a larger mean Dworak regression grade (p=0.072) and larger percentage of near-complete (yT0N0 or yT1N1) responses (43 versus 15%, p=0.116) that almost reached statistical significance in intention-to-treat analysis (50% versus 14%, p=0.018). In rectal cancer patients undergoing curative radiotherapy, a KD significantly reduced body weight and fat mass while preserving skeletal muscle mass. We could demonstrate a trend for KDs contributing synergistically to pathological tumor response, a finding in line with preclinical data that warrants future confirmation in larger studies. ClinicalTrials.gov identifier: NCT02516501, registered on August 06, 2015.

Diagnostic Performance of Vascular Permeability and Texture Parameters for Evaluating the Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Squamous Cell Carcinoma.

BackgroundEsophageal squamous cell carcinoma (ESCC) is an aggressive type of cancer, associated with poor prognosis. The development of an accurate and non-invasive method to evaluate the pathologic response of patients with ESCC to chemoradiotherapy remains a critical issue. Therefore, the aim of this study was to assess the importance of vascular permeability and texture parameters in predicting the response to neoadjuvant chemoradiotherapy (NACRT) in patients with ESCC.MethodsThis prospective analysis included patients with T1–T2 stage of ESCC, without either lymphatic or metastasis, and distant metastasis. All patients underwent surgery having received two rounds of NACRT. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) twice, i.e., before the first NACRT and after the second NACRT. Patients were assessed for treatment response at 30 days after the second NACRT. Patients were divided into the complete response (CR) and partial response (PR) groups based on their responses to NACRT. Vascular permeability and texture parameters were extracted from the DCE-MRI scans. After assessing the diagnostic performance of individual parameters, a combined model with vascular permeability and texture parameters was generated to predict the response to NACRT.ResultsIn this study, the CR and PR groups included 16 patients each. The volume transfer constant (Ktrans), extracellular extravascular volume fraction (ve), and entropy values, as well as changes to each of these parameters, extracted from the second DCE-MRI scans, showed significant differences between the CR and PR groups. The area under the curve (AUC) of Ktrans, ve, and entropy values showed good diagnostic ability (0.813, 0.789, and 0.707, respectively). A logistic regression model combining Ktrans, ve, and entropy had significant diagnostic ability (AUC=0.977).ConclusionsThe use of a combined model with vascular permeability and texture parameters can improve post-NACRT prognostication in patients with ESCC.

Neoadjuvant chemoimmunotherapy in resectable stage IIIA/IIIB non-small cell lung cancer.

BackgroundA small proportion of patients with non-small cell lung cancer (NSCLC) experience objective clinical benefit after neoadjuvant programmed cell death 1 (PD-1) blockade. A neoadjuvant therapeutic regimen combining immune checkpoint blockade with chemotherapy might improve the treatment effect, but such a regimen has not been tested in patients with resectable stage IIIA/IIIB NSCLC.MethodsA retrospective study of 35 patients with resectable stage IIIA and IIIB NSCLC who were treated with neoadjuvant chemoimmunotherapy (NCIO) was performed. Patients were evaluated for pathological complete response (pCR), major pathologic response (MPR), safety, and feasibility. The correlations of pathologic response with various clinical factors were studied to identify predictors of pathological response.ResultsNCIO was associated with few immediate adverse events. NCIO did not delay planned surgery and led to a pCR rate of 51.43% and an MPR rate of 74.29% for the primary tumor. No association was observed between programmed death-ligand 1 (PD-L1) expression before NCIO and the pathologic response (Pearson’s r=−0.071; P=0.685). However, a significant difference was observed in pathological response in patients with intracavitary and extracavitary tumors (P<0.05). Patients with intracavitary type had a higher pCR (76.47% vs. 31.58%) and MPR (100% vs. 50.00%) rate than patients with extracavitary type (Pearson’s r=0.7280; P=0.0009).ConclusionsNCIO was associated with few side effects, did not delay surgery, and achieved a pCR in 51.43% and MPR in 74.29% of resected tumors. No significant correlation was found between pathologic response and PD-L1 expression. While the intracavitary and extracavitary tumors type T was predictive of the pathological response to NCIO.

An Artificial Intelligence System to Predict Pathologic Response Using Longitudinal MRI in Locally Advanced Rectal Cancer: A Multicenter Study

Background: After neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer (LARC), about 20% of patients could achieve pathologic complete response (pCR) without residual tumor. This led to the proposition of organ preservation by omitting subsequent radical surgery. However, the clinical implementation of this strategy is significantly hindered by the lack of tools to reliably identify which patients would achieve pCR before surgery. The aim of this study was to develop and validate an artificial intelligence (AI) system for accurate prediction of pathologic response in patients with LARC. Methods: We conducted a retrospective, multi-cohort study of 1201 patients recruited from four hospitals in China. First, based on 112596 images from 638 patients from the 6th Hospital of Sun Yat-sen University, Guangzhou (SYSU6H), we trained a multi-task deep learning model that allows simultaneous tumor segmentation and response prediction using longitudinal multi-parametric MRI (T1 weighted with and without contrast, T1 contrast-enhanced, T2, DWI) acquired before and after NCRT. The model’s diagnostic performance was then independently tested in an internal validation set from SYSU6H (32912 images from 186 patients) and three external validation sets [the Cancer Center of Sun Yat-sen university, Guangzhou (SYSUCC), 41114 images from 235 patients; the Nanfang Hospital, Guangzhou (NFH), 13668 images from 79 patients; and the 1st Affiliated Hospital of Soochow University, Suzhou (SDFYY), 11932 images of 63 patients]. The model was compared with two experienced radiologists in 265 randomly selected patients from three validation sets. Further, the model’s performance for predicting pathologic downstage and non-response, as well as its prognostic significance were evaluated. Findings: The deep learning model achieved high performance in predicting pCR, with an area under the curve (AUC) values of 0·969 (0·942~0·996) for the SYSU6H internal validation set, and 0·946 (0·942~0·996), 0·943 (0·888~0·998), 0·919 (0·840~0·997) for the SYSUCC, NFH and SDFYY external validation sets, respectively. The model performed equally well in subgroups of patients defined by receipt of radiotherapy, clinical response, tumor location and age. The model also showed superior performance to radiologists and can be used to improve human reading. The continuous deep learning score was highly predictive of the degree of pathologic response, and was prognostic of survival independent of clinicopathologic factors. Interpretation: The AI system is accurate in identifying patients with pCR after NCRT. Its potential clinical utility of selecting patient for organ preservation warrants further investigation in future randomized trials. Funding Information: This research was supported by the National Key R&D Program of China (2017YFC1308800), National Natural Science Foundation of China（81970452, 81972212, 81770656). Declaration of Interests: We have no declarations of interest to declare. Ethics Approval Statement: All patients completed a written informed consent form before entering the study. The study was approved by the local medical ethics committee of the four centers and was conducted in accordance to the Declaration of Helsinki and good clinical practice.

Post-neoadjuvant chemoradiotherapy tumor resectability following induction chemotherapy in locally advanced proximal gastric and adenocarcinoma of the esophagogastric junction: A clinical trial.

Background:Pre-operative chemoradiotherapy (NACRT) of patients with proximal gastric and esophagogastric junction (EGJ) adenocarcinoma may result in increased local control and improved patients’ survival rate. This study aimed to investigate the effect of NACRT on resectability of tumor in patients with proximal gastric and EGJ adenocarcinoma.Methods:In this single-arm clinical trial, patients with locally advanced proximal gastric and EGJ adenocarcinoma were included. Two courses of paclitaxel/carboplatin chemotherapy alone followed by NACRT with a similar treatment regimen and a total radiation dose of 45-50.4/1.8-2 Grays were prescribed. After surgery, patients were evaluated for resection rate, pathologic response rate, and post-surgical complications.Results:A total of 61 patients with a mean age of 65.9 years participated. Grades 1 and 2 were the most prevalent side effects, with grade 3 being the worst grade and exhibiting as leukopenia (4.9%) and thrombocytopenia (1.6%). 25 (41%) patients underwent surgery after NACRT. Post-surgery complication was reported in 20% of cases (including 8% mortality and 12% morbidity). R0 and R2 resection was observed in 88% and 12% of cases, respectively. Complete pathologic-response was achieved in 24% of patients.Conclusion:Paclitaxel/carboplatin based neoadjuvant chemotherapy was associated with potential resectability and appropriate pathologic response in patients with locally advanced proximal gastric and EGJ adenocarcinoma. However, by reducing patient tolerance to complete courses of weekly chemotherapy, induction chemotherapy lowered the effectiveness of concurrent chemotherapy and radiotherapy (as a sensitizing agent). Hence, induction chemotherapy proved to be more unbeneficial causing delayed treatment and reducing concurrent chemoradiotherapy tolerance.

Combination of Simvastatin and FAC Improves Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

PurposeThe efficacy of neoadjuvant chemotherapy for locally advanced breast cancer (LABC) is limited due to drug resistance and cardiotoxic effects. Preclinical studies have shown that statin induces apoptosis and decreases breast cancer cell growth. This study aims to evaluate the role of statin in combination with fluorouracil, adriamycin, and cyclophosphamide (FAC) therapy in LABC patients.Materials and MethodsWe undertook a randomized, double-blinded, placebo-controlled trial in two centers of Indonesia. Patients were randomly assigned to FAC plus simvastatin (40 mg/day orally) or FAC plus placebo (40 mg/day) for 21 days. The FAC regimen was repeated every 3 weeks. We evaluated the clinical response, pathological response, and toxicities.ResultsThe objective response rate (ORR) for FAC plus simvastatin was 90% (95% confidence interval [CI], 0.99 to 1.67) by per-protocol analysis. No complete responses (CR) were recorded, but there were 48 partial responses. No significant difference was observed between the two groups with the ORR (p=0.103). The pathological CR rate was 6.25% (2 in simvastatin group and 1 in placebo group). Adverse events in both arms were generally mild, mainly consisted of myotoxicity. Human epidermal growth factor receptor 2 (HER2) expression was a factor related to the success of therapeutic response (odds ratio, 4.2; 95% CI, 1.121 to 15.731; p=0.033).ConclusionThis study suggests that simvastatin combined with FAC shows improvements in ORR and pathological response in patients with LABC. Although no statistically significant difference was documented, there was a trend for better activity and tolerability. The addition of 40 mg simvastatin may improve the efficacy of FAC in LABC patients with HER2 overexpression.

L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism.

18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.

Major Pathologic Response in Patients Treated for Non-small Cell Carcinoma of the Lung: Is There a Magic Number in the Histologic Sections to Be Evaluated?

Over the last years, great advancements have taken place in the medical approach to lung non-small cell carcinomas. Currently, with the use of biomarkers and diagnostic molecular pathology, tumors that in the past were treated with conventional chemotherapy, radiation therapy, or both, now similar patients afflicted by non-small cell carcinoma may have other alternative treatments. More importantly, because of those advancements in treatment options, it has become imperative that pathologists not only become familiar with the pathologic response to those treatments but also attempt to provide a pathologic assessment of the different changes that may be present as a result of a particular treatment. Even though for pathologists the demonstration of tumor necrosis and other inflammatory responses because of therapy as well as residual tumor does not represent a difficult task to accomplish, the issue is not in the diagnostic histopathologic assessment but in providing an adequate assessment of tumor viability as well as tumor necrosis and other histopathologic changes. More interesting is to acknowledge that it is in this particular area in which there may be differences in the approach because of the lack of a universal approach regarding how much of a particular tumor needs to be examined. Needless to say, the number of histologic sections examined may at the end be used as a specific parameter for tumor response to a particular treatment. The current review, will highlight, the different methodologies that over the years have been used or employed in the assessment of what is now referred as major pathologic response.

Effect of diabetes and smoking on the pathological response of neoadjuvant therapy in pancreatic adenocarcinoma

Presenter: Syed Omair Nadeem MD | Emory University Background: Increased utilization of neoadjuvant therapy (NT) for pancreatic adenocarcinoma (PDAC) has allowed for potential downsizing of the primary tumor, improved patient selection for curative resection and has demonstrated a safe and efficacious effect on survival of these patients. However, there exists limited data on patient factors that influence pathologic response in patients presenting with PDAC. We sought to explore the effect of diabetes and smoking on the pathologic response of tumors post NT. Methods: Patients with biopsy confirmed PDAC who received NT and underwent pancreaticoduodenectomy between January 2010 and December 2019 at a tertiary care center were reviewed. Surgical pathology reports were reviewed to determine treatment effect. Pathologic tumor response was assessed based on the College of American Pathologists (CAP) grading system. Grades 0-2 were defined as showing a treatment response while grade 3 was defined as no treatment response. Results: Overall 180 patients underwent pancreaticoduodenectomy at our institution. FOLFIRINOX was the most commonly employed neoadjuvant regimen (n=105, 58.3%) followed by Gemcitabine combination chemotherapy (n=68, 37.8%), while the rest got other treatment regimens. SBRT was utilized in 38 (21.1%) patients, while CRT was utilized in 17 (9.4%) patients. 20 patients (11.0%) had a complete or near complete pathologic response (CAP grade 0, 1 respectively), 53 (29.4%) patients had a partial response (CAP grade 2) and 107 (59.4%) patients had poor or no response to NT (CAP grade 3). Median overall survival was 13.6 months. On univariate analysis for factors predicting pathologic response, a diagnosis of Diabetes was associated with a significantly increased chance of poor or no pathologic response (p=0.033). On multivariate regression analysis, Diabetes again was culpable for predicting poor pathologic response (OR=0.262; 0.109-0.633, p=0.003). No other patient factors including age, gender, BMI, ethnicity, tobacco-use or other comorbidities and neoadjuvant treatment options (FOLFIRINOX vs Gemcitabine based therapy) were found to be significant for predicting pathologic tumor response. Despite Diabetes being associated with poor pathologic response, there were no differences in overall survival between diabetics and non-diabetics using Kaplan-Meier survival estimates (Figure1). Conclusion: Our results demonstrate that a diagnosis of Diabetes was associated with a significantly increased chance of predicting poor pathologic response to neoadjuvant therapy. This warrants the need for further discussion and randomized controlled trials to study patient factors which influence pathologic response to neoadjuvant therapy, which can help improve patient selection for neoadjuvant treatment.

Clinical and pathological response to neoadjuvant chemotherapy with different chemotherapy regimens predicts the outcome of locally advanced breast cancer.

This retrospective analysis was designed to research whether clinical response partial response (PR)/complete response (CR) and pathological response (PCR) to neoadjuvant chemotherapy can translate into prognosis benefit pathological response in patients with locally advanced breast cancer and whether different chemotherapy regimens will influence the outcomes. One hundred and thirty-five patients with breast cancer patients who received neoadjuvant chemotherapy were included in the retrospective analysis. Patients were followed up strictly. Overall survival (OS) was evaluated by the Kaplan-Meier analysis. The comparison of the clinical and pathological characteristics and recurrence was performed using the carried out by chi-squared and Fisher's exact tests. Univariate and multivariate analyses were performed by the Cox regression analysis. Clinical response was strongly correlated with lymph nodes status (P=0.032). The OS comparison of pathological response between the pCR group and non-pCR groups did not exhibit statistically significant differences (P=0.400). A similar non-significant response result was observed in the comparison of clinical response between the PR/CR and SD/PD groups group (P=0.108). Univariate and multivariate analyses did not support clinical response (P=0.156 P=0.095 respectively) or pathological response (P=0.600 P=0.144 respectively) as the predictors of prognosis. There were no significant differences in either the comparison of the clinical response group it seems no statistically significance (P=0.496) or the comparison of the pathological response group (P=0.460). OS analyses across different neoadjuvant chemotherapy regimens demonstrated no significant differences (P=0.307). In the PR/CR and PD/SD comparison of every single regimen, there were no significant differences. However, for patients with PR/CR patients from the comparison of five regimens, namely, TAC, FAC, AC-T, AT and TCBP demonstrated a significant difference (P=0.022). In the group of patients with luminal A breast cancer, the result of the Fisher's exact test approached significant (P=0.059). Neither PR/CR nor pCR can translate into long-term outcome benefit. PR/CR and PCR are not independent predictors in patients with advanced breast cancer. Patients who received a taxane + anthracycline regimen exhibited a higher recurrence rate than any other regimens, especially those patients with luminal A breast cancer.

Impact of interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer patients.

BACKGROUNDEpidemiologically, in China, locally advanced rectal cancer is a more common form of rectal cancer. Preoperative neoadjuvant concurrent chemoradiotherapy can effectively reduce the size of locally invasive tumors and improve disease-free survival (DFS) and pathologic response after surgery. At present, this modality has become the standard protocol for the treatment of locally advanced rectal cancer in many centers, but the optimal time for surgery after neoadjuvant therapy is still controversial.AIMTo investigate the impact of time interval between neoadjuvant therapy and surgery on DFS and pathologic response in patients with locally advanced rectal cancer.METHODSA total of 231 patients who were classified as having clinical stage II or III advanced rectal cancer and underwent neoadjuvant chemoradiation followed by surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from November 2014 to August 2017 were involved in this retrospective cohort study. The patients were divided into two groups based on the different time intervals between neoadjuvant therapy and surgery: 139 (60.2%) patients were in group A (≤ 9 wk), and 92 (39.2%) patients were in group B (> 9 wk). DFS and pathologic response were analyzed as the primary endpoints. The secondary endpoints were postoperative complications and sphincter preservation.RESULTSFor the 231 patients included, surgery was performed at ≤ 9 wk in 139 (60.2%) patients and at > 9 wk in 92 (39.8%). The patients’ clinical characteristics, surgical results, and tumor outcomes were analyzed through univariate analysis combined with multivariate regression analysis. The overall pathologic complete response (pCR) rate was 27.2% (n = 25) in the longer time interval group (> 9 wk) and 10.8% (n = 15) in the shorter time interval group (≤ 9 wk, P = 0.001). The postoperative complications did not differ between the groups (group A, 5% vs group B, 5.4%; P = 0.894). Surgical procedures for sphincter preservation were performed in 113 (48.9%) patients, which were not significantly different between the groups (group A, 52.5% vs group B, 43.5%; P = 0.179). The pCR rate was an independent factor affected by time interval (P = 0.009; odds ratio [OR] = 2.668; 95%CI: 1.276-5.578). Kaplan-Meier analysis and Cox regression analysis showed that the longer time interval (> 9 wk) was a significant independent prognostic factor for DFS (P = 0.032; OR = 2.295; 95%CI: 1.074-4.905), but the time interval was not an independent prognostic factor for overall survival (P > 0.05).CONCLUSIONA longer time interval to surgery after neoadjuvant therapy may improve the pCR rate and DFS but has little impact on postoperative complications and sphincter preservation.

Abstract 2014: Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer

Abstract Backgrounds: Tumor regression grade (TRG) reflects the chemoradiosensitivity of rectal cancer patients undergone neoadjuvant treatment, and relates to distinct probabilities of cancer recurrence and survival. However, in clinical practice, it is significantly challenging to rely solely on radiographic or clinical diagnostic information to obtain a patient's pathological response pre-treatment for treatment optimization. The aim was combining both the tumor information of macroscopic radiological and microscopic pathological images to develop and validated a more accurate signature for pretreatment prediction of TRG to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) on a multicenter dataset. Materials and Methods: We prospectively enrolled 981 patients (303 in the primary cohort, 678 in three external validation cohort) with clinicopathologically confirmed LARC treated with nCRT followed by surgery between Aug 2007 and Nov 2017, and collected their pretreatment multi-parametric MRI (mp-MRI), whole-slide image (WSI) of biopsy specimen, and pathologic response according to AJCC TRG system as well as clinical outcomes. Briefly, an artificial intelligence model integrating quantitative imaging features of mp-MRI and WSI was proposed to predict each nCRT treated patient into a particular 4-category TRG. The signature from the model (hereafter Rp-Grade) was further assessed in three independent validation cohort. Results: Rp-Grade yielded an overall ACC of 87.76% and revealed significant improvement than signature generating from model with mp-MRI or WSI features alone in all validation cohorts (P&amp;lt;0.0.5) (Table). Performance of radiopathomics signature for predicting 4-category AJCC/CAP TRGMetrics (%) [95% CI]Validation Cohort1 (N=480)Validation Cohort2 (N=150)Validation Cohort3 (N=48)Accuracy87.76 [84.86-90.66]79.71 [72.52-84.9]81.24 [70.15-92.34]PPV (TRG=0)94.58 [90.48-98.69]93.52 [84.68-100.0]83.09 [61.19-100.0]PPV (TRG=1)92.02 [86.19-97.85]70.26 [56.42-84.1]70.26 [56.42-84.1]PPV (TRG=2)83.9 [79.6-88.19]74.24 [63.57-84.92]71.49 [52.04-90.94]PPV (TRG=3)-92.54 [78.21-100.0]-Sensitivity (TRG=0)96.49 [93.03-99.95]96.62 [89.92-100.0]91.3 [74.73-100.0]Sensitivity (TRG=1)96.49 [93.03-99.95]75.57 [61.75-89.4]63.39 [42.96-83.82]Sensitivity (TRG=2)97.16 [95.02-99.29]100.0 [100.0-100.0]100.0 [100.0 100.0]Sensitivity (TRG=3)-35.55 [19.99-51.12]-Note: The evaluation results were represented by ‘-' when the number of categories was insufficient in the independent cohort test. Conclusions: Combining the macroscopic radiological information of the whole tumor and microscopic pathological information of local lesions from biopsy, radiopathomics was a potential strategy for the pretreatment prediction of the TRG in patients with LARC who underwent nCRT. Citation Format: Lizhi Shao, Zhenyu Liu, Lili Feng, Xiaoying Lou, Zhenhui Li, Xiao-Yan Zhang, Xuezhi Zhou, Kai Sun, Da-Fu Zhang, Lin Wu, Guanyu Yang, Ying-Shi Sun, Ruihua Xu, Xiangbo Wan, Xinjuan Fan, Jie Tian. Radiopathomics strategy combining multiparametric MRI with whole-slide image for pretreatment prediction of tumor regression grade to neoadjuvant chemoradiotherapy in rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2014.