non-pCR Group Research Articles

Prediction of pathological complete response in breast cancer patients during neoadjuvant chemotherapy: Is shear wave elastography a useful tool in clinical routine?

ObjectiveTo compare the validity of Shear Wave Elastography (SWE) for the preoperative assessment of pathological complete response (pCR) to standard clinical assessment in breast cancer patients undergoing neoadjuvant chemotherapy (NACT). Materials and MethodsThis prospective, consecutive clinical trial was conducted under routine clinical practice. Analysis included 134 patients. SWE served as index test, final pathology from surgical specimen as reference standard. PCR (ypT0) was defined as primary endpoint. Elasticity changes were compared for the pCR- vs. non-pCR group. To determine the validity of shear wave velocity (Vs), ROC analyses and diagnostic accuracy parameters were calculated and compared to the final standard clinical assessment by physical examination, mammography and B-mode ultrasound (ycT + vs. ycT0). ResultsVs was significantly reduced in pCR and non-pCR groups during NACT (pCR: ΔVs(abs) = 3.90 m/s, p < 0.001; non-pCR: ΔVs(abs) = 3.10 m/s, p < 0.001). The pCR-group showed significant lower Vs for all control visits (t1,2,END: p < 0.001). ROC analysis of Vs yielded moderate AUCs for the total population (t0: 0.613, t1: 0.745, t2: 0.685, tEND: 0.718). Compared to standard clinical assessment, Vs(tEND) (cut-off: ≤3.35 m/s) was superior in sensitivity (79.6 % vs. 54.5 %), NPV (86.4 % vs. 77.5 %), FNR (20.4 % vs. 45.5 %), inferior in specificity (58.6 % vs. 77.5 %), PPV (46.3 % vs. 54.5 %), FPR (41.4 % vs. 22.5 %). ConclusionSWE measures significant differences in tumour elasticity changes in pCR vs. non-pCR cases. SWE shows improved sensitivity compared to standard clinical assessment, high NPV and low FNR, but failed in specificity in order to predict pCR under routine conditions.

Whole-lesion histogram analysis of apparent diffusion coefficient for the prediction of pathological complete response to neoadjuvant chemotherapy in different subtypes of breast cancer

Objective To investigate the value of whole-lesion histogram parameters of apparent diffusion coefficient (ADC) in evaluating and predicting the pathological complete response(PCR) to neoadjuvant chemotherapy (NAC) in different subtypes of breast cancer. Methods This retrospective study included 117 patients with breast cancer who underwent MRI examination before NAC prior to surgery from January 2016 to December 2017 in the First Affiliated Hospital of Nanjing University. All cases were divided into Luminal B, HER2 positive (n=21) and triple negative (n=26) groups. The surgical pathology after chemotherapy was evaluated by Miller-Payne (M-P) system and the patients were divided into PCR group and non-PCR (nPCR) group. Firevoxel software was used to generate the whole-lesion ADC histogram. The parameters included mean (ADCmean), skewness, kurtosis, the minimum (ADCmin), the maximum (ADCmax), 10th percentile(ADC10%), 50th percentile (ADC50%) and 90th percentile (ADC90%). The two independent samples t test or Mann-Whitney U test was used to compare the differences between PCR and nPCR groups in each subtype. The diagnostic performance of statistically different ADC parameters for predicting PCR was evaluated by receiver operating characteristic (ROC) curve. Results Kurtosis was significantly higher in PCR group than that in nPCR group in HER2 positive subtype (P=0.039). It achieved an area under the curve (AUC) of 0.813 with sensitivity of 100% and specificity of 68.7% at the optimal cutoff value (1.861) for differentiating PCR from nPCR cases. In triple negative subtype, ADCmean and ADC50% were smaller in PCR group than those in nPCR group (P=0.028,0.013). They achieved AUCs of 0.800, 0.842, respectively. When ADCmean of 1.030×10-3 mm2/s and ADC50% of 0.976×10-3 mm2/s were used as cutoff value to differentiate PCR from nPCR, the sensitivities were 75.0%, 80.0% and the specificities were 83.3%, 83.3%, respectively. Conclusion Kurtosis can predict post-NAC PCR in patients with HER2 positive breast cancer, while ADC50% has a high value in predicting post NAC PCR of triple negative breast cancer patients. Key words: Breast neoplasms; Molecular subtype; Neoadjuvant chemotherapy; Magnetic resonance imaging

Clinical factors of pathological complete response after neoadjuvant chemoradiotherapy in rectal cancer

Objective: To explore the feasibility of clinical factors to predict the pathological complete response after neoadjuvant chemoradiotherapy in rectal cancer. Methods: A retrospective analysis was performed on clinical factors of 162 patients with rectal cancer, who underwent neoadjuvant chemoradiotherapy in the General Hospital of People's Liberation Army from January 2011 to December 2018.According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) group and non-pathological complete response group (non-pCR group) to check the predictive clinical factors for pCR. Results: Twenty-eight cases achieved pCR after neoadjuvant chemoradiation (17.3%, 28/162). Univariate analysis showed that patients with higher differentiation (P=0.024), tumor occupation of the bowel lumen≤1/2 (P=0.006), earlier clinical T stage (P=0.013), earlier clinical N stage (P=0.009), the time interval between neoadjuvant chemoradiotherapy and surgery>49 days (P=0.006), and maximum tumor diameter≤5 cm (P=0.019) were more likely to obtain pCR, and the differences werestatistically significant. Multivariate analysis showed that tumor occupation of the bowel lumen≤1/2 (P=0.01), maximum tumor diameter≤5 cm (P=0.035), and the interval>49 days (P=0.009) were independent factors in predicting pCR after neoadjuvant therapy. Conclusion: Tumor occupation of the bowel lumen, maximum tumor diameter, and the time interval between neoadjuvant chemoradiotherapy and surgery can predict the pCR in rectal cancer.

Abstract P6-10-06: Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy

Abstract Importance: It is essential to refine the populations most likely to benefit from targeted chemotherapy combinations. Background: MINDACT showed that molecularly low risk patients, as assessed by the Amsterdam 70-gene profile MammaPrint® (Agendia) (MP), did not benefit from chemotherapy. In the I-SPY2 trial, MP low risk Hormone Receptor (HR) positive/HER2 negative patients are not eligible; however, HR negative or HER2 positive patients were considered high risk and included for treatment with chemotherapy plus novel agents. The neoadjuvant setting provides an opportunity to evaluate whether molecularly low risk HER2 positive patients are good candidates for neoadjuvant chemo/anti-HER2 therapy, where pathologic complete response (pCR) and 3-year outcomes are measured. Objective: To evaluate and further characterize the fraction of and outcomes for patients molecular low-risk disease in the I-SPY2 trial. Methods: The I-SPY2 platform trial is an ongoing multicenter phase 2 multi-arm study utilizing adaptive design and evaluating efficacy and tolerability of investigational agents in combination with standard-of-care chemotherapy for patients with high-risk anatomic stage II/III breast cancer. Patients with HR+HER2- MP low-risk tumors are not eligible. All enrolled patients undergo pretreatment biopsy for genomic evaluation of early recurrence risk with MP for risk stratification and with the 80-gene BluePrint® (Agendia) test for intrinsic subtype classification. Primary endpoint of the study is pCR in breast and lymph nodes (ypT0/is, ypN0). Secondary outcomes included event-free survival (EFS) and distant-recurrence free survival (DRFS). Following standard neoadjuvant treatment with or without a concomitant investigational agent, patients are followed for long-term outcomes. EFS and DRFS at 3 and 5 years in the pCR vs non-pCR groups within histologic and molecular subtypes are determined using the Kaplan Meier method. Results: Of the 1038 enrolled patients by November 2016, 24 patients (3.2%) had molecular low-risk disease as determined by MP. Of these, 21 (87.5%) had HR+HER2+, 1 (4.2%) had HR-HER2+, and 2 (8.4%) had HR-HER2-. BluePrint expression subtyping classified 17 as luminal-type, 6 HER2 enriched-type and 1 basal type. One patient withdrew consent for follow-up. Of the 23 remaining, none achieved pCR and only one (HR+/HER2+) had an EFS event (with median follow-up of 4.3 years). Overall, EFS and DRFS data were available for 950 of the 1038 patients (as of February 2019), with median follow-up of 3.8 years. Of the 173 HR+HER2+ in this cohort, 20 (11.6%) had molecular low-risk tumors. The EFS and DRFS for the 173 HER2+HR+ pCR group is 97% and 98% (non-pCR group 89% and 94%), respectively at 3 years. Removing the molecular low-risk HER2+ patients from the denominator reveals the worse outcome for patients with non pCR: EFS 86% and DRFS 92% at 3 years. The difference is more apparent at 5 years, changing from 74% to 66% for EFS and from 81% to 75% for DRFS. Intrinsic subtypes vary and do not predict early risk. Conclusions: I-SPY2 focuses on women with high clinical risk with only 3.2% of enrolled patients having low molecular risk tumors. However, 12% of HER+ breast cancer enrolled patients had molecular low risk tumors of which 95% were also HR+. In this group, early recurrence is very low despite absence of pCR and irrespective of intrinsic subtype. Refining the population using molecular high-risk classification of patients reveals a greater difference between the pCR and non-pCR groups within the HR+HER2+ subtype in the EFS and DRFS analysis. Clinical trial designs could address the opportunity to find more targeted and less toxic treatments for the HER2+ low molecular risk patient population. Citation Format: Paula R Pohlmann, Christina Yau, Angela DeMichele, Claudine Isaacs, Judy C Boughey, Nola Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, W. Fraser Symmans, I-SPY 2 TRIAL Consortium, Donald A Berry, Laura Esserman. Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy [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 P6-10-06.

Abstract P3-08-63: Predictors of pathologic complete response in HER2 positive breast cancer patients treated with neoadjuvant targeted therapy

Abstract Background: Anti-HER2 therapy is a standard treatment for HER2-positive tumors, however, the response to targeted therapy varies with a pathologic complete response rate of approximately 40%. Additionally, the relationship between the level of HER2 gene amplification and the clinical outcome is unclear. Purpose: The aim of this study was to determine clinico-pathologic predictors of pathologic complete response after neoadjuvant targeted therapy in HER2 positive breast cancers. Materials and Methods: We performed a retrospective review of HER2-positive breast cancer patients treated with Neoadjuvant Systemic Therapy (NST). PCR was defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is, pN0). We divided our cohort into two groups: patient with pathologic complete response (pCR) and patients without complete responses (non-pCR). We compared the HER2 copy number, HER2/CEP-17 ratio, and clinical and pathologic features using univariate and multivariate analyses. Results: A total of 163 patients with HER2 gene amplification (copy number ≥4) or HER2/CEP17 ratio ≥ 2.0 who received neoadjuvant chemotherapy along with Trastuzumab or Trastuzumab-Pertuzumab therapy were included in the study. Only 33.3% of patients achieved pCR. Patients who achieved pCR had tumors with higher HER2 copy numbers (median: 19.1, range: 4.5 - 45.6), compared to those who did not achieve pCR (median:15.22, range: 4.12 - 35.0, p=0.003). The HER2/CEP17 ratio was higher in the pCR group (median 7.43, range 2.1 - 17.94) compared with non-pCR group (median 6.1, range 1.72 - 12.6, p= 0.32). A receiver operating characteristic curve (ROC) to identify the optimal cutoff point to predict pCR revealed the area under the curve for HER2 copy number and HER2/CEP17 ratio to be 0.639 and 0.600, respectively. Univariate analysis showed significant correlation of pCR with HER2 copy number of ≥14 (p=0.003) and an HER2/CEP17 ratio of 4 or greater (p=0.044), and Ki-67 ≥ 40 % (p=0.002). Consistent with previous studies, tumors with negative hormone receptor (HR) statuses had higher pCR rates (p&amp;lt;0.005). In contrast, variables including age (&amp;lt;50 years), and tumor size (&amp;gt;5cm), were not associated with pCR. In our study, all patients with who negative lymph nodes, achieved pCR. In multivariate regression analysis, only HR negativity (OR=2.60, p=0.008), Ki-67 ≥ 40 % (p=0.015 OR=2.625) and HER 2 copy number ≥14 (p=0.009 OR=2.689) remained as a significant factors associated with pCR. Conclusion: Patients with PCR tend to have higher HER/CEP-17 ratios, smaller tumors and negative nodal statuses. Based on our result, HER2 copy number, negative HR status and high KiI-67 are one of the strongest predictors of pCR in HER2 positive tumors. Citation Format: Mariela Huerta Rosario, Sunati Sahoo. Predictors of pathologic complete response in HER2 positive breast cancer patients treated with neoadjuvant targeted therapy [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 P3-08-63.

Abstract P1-10-19: Tyrosine aminoacyl-tRNA synthetase sensitizes breast cancer to chemotherapy througha necroptosis-mediated mechanism: High-throughput proteomics and machine learningalgorithm based feature selection analyses

Abstract Although more than 70% of entire patients are currently receiving the chemotherapy regimen, pathologic complete response (pCR) rate is still low. Therefore, the need for a marker predictive of response to a particular cytotoxic regimen is becoming all the more necessary to optimize therapeutic efficacy and to avoid unnecessary complications. We performed quantitative proteomics in FFPE biopsy breast cancer samples consist of non-responsive and responsive groups to chemotherapy. To define the best classifier to evaluate the predictive power of signatures, we employed four different machine learning algorithms and performed repeated cross-validation on the training set to classify samples between pCR and non-pCR groups. The candidate proteins selected from the machine-learning algorithms were subsequently validated by immunohistochemistry of 123 cases of independent needle biopsy FFPE samples. The further experimental model of breast cancer was performed to identify the molecular mechanism of how the biomarker potentiates sensitivity of multiple breast cancer cells to chemotherapy response and synergistic effect with a combination of necroptotic mimetics. The filtered dataset was subjected to statistical analysis using Student’s t-test (p-value &amp;lt; 0.05), which resulted in 539 proteins with differential abundances. To identify the most meaningful changes in two conditions, the volcano plot was used and 13 proteins were prioritized. We searched for biological process in the Gene Ontology (GO) enrichment analysis in each proteomic cluster. Several immune responses process, apoptotic process, DNA replication process, and aminoacylation for protein translation process primarily were represented in the group with complete remission. On the other hand, cell adhesion process, cytoskeleton organization process, vesicle organization process and Golgi organization process overrepresented in breast cancer which showed poor responses to the therapy. The machine learning approaches demonstrated the highest AUC value, 0.978 (sensitivity 1.0 and specificity 0.714) with a combination of 11 proteins. For the accuracy prediction, four different algorithms demonstrated evenly high accuracy rates from 0.85 to 0.95 with a combination of the selected seven candidates. They were evaluated in the subsequent steps of verification using immunohistochemistry (IHC) in 123 patient cohorts. The predictive relevance of individual proteins, YARS to distinguish CR from nCR was AUC of 0.749 for all cases. The overexpression of YARS induced chemotherapeutic sensitivity in hormone receptor-positive breast cancer cell lines such as T47D, which was confirmed with multiple molecular biology-driven assays. The further experimental model of breast cancer demonstrated that YARS induced tumor necroptosis which enhanced chemotherapy response and was synergized with a combination of SMAC mimetics that is a potent necroptosis inducer. In summary, our discovery data provide a global molecular landscape for determining chemotherapy response in breast cancer at the proteome level. Furthermore, we provided a novel protein candidate to predict chemotherapy response and identify a novel protein YARS in combination with Smac mimetics synergistically induced necroptosis which produces more cell death in response to combined chemotherapy in breast cancer. Citation Format: Han Suk Ryu. Tyrosine aminoacyl-tRNA synthetase sensitizes breast cancer to chemotherapy througha necroptosis-mediated mechanism: High-throughput proteomics and machine learningalgorithm based feature selection analyses [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 P1-10-19.

Preoperative Prediction of Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Cancer Using 18F-FDG PET/CT and DW-MRI: A Prospective Multicenter Study

Accurate preoperative prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal cancer could enable omission of esophagectomy in patients with a pathologic complete response (pCR). This study aimed to evaluate the individual and combined value of 18F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (18F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) during and after nCRT to predict pathologic response in patients with esophageal cancer. In this multicenter prospective study, patients scheduled to receive nCRT followed by esophagectomy for esophageal cancer underwent 18F-FDG PET/CT and DW-MRI scanning before the start of nCRT, during nCRT, and before esophagectomy. Response to nCRT was based on histopathologic evaluation of the resection specimen. Relative changes in 18F-FDG PET/CT and DW-MRI parameters were compared between patients with pCR and non-pCR groups. Multivariable ridge regression analyses with bootstrapped c-indices were performed to evaluate the individual and combined value of 18F-FDG PET/CT and DW-MRI. pCR was found in 26.1% of 69 patients. Relative changes in 18F-FDG PET/CT parameters after nCRT (Δ standardized uptake value [SUV]mean,postP = .016, and Δ total lesion glycolysis postP = .024), as well as changes in DW-MRI parameters during nCRT (Δ apparent diffusion coefficient [ADC]duringP = .008) were significantly different between pCR and non-pCR. A c-statistic of 0.84 was obtained for a model with ΔADCduring, ΔSUVmean,post, and histology in classifying patients as pCR (versus 0.82 for ΔADCduring and 0.79 for ΔSUVmean,post alone). Changes on 18F-FDG PET/CT after nCRT and early changes on DW-MRI during nCRT can help identify pCR to nCRT in esophageal cancer. Moreover, 18F-FDG PET/CT and DW-MRI might be of complementary value in the assessment of pCR.

Changes in Tumor-Infiltrating Lymphocytes and Vascular Normalization in Breast Cancer Patients After Neoadjuvant Chemotherapy and Their Correlations With DFS.

Objective: Changes in the number of various tumor-infiltrating lymphocytes (TILs) and degrees of vascular normalization in breast cancer (BC) patients after neoadjuvant chemotherapy (NAC) were analyzed to screen key factors that can predict the prognosis.Methods: HE-stained sections were used to assess the degree of TILs infiltration; immunohistochemically stained sections were used to assess the infiltration of CD8+, CD4+, FOXP3+ Tregs and the expression of PD-L1; immunofluorescence-stained sections were used to assess the microvessel density (MVD) and microvessel pericyte coverage index (MPI). The expression of them before NAC were compared with those after NAC, and correlations between changes in these parameters and the pathological complete remission (pCR) and DFS of BC patients were analyzed.Results: After NAC, the percentage of patients with enhanced sTILs in the pCR group was significantly higher than that in the Non-pCR group (P < 0.05). Univariate and multivariate analyses showed that the number of FOXP3+ Tregs and MPI before NAC were correlated with pCR (P < 0.05). Survival analysis showed that the DFS of BC patients with reduced FOXP3+ Tregs was significantly better than that of patients with elevated FOXP3+ Tregs (P = 0.029). The sTILs count and MPI were significantly higher in primary tumors than lymph nodes (P < 0.05).Conclusion: After NAC, the reduced infiltration of FOXP3+ Tregs was correlated with an improvement in DFS in BC patients. Changes in the number of FOXP3+ Tregs and the MPI may be used as prognostic markers for BC patients.

Texture Analysis of Dynamic Contrast-Enhanced MRI in Evaluating Pathologic Complete Response (pCR) of Mass-Like Breast Cancer after Neoadjuvant Therapy.

Objectives MRI is the standard imaging method in evaluating treatment response of breast cancer after neoadjuvant therapy (NAT), while identification of pathologic complete response (pCR) remains challenging. Texture analysis (TA) on post-NAT dynamic contrast-enhanced (DCE) MRI was explored to assess the existence of pCR in mass-like cancer. Materials and Methods A primary cohort of 112 consecutive patients (40 pCR and 72 non-pCR) with mass-like breast cancers who received preoperative NAT were retrospectively enrolled. On post-NAT MRI, volumes of the residual-enhanced areas and TA first-order features (19 for each sequence) of the corresponding areas were achieved for both early- and late-phase DCE using an in-house radiomics software. Groups were divided according to the operational pathology. Receiver operating characteristic curves and binary logistic regression analysis were used to select features and achieve a predicting formula. Overall diagnostic abilities were compared between TA and radiologists' subjective judgments. Validation was performed on a time-independent cohort of 39 consecutive patients. Results TA features with high consistency (Cronbach's alpha >0.9) between 2 observers showed significant differences between pCR and non-pCR groups. Logistic regression using features selected by ROC curves generated a synthesized formula containing 3 variables (volume of residual enhancement, entropy, and robust mean absolute deviation from early-phase) to yield AUC = 0.81, higher than that of using radiologists' subjective judgment (AUC = 0.72), and entropy was an independent risk factor (P < 0.001). Accuracy and sensitivity for identifying pCR were 83.93% and 70.00%. AUC of the validation cohort was 0.80. Conclusions TA may help to improve the diagnostic ability of post-NAT MRI in identifying pCR in mass-like breast cancer. Entropy, as a first-order feature to depict residual tumor heterogeneity, is an important factor.

Prediction of Neoadjuvant Radiotherapy and Chemotherapy for Locally Advanced Rectal Cancer Based on 3.0T MRI Intravoxel Incoherent Motion Diffusion Weighted-Imaging with Fe3O4 Nanocontrast Agent

The purpose of this study was to preliminarily explore the feasibility of pre-treatment intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for predicting the efficacy of neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). Fifty-four patients underwent preoperative IVIM-DWI before (pre-nCRT) and after nCRT (post-nCRT). The values of pre-nCRT and post-nCRT IVIM-DWI parameters (apparent diffusion coefficient standard (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f), together with the percentage changes (Δ% parametric value) induced by nCRT, were compared between pathological complete response (pCR) and non-pCR groups. After nCRT, the ADC and Dvalues for LARC increased significantly (all P &lt;0.05). The TRG score revealed positive correlations with pre f (r = 0.357, P = 0.020), postD (r =0.551,P &lt;0.001), and Δ%D (r =0.605, P &lt;0.001). The pCR group (n =10) had higher preD *, pref, postD, Δ%ADC, and Δ%D values than the non-pCR group (n =32) (allP &lt;0.05). The GR group (n =15) exhibited higher postD, %ADC, and %D values than the PR group (n =27) (allP &lt;0.05). Based on ROC analysis, Δ%D had a higher area under the curve value than Δ%ADC (P =0.009) in discriminating the pCR and non-pCR groups. IVIM-DWI may be helpful in identifying pCR to nCRT for LARC and is more accurate than traditional DWI.

The value of MR T2WI signal intensity related parameters for predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Objective: To evaluate the value of T2WI signal intensity related parameters that can be obtained by magnetic resonance imaging (MRI) for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanved rectal cancer (LARC). Methods: Signal Intensity of Tumor (SIT) and Signal Intensity of Tumor/Muscle (SIT/M) of MR T2WI before and after neoadjuvant chemoradiotherapy of 101 patients with locally advanced rectal cancer were evaluated by two experienced readers independently. Signal Intensity of Tumor Reduction Rate (SITRR) and Signal Intensity of Tumor/Muscle Reduction Rate (SIT/MRR) were calculated. The difference of related parameters of T2WI tumor signal intensity between the pCR and the non-pCR group were analyzed. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance for predicting pCR. Results: Of the 101 patients, 18 were in pCR group and 83 were in non-pCR group. In all patients, the SITpre, SITpost, SITRR, SIT/Mpre, SIT/Mpost and SIT/MRR measured by reader 1 were 197.0 (133.0), 144.2 (69.7), 0.4% (0.5%), 2.6 (0.6), 3.0 (2.3) and 0.4 (0.2)% in pCR group, and 227.0 (99.0), 205 (95.4), 0.1% (0.6%), 2.6 (0.6), 2.6 (1) in non-pCR group, respectively. SITpre, SITpost, SITRR, SIT/Mpre, SIT/Mpost and SIT/MRR measured by reader 2 were 193.0 (135.0), 143.0 (69.8), 0.4% (0.2%), 2.6 (0.6), 1.5 (0.5) and 0.39% (0.2%) in pCR group, and 234.0(108.0), 203(96.5), 0.1% (0.3%), 2.6 (0.6%), 1.7 (0.7) and 0.25% (0.2%) in non-pCR group, respectively. Between the pCR and non-pCR group, there were significant differences in SITpost, SIT/Mpost and SIT/MRR measured by both readers (all P<0.01), but there was no significant differences in SITpre and SIT/Mpre (P>0.05). The difference of SITRR measured by reader 1 was not statistically significant (P=0.415), while the difference of SITRR measured by reader 2 was statistically significant (P=0.001). In patients with rectal non-mucinous adenocarcinoma, SITpost, SIT/Mpost, SITRR and SIT/MRR measured by two physicians were still statistically significant between the pCR and non-pCR group (all P<0.01), but SITpre and SIT/Mpre had no significant difference (P>0.05). ROC curve analysis showed that in all patients, the area under curve (AUC) of SITpost, SIT/Mpost and SIT/MRR for predicting pCR to neoadjuvant chemoradiotherapy in locally advanced rectal cancer was 0.694-0.762, the sensitivity was 68.2%-77.3%, and the specificity was 63.6%-77.3%. In rectal non-mucinous adenocarcinoma patients, the AUC, sensitivity and specificity was 0.704-0.764, 62.7%-78.9% and 66.2%-84.2%, respectively. Conclusions: T2WI signal intensity related parameters are potential predictors for pCR in locally advanced rectal cancer after neoadjuvant chemoradiptherapy. The predictive value is higher in non-mucinous adenocarcinoma.

Pretreatment Esophageal Wall Thickness Associated with Response to Chemoradiotherapy in Locally Advanced Esophageal Cancer.

A multimodality approach using concurrent chemoradiotherapy (CRT) followed by esophagectomy has been the standard treatment in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Computed tomography (CT) is widely utilized to evaluate esophageal cancer before and after CRT. This study evaluated the utility of pretreatment maximal esophageal wall thickness on CT scans to predict treatment outcomes after CRT in patients with locally advanced ESCC. Eighty-one patients with T3 locally advanced ESCC, whom were treated completely with CRT with and without surgery, and had available CT scans before and after CRT at a university hospital between 2005 and 2015, were retrospectively reviewed. Twenty patients (24.7%) had esophagectomy after neoadjuvant CRT and sixty-one patients (75.3%) had definitive CRT. The maximal esophageal wall thicknesses were measured retrospectively and correlated with the response and survival after treatment. A total of 40% of neoadjuvant CRT patients achieved a pCR. There was a significant difference in pretreatment maximal esophageal wall thickness between the pCR and non-pCR groups (mean 11.9 ± 5.3 mm versus 16.9 ± 3 mm; p = 0.01). Pretreatment maximal esophageal wall thickness < 10 mm was significantly related to better overall survival than ≥ 10 mm (median survival 79 months versus 15 months; HR 3.21, 95%CI 1.14-9; p = 0.02). The neoadjuvant CRT group had significantly better survival than the definitive CRT group (median survival 51 months versus 14.5 months; HR 0.46; 95%CI 0.25-0.85; p = 0.01). In our study, pretreatment esophageal wall thickness of T3 locally advanced ESCC is a useful indicator for predicting survival and pCR after treatment.

Predictive factors and prognostic value of pathologic complete response of ipsilateral supraclavicular lymph nodes in breast cancer after neoadjuvant chemotherapy

Breast cancer with ipsilateral supraclavicular lymph node metastasis is one of the indicators of poor prognosis. Patients who attain pathologic complete response in breast and axillary sites have improved survival and are highest in aggressive HR-HER2- and HER2-positive tumor subtypes. However, there is no study on the related factors and prognostic value of supraclavicular pathologic complete response in breast cancer after neoadjuvant chemotherapy. The aim of our work was to investigate the factors and prognostic significance of pathologic complete response of ipsilateral supraclavicular lymph node metastasis in breast cancer after neoadjuvant chemotherapy. A total of 214 patients with breast cancer who had primary ISLN metastasis, receiving NAC and subsequent ISLN dissection, were retrospectively and consecutively reviewed. Univariate and multivariate analyses were performed using χ2 test and the logistic regression model, and the prognosis was analyzed by Kaplan-Meier curve. All patients included were women who were 26-74 years old. The rate of supraclavicular pathologic complete response (pCR) was 53.7%. Multivariate analysis showed that the expression of Ki67, breast pCR, and axillary pCR were independent predictors of supraclavicular pCR (P<0.05). After a median follow-up of 16.2 months, the risk of recurrence and metastasis in patients with supraclavicular pCR was half reduced compared to that of the non-pCR group (HR 0.51, 95% CI, 0.32-0.80, P<0.01), mainly manifested in HR-HER2- and HER2-positive disease. The expression level of Ki67, breast pCR, and axillary pCR were independent predictors of supraclavicular pCR. Supraclavicular pCR was an independent predictor of disease-free survival (DFS). Surgical removal of supraclavicular lymph nodes can accurately evaluate the rate of supraclavicular pCR, which is of great significance for patient prognosis.

Improved survival with adjuvant chemotherapy in locally advanced rectal cancer patients treated with preoperative chemoradiation regardless of pathologic response

ObjectiveThe aim of this study is to examine the effect of postoperative chemotherapy on survival in patients with stage II or III rectal adenocarcinoma who undergo neoadjuvant chemoradiation (CRT) and surgical resection. MethodsA retrospective review of the National Cancer Database (NCDB) from 2006 to 2013 was performed. Cases were analyzed based on pathologic complete response (pCR) status and use of adjuvant therapy. The Kaplan-Meier method was used to estimate overall survival probabilities. Results23,045 cases were identified, of which 5832 (25.31%) achieved pCR. In the pCR group, 1513 (25.9%) received adjuvant chemotherapy, and in the non-pCR group, 5966 (34.7%) received adjuvant therapy. In the pCR group, five-year survival probability was 87% (95% CI 84%–89%) with adjuvant therapy and 81% (95% CI 79%–82%) without adjuvant therapy. In the non-pCR group, five-year survival probability was 78% (95% CI 76%–79%) with adjuvant therapy and 70% (95% CI 69%–71%) without adjuvant therapy. In the non-pCR and node-negative subgroup (ypN-), five-year survival probability was 86% (95% CI 84%–88%) with adjuvant therapy and 76% (95% CI 74%–77%) without adjuvant therapy. In the non-pCR and node-positive subgroup (ypN+), five-year survival probability was 67% (95% CI 65%–70%) with adjuvant therapy and 60% (95% CI 58%–63%) without adjuvant therapy. ConclusionsAdjuvant chemotherapy in stage II or III rectal adenocarcinoma is associated with increased five-year survival probability regardless of pCR status. We observed similar survival outcomes among non-pCR ypN- treated with adjuvant chemotherapy compared with patients achieving pCR treated with adjuvant chemotherapy.

Predicting pathological complete response by comparing MRI-based radiomics pre- and postneoadjuvant radiotherapy for locally advanced rectal cancer.

BackgroundTotal mesorectal excision following neoadjuvant chemoradiotherapy (nCRT) is recommended in the latest treatment of locally advanced rectal cancer (LARC).ObjectiveTo predict whether patients with LARC can achieve pathologic complete response (pCR), comparing MRI‐based radiomics between before and after neoadjuvant radiotherapy (nRT) was performed.MethodsOne hundred and sixty‐five MRI‐based radiomics features in axial T2‐weighted images were obtained quantitatively from Imaging Biomarker Explorer Software. The specific features of conventional and developing radiomics were selected with the analysis of least absolute shrinkage and selection operator logistic regression, of which the predictive performance was analyzed with receiver operating curve and calibration curve, and applied to an independent cohort.ResultsOne hundred and thirty‐one target patients were enrolled in the present study. A radiomics signature founded on seven radiomics features was generated in the primary cohort. A remarkable difference about Rad‐score between pCR and non‐pCR group occurred in both of primary (P < .001) or validation cohorts (P < .001). The value of area under the curves was 0.92 (95% CI, 0.86‐0.99) and 0.87 (95% CI, 0.74‐1.00) in the primary and validation cohorts, respectively. The Rad‐score (OR = 23.581; P < .001) from multivariate logistic regression analysis was significant as an independent factor of pCR.ConclusionOur predictive model based on radiomics features was an independent predictor for pCR in LARC and could be a candidate in clinical practice.

1859P - A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC)

BackgroundEven though preoperative chemoradiotherapy (CRT) showed survival improvement in patients with resectable ESCC in a randomized trial over upfront surgery, ESCC still has a dismal prognosis. With the potential benefit of combining PD-1 blockade to CRT, we conducted a phase II trial which assessed the efficacy, feasibility, and safety of the combination of preoperative CRT and pembrolizumab (PEM) in ESCC (NCT02844075). MethodsPatients (pts) with histologically confirmed ESCC (clinical stage Ib to III according to the American Joint Committee on Cancer 7th staging system) were enrolled. Pts received concurrent neoadjuvant chemotherapy (weekly paclitaxel and carboplatin), radiotherapy (44.1Gy in 21 fractions), and PEM (every 3 weeks, 200mg) during 5 weeks followed by surgery. After surgery, pts were treated with PEM during 2 years or until progression, unacceptable toxicity, death, or pts’ refusal, which came first. The primary endpoint was pathologic complete response (pCR) rate in the primary tumor and secondary endpoints were overall survival (OS), disease-free survival (DFS), the incidence of adverse events, and etc. ResultsIn a total of 28 enrolled pts (median age 60), 26 pts received esophagectomy. Two pts did not undergo surgery due to death (hematemesis) and consent withdrawal. There were two in-hospital mortality cases after surgery due to acute lung injury and four mortality cases due to disease progression. The pCR in primary tumor was achieved in 46.1% of pts who underwent resection (95% CI: 28.8 – 64.6). With a median follow-up of 12.4 months, median OS was not reached. Six, 12, and 18-month OS rates were 89.3%, 80.8%, and 73.1% respectively. There was a trend toward better DFS in the pCR group (n=12) compared with the non-pCR group (n=14) (HR=0.33, p=0.1). Most common treatment-related adverse events were neutropenia (50.0%) and liver enzyme elevation (30.8%) in the neoadjuvant and adjuvant period, respectively. ConclusionsThe addition of PEM to preoperative CRT in ESCC demonstrated promising efficacy with acceptable toxicity. Based on the results, further investigation is warranted in a phase III clinical trial. The exploratory endpoints including biomarkers analyses are ongoing. Clinical trial identificationNCT02844075. Legal entity responsible for the studyThe authors. FundingMSD. DisclosureAll authors have declared no conflicts of interest.

The Value of Preoperative Radiotherapy in the Treatment of Locally Advanced Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma: A Single Institutional Experience

The value of preoperative radiotherapy in the comprehensive treatment of locally advanced nasal cavity and paranasal sinus squamous cell carcinomas (NPSCCs) remains controversial. The aim of our study was to compare the efficacy of preoperative and postoperative radiotherapy and further to explore the value of preoperative radiotherapy in the treatment of locally advanced NPSCCs. One hundred and forty-two patients with locally advanced NPSCCs treated with pre- / postoperative radiotherapy plus surgery from our institution between January 1998 and December 2014 were retrospectively reviewed. All enrolled patients were divided into the two groups: preoperative radiotherapy (Pre-S RT) group and postoperative radiotherapy (PORT) group. The overall survival (OS), local control (LC), distance metastasis free survival (DMFS) and disease-free survival (DFS) between treatment groups were evaluated. A higher proportion of adverse prognostic factors, such as orbital content invasion, low RT dose, and 2D/3DCRT were found in preoperative radiotherapy group, which were confirmed to be associated with overall survival and/or local control by univariate and multivariate analysis. The median radiation dose of preoperative and postoperative radiotherapy was 60Gy and 69Gy (P value < 0.001). At a median follow-up of 49 months, preoperative radiotherapy achieved good LC, DFS, DMFS, and OS, not worse than postoperative radiotherapy. The 5-year OS, LC, DMFS, and DFS of Pre-S RT group were 55.1%, 59.1%, 78.7%, and 49.0%, while those of PORT group were 52.2%, 60.0%, 76.6%, and 47.3%, respectively (P value > 0.05). After preoperative radiotherapy, the complete resection rate reached 93.5%, significantly higher than 31.2% in the postoperative radiotherapy group (P value <0.001). Among the 50 patients with orbital contents invasion, the actual orbital content preservation rate of preoperative radiotherapy group was nearly 76%, higher than that of postoperative radiotherapy group (57%). The pathologic complete response (pCR) rate of the preoperative radiotherapy group was up to 30.6%. Compared with non-pCR group, pCR group had significantly higher 5-year OS, LC, DFS (P value < 0.05), and similar 5-year DMFS (P value > 0.05). In the absence of randomized controlled studies to guide treatment, this study confirmed the value of preoperative radiotherapy. Under the condition of more adverse factors, preoperative radiotherapy plus surgery not only achieved similar clinical outcomes to surgery plus postoperative radiotherapy, but also significantly improved complete resection rate and increased the chance of orbital contents preservation. More importantly, nearly a third of patients achieved pCR in the preoperative radiotherapy group, and this subgroup had the best prognosis.

Clinical value of endorectal ultrasonography in predicting neoadjuvant treatment response for locally advanced rectal cancer

Objective To assess the value of endorectal ultrasonography(ERUS) in predicting the pathological response to neoadjuvant chemoradiotherapy(NCRT) for locally advanced rectal cancer(LARC). Methods Ninety-nine patients with LARC received NCRT and total mesorectal excision in our hospital were retrospectively analyzed. The maximum length and thickness of rectal tumor were measured by ERUS both before NCRT(ERUS1) and after NCRT following sugery(ERUS2), and the length and thickness reduction rate were calculated. The patients were classified into good responder group(n=47) and poor responder group(n=52), or pathological complete response(pCR) group(n=25) and non-pCR group (n=74) according to pathological tumor regression grade(TRG). The differences of various parameters were compared between groups. The correlations between these parameters and TRG grading were analyzed by Spearman correlation analysis. The ROC curve was used to evaluate the diagnostic efficacy of the parameter. Results The length and thickness of ERUS2 were significantly shorter than that of ERUS1(all P<0.05). The length and thickness of ERUS2 in good responder group were shorter than those in poor responder group, while the length and thickness reduction rate were higher than those in poor responder group with significant difference(all P<0.05). The length and thickness of ERUS2 in pCR group were shorter than those in non-pCR group, while the length and thickness reduction rate were higher than those in non-pCR group with significant difference(all P<0.05). The length and thickness of ERUS2 were positively correlated with TRG grading(r=0.577, 0.605; all P<0.01) and the length and thickness reduction rate were negatively correlated with TRG grading(r=-0.681, -0.598; all P<0.01). ROC curve showed the cut-off value of the length and thickness reduction rate to predict good responder were 41.34%, 46.46%, with corresponding AUC areas of 0.843, 0.796, sensitivity of 74.5%, 70.2%, and specificity of 76.9%, 80.8%, respectively. ROC curve showed the cut-off value of the length and thickness reduction rate to predict pCR were 57.36%, 58.52%, with corresponding AUC areas of 0.851 and 0.895, sensitivity of 68.0%, 76.0%, and specificity of 94.6%, 93.2%, respectively. Conclusions The changes of length and thickness of tumor after NCRT are well correlated with treatment response. The length and thickness reduction rate measured on ERUS present high accuracy in prediction of good response and pCR in LARC patients. Key words: Ultrasonography, transrectal; Rectal cancer; Neoadjuvant therapy; Tumor regression grade

A prognostic 10-miRNA risk score (10-miRNA RS) in predicting neoadjuvant chemotherapy sensitivity of luminal breast cancer.

3139 Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B1; 14.7% vs. 30.1% in luminal B2; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.

A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC).

4027 Background: Even though preoperative chemoradiotherapy (CRT) showed survival improvement in patients with resectable ESCC in a randomized trial over upfront surgery, ESCC still has a dismal prognosis. With the potential benefit of combining PD-1 blockade to CRT, we conducted a phase II trial which assessed the efficacy, feasibility, and safety of the combination of preoperative CRT and pembrolizumab (PEM) in ESCC. Methods: Patients (pts) with histologically confirmed ESCC (clinical stage Ib to III according to the American Joint Committee on Cancer 7th staging system) were enrolled. Pts received concurrent neoadjuvant chemotherapy (weekly paclitaxel and carboplatin), radiotherapy (44.1 Gy in 21 fractions), and PEM (every 3 week, 200 mg) during 5 weeks followed by surgery. After surgery, pts were treated with PEM during 2 years or until progression, unacceptable toxicity, death, or pts’ refusal, which came first. The primary endpoint was pathologic complete response (pCR) rate in the primary tumor and secondary endpoints were overall survival (OS), disease-free survival (DFS), the incidence of adverse events, and etc. Results: In a total of 28 enrolled pts (median age 60), 26 pts received esophagectomy. Two pts did not undergo surgery due to death (hematemesis) and consent withdrawal. There were two in-hospital mortality cases after surgery, which were resulted from acute lung injury. The pCR in primary tumor was achieved in 46.1% of pts who underwent resection (95% CI: 28.8 – 64.6). With a median follow-up of 11.7 months, median OS was not reached. Six-month and 12-month OS rates were 89.3% and 82.1%, respectively. There was a trend toward better DFS in the pCR group (n = 12) compared with the non-pCR group (n = 14) (HR = 0.33, p = 0.1). Most common treatment-related adverse events were neutropenia (50.0%) and liver enzyme elevation (30.8%) in the neoadjuvant and adjuvant period, respectively. Conclusions: The addition of PEM to preoperative CRT in ESCC demonstrated promising efficacy with acceptable toxicity. Based on the results, further investigation is warranted in a phase III clinical trial. The exploratory endpoints including biomarkers analyses are ongoing. Clinical trial information: NCT02844075.