Predictive Factor For Tumor Response Research Articles

Tumor-stroma contact ratio - a novel predictive factor for tumor response to chemoradiotherapy in locally advanced oropharyngeal cancer

The growth pattern of oropharyngeal squamous cell carcinomas (OPSCC) varies from compact tumor cell aggregates to diffusely infiltrating tumor cell-clusters. The influence of the growth pattern on local tumor control and survival has been studied mainly for surgically treated oral cavity carcinomas on a visual basis. In this study, we used multiplex immunofluorescence staining (mIF) to examine the antigens pan-cytokeratin, p16INK4a, Ki67, CD271, PD-L1, and CD8 in pretherapeutic biopsies from 86 OPSCC. We introduce Tumor-stroma contact ratio (TSC), a novel parameter, to quantify the relationship between tumor cells in contact with the stromal surface and the total number of epithelial tumor cells. mIF tumor cores were analyzed at the single-cell level, and tumor-stromal contact area was quantified using the R package "Spatstat". TSC was correlated with the visually assessed invasion pattern by two independent investigators. Furthermore, TSC was analyzed in relation to clinical parameters and patient survival data to evaluate its potential prognostic significance.Higher TSC correlated with poor response to (chemo-)radiotherapy (r = 0.3, p < 0.01), and shorter overall (OS) and progression-free (PFS) survival (median OS: 13 vs 136 months, p < 0.0001; median PFS: 5 vs 85 months, p < 0.0001). Visual categorization of growth pattern according to established criteria of tumor aggressiveness showed interobserver variability increasing with more nuanced categories (2 categories: k = 0.7, 95 %-CI: 0.55 - 0.85; 4 categories k = 0.48, 95 %-CI: 0.35 - 0.61).In conclusion, TSC is an objective and reproducible computer-based parameter to quantify tumor-stroma contact area. We demonstrate its relevance for the response of oropharyngeal carcinomas to primary (chemo-)radiotherapy.

The impact of curative conversion therapy aimed at a cancer-free state in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

We aimed to validate the predictive factors for tumor response and the prognostic impact of conversion therapy aimed at cancer- and drug-free states in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing atezolizumab plus bevacizumab (Atez/Bev) therapy. This retrospective study enrolled 156 patients who were Child-Pugh class A with u-HCC treated using Atez/Beva. The profile of objective response was investigated using decision-tree analysis. Progression-free, recurrence-free, and overall survival were assessed. The progression-free and overall survival were 6.1 and 18.0 months, respectively. Objective response and disease control rates were 32.0% and 84.0%, respectively. Decision-tree analysis revealed that neutrophil-to-lymphocyte ratio (NLR) <3, modified albumin-bilirubin grade (m-ALBI) 1 or 2a, and age < 75 were sequential splitting variables for the objective response, respectively. In the multivariate analysis, NLR <3 and m-ALBI grade 1 or 2a were identified as predictive factors for objective response. We successfully achieved eligibility for conversion therapy in 17 patients after Atez/Bev therapy significant response. Following conversion therapy, the curative therapy group, including surgical resection or radiofrequency ablation (RFA), had significantly higher recurrence-free survival than did the transcatheter arterial chemoembolization (TACE) and Atez/Bev discontinuation (surgical resection or RFA; not reached vs. TACE; 5.3 months, p = 0.008, Atez/Bev discontinuation; 3.9 months, p = 0.048, respectively) groups. NLR <3 and m-ALBI grade 1 or 2a were predictive factors for conversion therapy, leading to cancer- and drug-free states in patients with u-HCC undergoing Atez/Bev therapy. Moreover, surgery or RFA may be suitable for conversion therapy for cancer-free status.

Response prediction of vestibular schwannoma after gamma-knife radiosurgery using pretreatment dynamic contrast-enhanced MRI: a prospective study.

There are few known predictive factors for response to gamma-knife radiosurgery (GKRS) in vestibular schwannoma (VS). We investigated the predictive role of pretreatment dynamic contrast-enhanced (DCE)-MRI parameters regarding the tumor response after GKRS in sporadic VS. This single-center prospective study enrolled participants between April 2017 and February 2019. We performed a volumetric measurement of DCE-MRI-derived parameters before GKRS. The tumor volume was measured in a follow-up MRI. The pharmacokinetic parameters were compared between responders and nonresponders according to 20% or more tumor volume reduction. Stepwise multivariable logistic regression analyses were performed, and the diagnostic performance of DCE-MRI parameters for the prediction of tumor response was evaluated by receiver operating characteristic curve analysis. Ultimately, 35 participants (21 women, 52 ± 12years) were included. There were 22 (62.9%) responders with a mean follow-up interval of 30.2 ± 5.7months. Ktrans (0.036min-1 vs. 0.057min-1, p = .008) and initial area under the time-concentration curve within 90s (IAUC90) (84.4 vs. 143.6, p = .003) showed significant differences between responders and nonresponders. Ktrans (OR = 0.96, p = .021) and IAUC90 (OR = 0.97, p = .004) were significant differentiating variables in each multivariable model with clinical variables for tumor response prediction. Ktrans showed a sensitivity of 81.8% and a specificity of 69.2%, and IAUC90 showed a sensitivity of 100% and a specificity of 53.8% for tumor response prediction. DCE-MRI (particularly Ktrans and IAUC90) has the potential to be a predictive factor for tumor response in VS after GKRS. •Pretreatment prediction of gamma-knife radiosurgery response in vestibular schwannoma is still challenging. •Dynamic contrast-enhanced MRI could have predictive value for the response of vestibular schwannoma after gamma-knife radiosurgery.

Dysphagia predict the response to second cycle neoadjuvant chemotherapy in first cycle no response esophageal carcinoma.

After the first-cycle of neoadjuvant chemotherapy (NAC), many patients with esophageal squamous cell carcinoma (ESCC) experience a stable disease (SD)/progressive disease (PD) response. Clinically, SD patients are recommended to receive a second cycle of NAC, and PD patients are recommended to undergo surgery if possible. However, we found some PD tumors shrank after a second-cycle of NAC. Some first-cycle SD patients may develop PD after second-cycle NAC and lose the chance of surgery. Thus, how to predict the response to second-cycle NAC for first-cycle SD/PD patients is important for clinical practice. This retrospective single-center study was approved by the Institutional Review Board at the Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital. We retrospectively reviewed patients with ESCC who had NAC and evaluated SD by computed tomography (CT) scan after the first-cycle between March 9, 2013 and October 24, 2016. Univariate and multivariate analyses of the clinical parameters were performed to identify markers predictive of a clinically response by using IBM-SPSS version 23. There were 64 patients included in the study. Thirty-one first-cycle NAC-SD/PD patients (48.4%) showed a response after second-cycle NAC, which was significantly correlated with alleviated dysphagia (P=0.006) and smoking (P=0.025). In the multivariate analyses, alleviated dysphagia [odds ratio (OR) 3.978; 95% confidence interval (CI), 1.335-11.856; P=0.013] was identified as the only independent predictive factor for tumor response after second-cycle of NAC for first-cycle SD/PD patients. Alleviated dysphagia might be a useful factor to predict the response to second-cycle NAC for first-cycle SD/PD patients.

P-085 - Rectal adenocarcinoma: clinical predictive factors for tumor response after chemoradiotherapy

P-085 - Rectal adenocarcinoma: clinical predictive factors for tumor response after chemoradiotherapy

The Relationship between Primary Gross Tumor Volume and Tumor Response of Locally Advanced Rectal Cancer: pGTV as a More Accurate Tumor Size Indicator

Purpose: To identify the clinical predictive factors of tumor response and to evaluate the significance of primary gross tumor volume (pGTV), obtained from radiotherapy planning, in predicting tumor response. Materials and Methods: We retrospectively analyzed data of consecutive locally advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery at our institution between March 2009 and December 2017. We identify independent predictors of tumor response to nCRT by statistical analysis. Disease-free survival (DFS) starting from the time of surgery was calculated by the Kaplan–Meier method, and log-rank tests were performed to compare DFS between patients with superior and inferior tumor response. Results: Overall, 185 LARC patients received nCRT, of whom 89 (48.11%) achieved superior tumor response. Diminutive pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were independent predictive factors of superior tumor response. Meanwhile, pGTV can be regarded as an independent predictor of pathologic complete response (pCR) (p = 0.036). The log-rank test revealed that DFS was longer in the diminutive pGTV group than in the giant pGTV group (p = 0.001). Conclusions: pGTV, as a measure of tumor size, is not only an important prognostic indicator but also an independent predictive factor of tumor response, even pCR.

RAS mutations in patients with metastatic colorectal cancer in Central America and the Caribbean.

e15126 Background: Metastatic colorectal cancer (MCRC) survival has been improved in the last decade due to the identification of predictive and prognostic factors such as RAS gene status and also by the addition of targeted therapies to chemotherapy schemes. RAS mutation, a prognostic factor but must importantly a predictive factor for tumor response to monoclonal antibodies against the epidermal growth factor receptor in MCRC, has been reported between 16.3% and 43.6%. The aim of this study is to determine the frequency of RAS mutations in patients with MCRC in Central America and the Caribbean. Methods: This is a retrospective-descriptive analysis of RAS mutations performed in patients with MCRC in Central America and the Caribbean. An informed consent was required for the mutational analysis. The information obtained has been kept in an anonymized database. Results: 2,138 tissue samples were analyzed by real time PCR. RAS mutations were documented in 46.7% of the cases, of these 94.8% correspond to mutations in kRAS and 5.2% to mutations in nRAS. 67.5% of RAS mutations were found in codon 12, 21.3% in codon 13, 5.8% in codon 146 and 4% in codon 61. 51.5% of the mutations were in males and 48.5% in females. RAS mutations in central american population were identified in a 45.8% and in a 42.5% in the caribbean. Conclusions: This is the first report of RAS mutations in patients with MCRC in Central America and the Caribbean. Our findings are similar to the data reported in other regions of the world. A clinical and epidemiological analysis and correlation of these findings is underway.

Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study

PurposeThe HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. Patients and methodsThe HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5–8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. ResultsThirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose–response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. ConclusionTumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

Tumor Targeting and Three-Dimensional Voxel-Based Dosimetry to Predict Tumor Response, Toxicity, and Survival after Yttrium-90 Resin Microsphere Radioembolization in Hepatocellular Carcinoma

PurposeTo identify predictive factors of tumor response, progression-free survival (PFS), overall survival (OS), and toxicity using three-dimensional (3D) voxel-based dosimetry in patients with intermediate and advanced stage hepatocellular carcinoma (HCC) treated by yttrium-90 (90Y) resin microspheres radioembolization (RE). Materials and MethodsFrom February 2012 to December 2015, 45 90Y resin microspheres RE procedures were performed for HCC (Barcelona Clinic Liver Cancer stage B/C; n = 15/30). Area under the dose-volume histograms (AUDVHs) were calculated from 3D voxel-based dosimetry to measure 90Y dose deposition. Factors associated with tumor control (ie, complete/partial response or stable disease on Modified Response Evaluation Criteria in Solid Tumors) at 6 months were investigated. PFS and OS analyses were performed (Kaplan-Meier). Toxicity was assessed by occurrence of radioembolization-induced liver disease (REILD). ResultsTumor control rate was 40.5% (17/42). Complete tumor targeting (odds ratio = 36.97; 95% confidence interval, 1.83–747; P < .001) and AUDVHtumor (odds ratio = 1.027; 95% confidence interval, 1.002–1.071; P = .033) independently predicted tumor control. AUDVHtumor ≥ 61 Gy predicted tumor control with 76.5% sensitivity and 75% specificity. PFS and OS in patients with incomplete tumor targeting were significantly shorter than in patients with complete tumor targeting (median PFS, 2.7 months [range, 0.8–4.6 months] vs 7.9 months [range, 2.1–39.5 months], P < .001; median OS, 4.5 months [range, 1.4–23 months] vs 19.2 months [range, 2.1–46.9 months], P < .001). Patients with incomplete tumor targeting and AUDVHtumor < 61 Gy, incomplete tumor targeting and AUDVHtumor > 61 Gy, complete tumor targeting and AUDVHtumor < 61 Gy, and AUDVHtumor > 61 Gy had median PFS of 2.7, 1.8, 6.3, and 12.1 months (P < .001). REILD (n = 4; 9.5%) was associated with higher dose delivered to normal liver (P = .04). ConclusionsComplete tumor targeting and 90Y dose to tumor are independent factors associated with tumor control and clinical outcomes.

Predictors of sensitivity to preoperative chemoradiotherapy of rectal adenocarcinoma.

The purpose of the study was to identify predictive factors of tumor response to preoperative chemoradiotherapy for rectal adenocarcinoma. Ninety-eight patients with nonmetastatic rectal adenocarcinoma received preoperative concurrent chemoradiotherapy and underwent mesorectal excision. After treatment, tumor response according to tumor regression grade were evaluated. The correlation of clinicopathologic factors to tumor response was analyzed. The results from a univariate analysis indicated that pretreatment carcinoembryonic antigen level ≤3.0 ng/ml (P = 0.002), non-fixed tumor (P = 0.001), and tumor circumferential extent ≤50% (P = 0.001) were associated significantly with a good tumor response. They also indicated that pretreatment positive lymph nodes (P = 0.032) were associated significantly with a poor tumor response. In multivariate analysis, the results indicated that pretreatment carcinoembryonic antigen level (hazard ratio, 2.930; P = 0.003), tumor mobility (hazard ratio, 2.651; P = 0.002) and circumferential extent of tumor (hazard ratio, 2.394; P = 0.019) independently predicted a good pathologic response rate. Pretreatment positive lymph nodes were not significantly associated with a good response (hazard ratio, 0.361; P = 0.191). Pretreatment carcinoembryonic antigen level, tumor mobility and circumferential extent of tumor may be helpful in predicting responsiveness in rectal adenocarcinoma to preoperative chemoradiotherapy, although the results should be confirmed in larger, more homogeneous studies.

Mean Corpuscular Volume as a Predictive Factor of Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer.

Background The aim of this study was to identify if blood routine parameters and serum tumor marker are potential predictive factors for tumor response to preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. Materials and Methods 55 locally advanced rectal cancer patients were treated with preoperative CRT in this study. The total dose of preoperative radiotherapy was 45 Gy in 25 fractions of 1.8 in 5 weeks. All patients concurrently received 825 mg/m2 capecitabine orally twice daily on days 1 to 14 and 22 to 35. Total mesorectal excision (TME) was performed 6 weeks after the end of preoperative CRT. Blood routine examination and serum tumor marker were checked before preoperative CRT. Tumor response to preoperative CRT was evaluated with the semiquantitative tumor regression grading (TRG) system proposed by Dworak criteria according to histopathological examination of the surgical specimens. Univariable and multivariable logistic regression analyses were used to test the association between blood routine parameters and serum tumor marker and tumor response to preoperative CRT. Results Univariate logistic regression analysis revealed that differentiation, lymphocyte, LMR, MCV, PLR, and CEA have been significantly associated with tumor response to preoperative CRT. Multivariate logistic regression analysis revealed that differentiation, MCV, and CEA were the predictors of tumor response to preoperative CRT. According to the ROC analysis, the AUC of differentiation, MCV, and CEA was 0.794, 0.802, and 0.723, respectively. Optimal cutoff points for MCV and CEA were 87.65 fl and 4.05 ng/ml, respectively. Conclusion MCV is a potential predictive factor for tumor response to preoperative chemoradiation in locally advanced rectal cancer.

Tumor kinetic modeling and identification of predictive factors for tumor response to durvalumab in patients with non-small cell lung cancer (NSCLC).

11555 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objectives of this analysis were to describe the longitudinal tumor size profiles and identify the key factors predicting tumor growth and regression following durvalumab. Methods: Longitudinal tumor size data obtained from NSCLC patients in study 1108 (all lines of therapy) and ATLANTIC (third line and beyond) following durvalumab treatment were modeled using nonlinear mixed effect modeling. Tumor kinetics were described by four key parameters: tumor growth and killing rate constants, fraction of durvalumab-sensitive tumor cells, and delay time for tumor killing. Potential predictive factors for tumor growth and regression were evaluated in a multi-variable covariate analysis. The model was used to simulate response rates at different tumor PD-L1 expression cutoffs. Results: Tumor kinetic modeling accurately described the longitudinal tumor response profiles from NSCLC patients in both studies. The factors associated with more rapid tumor growth were liver metastases, ECOG score &gt; 0, high neutrophil-to-lymphocyte ratio and EGFR/ALK mutation. Tumor cell PD-L1 expression, baseline tumor size and smoking history were identified as significant predictive factors for tumor killing or the fraction of sensitive tumor cells. Simulations using the tumor kinetic model showed increased response rates in patients with higher tumor cell PD-L1 expression (increased by 9-11% and 10-14% with 25% and 50% cutoff, respectively), patients receiving durvalumab as first-line therapy (increased by 12% vs. 2nd line/above), and patients with smoking histories (increased by 4-5% vs. non-smokers). Conclusions: Tumor kinetic modeling identified factors that predict tumor progression and response following durvalumab in NSCLC patients. The multivariate analysis accounts for various predictive factors within predictive biomarker strata, allowing better interpretation of different biomarker cutoffs. The modeling technique can potentially guide patient selection/enrichment, clinical trial design strategies and tumor biology. Clinical trial information: NCT02087423 and NCT01693562.

Nodal tumor response according to the count of peripheral blood lymphocyte subpopulations during preoperative chemoradiotherapy in locally advanced rectal cancer.

PurposeThe objective of this prospective study was to evaluate the relationship between the circulating lymphocyte subpopulation counts during preoperative chemoradiotherapy (CRT) and tumor response in locally advanced rectal cancer.Materials and MethodsFrom August 2015 to June 2016, 10 patients treated with preoperative CRT followed by surgery were enrolled. Patients received conventional fractionated radiotherapy (50.4 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. The absolute blood lymphocyte subpopulation was obtained prior to and after 4 weeks of CRT. We analyzed the association between a tumor response and change in the lymphocyte subpopulation during CRT.ResultsAmong 10 patients, 2 (20%) had evidence of pathologic complete response. In 8 patients with clinically node positive, 4 (50%) had nodal tumor response. All lymphocyte subpopulation counts at 4 weeks after CRT were significantly lower than those observed during pretreatment (p < 0.01). A high decrease in natural killer (NK) cell, count during CRT (baseline cell count − cell count at 4 weeks) was associated with node down staging (p = 0.034).ConclusionOur results suggest that the change of lymphocyte subset to preoperative CRT may be a predictive factor for tumor response in rectal cancer.

Pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first-line chemotherapy.

To explore the influence of pretreatment lymphopenia on the toxicity and efficacy of first‐line chemotherapy in patients with metastatic esophagus squamous cell carcinoma (ESCC). In total, 215 patients were included in this retrospective study. Correlations between pretreatment lymphopenia (lymphocyte count <1 × 109/L) and the occurrence of toxicity and the efficacy of first‐line palliative chemotherapy were investigated. Pretreatment lymphopenia was found in 19.1% of the patients. The overall response rate (ORR) was 35.5% (65 of 183 patients). Patients with pretreatment lymphopenia had a lower ORR to chemotherapy compared with those without lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). Furthermore, the patients with pretreatment lymphopenia have higher grade 3–4 hematological toxicity than that of patients without pretreatment lymphopenia (19 of 41 patients, 46.3% vs. 54 of 174 patients, 31.0%; P = 0.048). Pretreatment lymphopenia was not correlated with grade 3–4 nonhematological toxicity. Multivariate analysis showed that pretreatment lymphopenia is an independent prognostic factor. Patients with pretreatment lymphopenia had a significantly shorter overall survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020). This study shows that pretreatment lymphopenia is a good prognostic factor as well as a predictive factor for tumor response and chemotherapy‐related hematological toxicity in metastatic ESCC.

Decline of serum CA724 as a probable predictive factor for tumor response during chemotherapy of advanced gastric carcinoma.

To evaluate the predictive value of decline in the serum level of carbohydrate antigen 724 (CA724) on tumor response during the chemotherapy in patients with advanced gastric carcinoma (GC). The serum CA724 level was determined by electrochemiluminescence immunoassay, while the objective response rate (ORR) was assessed according to response evaluation criteria in solid tumors (RECIST). The association of the changes of serum concentration of CA724 with ORR was analyzed. The ORR in CA724 (pretreatment serum level) high and low groups was 32.3% (20/62) and 52.8% (19/36), respectively (P=0.045). The relationship between the reduction of CA724 and the ORR was statistically significant (P=0.044). Receiver operating characteristic (ROC) curve established the best cutoff value of the decrease ratio of CA724 as 20.5%. CA724 decline seems to indicate chemotherapy efficacy in patients with advanced GC, and an average drop of 20.5% in serum CA724 appears to predict the sensitivity to chemotherapy.

MRI Predictive Factors for Tumor Response in Rectal Cancer Following Neoadjuvant Chemoradiation Therapy - Implications for Induction Chemotherapy?

Clinical and magnetic resonance imaging (MRI) characteristics at baseline and following chemoradiation therapy (CRT) most strongly associated with histopathologic response were investigated and survival outcomes evaluated in accordance with imaging and pathological response. Responders were defined as mrT3c/d-4 downstaged to ypT0-2 on pathology or low at risk mrT2 downstaged to ypT1 or T0. Multivariate logistic regression of baseline and posttreatment MRI: T, N, extramural venous invasion (EMVI), circumferential resection margin, craniocaudal length <5 cm, and MRI tumor height ≤5 cm were used to identify independent predictor(s) for response. An association between induction chemotherapy and EMVI status was analyzed. Survival outcomes for pathologic and MRI responders and nonresponders were analyzed. Two hundred eighty-one patients were eligible; 114 (41%) patients were pathology responders. Baseline MRI negative EMVI (odds ratio 2.94, P=.007), tumor height ≤5 cm (OR 1.96, P=.02), and mrEMVI status change (positive to negative) following CRT (OR 3.09, P<.001) were the only predictors for response. There was a strong association detected between induction chemotherapy and ymrEMVI status change after CRT (OR 9.0, P<.003). ymrT0-2 gave a positive predictive value of 80% and OR of 9.1 for ypT0-2. ymrN stage accuracy of ypN stage was 75%. Three-year disease-free survival for pathology and MRI responders were similar at 80% and 79% and significantly better than poor responders. Tumor height and mrEMVI status are more important than baseline size and stage of the tumor as predictors of response to CRT. Both MRI- and pathologic-defined responders have significantly improved survival. "Good response" to CRT in locally advanced rectal cancer with ypT0-2 carries significantly better 3-year overall survival and disease-free survival. Use of induction chemotherapy for improving mrEMVI status and knowledge of MRI predictive factors could be taken into account in the pursuit of individualized neoadjuvant treatments for patients with rectal cancer.

Circulating Lymphocytes as Predictors of Sensitivity to Preoperative Chemoradiotherapy in Rectal Cancer Cases

The objective of this study was to identify clinical predictive factors for tumor response after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). All factors were evaluated in 88 patients with LARC treated with nCRT. After a long period of 4-8 weeks of chemoradiotherapy, 3 patients achieved clinical complete response (cCR) and thus aggressive surgery was avoided, and the remaining 85 patients underwent a curative-intent operation. The response to nCRT was evaluated by tumor regression grade (TRG) system. There were 32 patients (36.4%) with good tumor regression (TRG 3-4) and 56 (63.6%) with poor tumor regression (TRG 0-2). Lymphocyte counts and ratios were higher in good response cases (P=0.01, 0.03, respectively) while neutrophil ratios and N/L ratios were higher in poor response cases (P=0.04, 0.02, respectively). High lymphocyte ratios before nCRT and good tumor regression (TRG3-4) were significantly associated with improved 5-year disease-free survival (P<0.05). Pretreatment nodal status was also significantly associated with 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment lymphocyte ratio and lymph nodal status were independent prognostic factors. Our study suggested that LARC patients with high lymphocyte ratios before nCRT would have good tumor response and high 5-year DFS and OS.

Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NACT) is used as a primary treatment for locally advanced breast carcinoma (LABC) and also extended to operable breast cancer. The aim of this study was to evaluate the predictive value of different histological parameters in core biopsy of LABC patients treated with anthracycline-based chemotherapy regimen. Pathological assessment of the excised tumor bed is the gold standard and is essential for identifying the group of patients with pathologic complete response (pCR) or pathologic noncomplete response (pNR). A total of 50 patients with stage II and III breast carcinoma were included in the study. Pretreatment core biopsy histological features include tumor type, histological grade, presence of tumor necrosis, lymphovascular emboli (LVE) and immunohistochemical stains for estrogen receptor (ER) and progesterone receptor (PR) were obtained. Patients were given 3-6 cycles of NACT. Pathological response was assessed. Seven out of 50 patients achieved pCR. A total of 71.4% patients who achieved pCR had tumor necrosis on initial core biopsy while only 30% pNR cases had this feature (P =0.035). Breast carcinoma other than ductal type was chemoresistant. Of 47 core biopsies, LVE was observed in 13 cases (28 %) of which 11 showed axillary node metastasis. None of these 13 cases had pCR, thus having poor predictive value. Pathological parameters like type of tumor, presence of LVE and tumor necrosis in the core biopsy can predict the response to NACT in routine stain. Tumor necrosis and type of breast carcinoma are predictive parameters for tumor responsiveness to NACT. LVE was reliable in predicting axillary lymph node metastasis.

Bcl-2—Enhanced Efficacy of Microtubule-Targeting Chemotherapy through Bim Overexpression: Implications for Cancer Treatment

Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2– overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 overexpression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box-containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1–mediated mitochondrial fragmentation. The Bcl-2–governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2–overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2.

Abstract 4532: Peripheral blood lymphocyte subsets can predict the pathological response of rectal cancer patients to chemoradiation

Abstract Purpose Neoadjuvant chemoradiotherapy (CRT) is used to downstage locally advanced rectal cancer (RC), prior to surgery. Although CRT is the standard treatment for RC, markers to predict the treatment response have not been fully established. Although some biomarkers, such as the absolute number of lymphocytes subsets and the proportion of CD57(+) T cells have been shown to be associated with prognosis in advanced cancer patients, only few studies report on the predictive factors of response to therapy. Recently, the neutrophil to lymphocyte (N/L) ratio has been reported as a promising marker with ability to predict the effectiveness of CRT in advanced rectal cancer. Thus, in the present study, we aimed to identify other potential predictive factors of tumor response to CRT in RC patients. Patients and Methods From April, 2010 to August, 2011, 15 patients with histologically-proven locally advanced adenocarcinoma, receiving preoperative CRT and total mesorectal excision, were enrolled. They received a radiation dose of 50-50.4 Gy with a concomitant 5-fluorouracil-based chemotherapy. Analysis of tumor response was based on the lowering of T stage. The association of the response to treatment and the predictive factors was analyzed. Peripheral venous blood samples were obtained before neoadjuvant CRT, after 2 and 4 weeks of the start of neoajuvant CRT, and before surgery. Peripheral blood lymphocytes were stained by the antibody combination of CD3/CD8 or CD4/CD8/CD19/CD56, and analyzed by flow-cytometry. Results Among the 15 patients, 13 had received total mesorectal excision at 6∼8 weeks after the end of CRT. Two patients showed a clinical complete remission (cCR) after CRT, and thus were followed without surgery. Those patients with response grade 2 or 3, and those with cCR, were considered good response (6 cases), and those with response grade 1a or 1b were considered poor response (9 cases), according to the histological response grade defined in the Japanese Classification of Colorectal Carcinoma. The absolute number of CD3(+) and CD4(+) T cells was significantly higher in the good response than the poor response group (P&amp;lt;0.01). Both markers showed a significant correlation with tumor response to CRT. Also, the N/L ratio could effectively predict response to CRT, with higher values obtained in the poor response group (P=0.01). Other markers, such as the percentage of NK cell and the CD4+/CD8+ ratio, did not correlate with response to CRT in our study. Conclusion In this study, the absolute number of CD3(+) and CD4(+) T cells in peripheral blood obtained prior to initiation of treatment, as well as the N/L ratio, were associated with tumor downstaging. Despite the small number of patients and the possible biologic variations of the lymphocyte subsets, this finding highlights the potential prognostic value of the baseline lymphocyte count in patients with RC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4532. doi:1538-7445.AM2012-4532