Good Pathological Response Research Articles

PS02.108: EFFECTS OF PREOPERATIVE CHEMOTHERAPY FOR ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background In Japan, preoperative chemotherapy followed by surgery is the standard treatment for clinical stage II or III, excluding T4 thoracic esophageal squamous cell carcinoma (SCC). Here, we investigated the efficacy of preoperative chemotherapy in our hospital. Methods From January 2010 through December 2017, 33 patients with clinical stage II/III esophageal SCC underwent esophagectomy after preoperative chemotherapy with two cycles of cisplatin and 5-fluorouracil. Overall survival (OS) and clinical and pathological tumor responses were retrospectively evaluated. In addition, fluorodeoxyglucose (FDG) uptake was assessed by FDG-positron emission tomography/computed tomography (PET/CT). Results There were 9 patients with stage II and 24 with stage III esophageal SCC, and two cycles of chemotherapy were completed by 27 patients (81.8%). Three-year OS rates were 100% in patients with stage II and 66.7% in patients with stage III esophageal SCC, whose observation period exceeded beyond 3 years. Of the 33 patients who showed a clinical response at the primary site, 22 (66.7%) had a partial response (PR), and a 3-year OS of 85.7%, while 4 (12.1%) had a complete response (CR), and a 3-year OS of 100%. In regards to pathological response, as evaluated using The Japan Esophageal Society histological evaluation criteria, 3 patients (9.1%) were classified as grade 0, 18 (54.5%) as grade 1a, 4 (12.1%) as grade 1b, 6 (18.2%) as grade 2, and 2 (6.1%) as grade 3. Of the 22 patients who achieved PR, 14 (63.6%) were classified as either grade 0 or 1a. On the other hand, when we compared the maximum standardized uptake value (SUVmax) of FDG − PET/CT at the primary site before and after preoperative chemotherapy, the patients with high decreasing rates mostly belonged to the grade 1b-3 group. The OS rate tended to be higher in the grade 1b-3 group than in the grade 0–1a group. Conclusion Our present results suggest that, although pathological responses do not necessarily correspond to clinical tumor reduction, a good pathological response is potentially related to a better prognosis. Furthermore, the FDG uptake value may reflect pathological effects that occur owing to preoperative chemotherapy. Disclosure All authors have declared no conflicts of interest.

Correlation between high FBXW7 expression in pretreatment biopsy specimens and good response to chemoradiation therapy in patients with locally advanced esophageal cancer: A retrospective study.

Esophageal squamous cell carcinoma (ESCC) exhibits good reactivity to chemoradiation therapy (CRT). The dysregulation of F-Box and WD Repeat Domain Containing 7 (FBXW7) is associated with therapeutic resistance in cancer cells. However, the correlation between FBXW7 expression and CRT sensitivity in patients with clinical ESCC has been investigated only in few studies. Therefore, this study aimed to elucidate the significance of FBXW7 expression in pretreatment biopsy specimens from patients with ESCC receiving CRT. We investigated the relationship between FBXW7 expression and CRT sensitivity in 30 pretreatment biopsy specimens with histological grades of post-CRT surgically resected tumors. Furthermore, we evaluated the effects of high FBXW7 expression on the sensitivity to cytotoxic agents, including docetaxel and nedaplatin, and radiation in ESCC cells in vitro. High FBXW7 expression before CRT correlated with a good pathological CRT response in patients with advanced ESCC (P < .05). Further, our in vitro data showed that both chemo and radiation sensitivity increased in TE-8 and KYSE140 cells overexpressing FBXW7 compared with mock cells because of the degradation of the anti-apoptotic protein MCL1. The evaluation of FBXW7 expression before CRT treatment is a potential predictor of good responders among patients with ESCC receiving CRT.

Abstract 563: Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Abstract Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Good pathologic response to CRT is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from CRT. Therefore, we aimed to perform whole-exome sequencing (WES) for rectal cancer to identify the novel genetic variations predicting CRT benefit in LARC. Two independent sets were used to evaluate the genetic differences between the good response group and poor response group to CRT. Fifteen patients who achieved pathologic complete response were divided into the good response group and 15 patients with pathologic stage III were classified as poor response group. Among these 30 patients, WES was examined. To validate discovery set, additional samples (n=67) were genotyped for candidate variants using TaqMan SNP genotyping assays or Sanger sequencing. Overall, the current study included a total of 97 LARC patients who were treated with neoadjuvant CRT followed by curative surgery at Kyungpook National University Medical Center. We found 5 candidate variants significantly associated with pathologic complete response (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) using WES. In the dominant model, patients with GC/CC genotype of DLC1 rs3816748 (p=0.032), AC/CC genotype of DNAH14 rs3105571 (p=0.009) and TT genotype of RAET1 rs912565 (p&amp;lt;0.0001) showed higher rate of pCR compared to those of other genotype patients. In the recessive model, the BCL2L10 rs2231292 (p=0.036) and ITIH5 rs3824658 (p=0.003) were significantly associated with pathologic CR. Four SNPs (DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, RAET1L rs912565) found to be significantly correlated with pCR in codominant model. However, none of the SNPs was associated with the relapse-free survival or overall survival. The present results suggest that the genetic variation of the BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565 genes can be used as biomarkers predicting CRT response for patients with LARC. Citation Format: Jong Gwang Kim, In Hee Lee, Soo Jung Lee, Yee Soo Chae, Byung Woog Kang. Identification of a novel biomarker to predict pathologic complete response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 563.

Model predicting the ypN0 status after good response to chemoradiotherapy in rectal cancer

BackgroundThe purpose of this study was to identify the predictive factors for ypN0 status in tumors with good pathologic response to chemoradiotherapy (CRT). MethodsA retrospective chart review was conducted on patients at two tertiary cancer center who underwent rectal resection after good response to CRT between 2000 and 2013. ResultsNo preoperative treatment (oxaliplatin use, radiotherapy boost of 5,4 Gy, delay CRT-surgery) impacted on the ypN status. In the multivariate analysis, only a ypT<3 (HR 7.5 [2,9–19.5]) was significant and no lymphovascular invasion (HR 8,9 [1.6–49.8]) was limited to significance.The best model predicting the ypN0 status used only the ypT status<3. The major part (92.2%) of patients with ypT0-2 tumors had no LN invasion. ConclusionThe risk of lymph node involvement metastases was only 7.8% for the patients with an ypT0-2 status. A fullthickness transanal resection coud be the futur treatment of these patients.

Cytokine serum levels in patients with cervical intraepithelial neoplasia grade II-III treated with intralesional interferon-α 2b.

Cervical intraepithelial neoplasia (CIN) grade II-III is being diagnosed in younger women and, because of the reproductive age range for women and the habits associated with a modern lifestyle, is now affecting a broad age range. Surgical treatment for CIN has been associated with premature amenorrhea, low birth weight, and premature labor and birth. It is therefore imperative to develop clinical treatments for CIN, such as conservative treatment with interferons. The object of the present study was to evaluate the behavior of cytokines (IFN- g, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF β) in the serum of patients with an initial diagnosis of CIN II-III. Ten patients with CIN-CIN II (60%, n = 6) and CIN III (40%, n = 4), 23 to 51 years of age and who had not received any prior treatments, were evaluated. The patients were given 3 million/UI (per cm2 of colposcopic lesion) of human recombinant IFN-α 2b by intralesional administration (18 applications on alternate days). Before treatment, in the 6th, 12th, and 18th applications, blood was collected from the patients for cytokine analysis using ELISA. Half of the patients had a good pathologic response; the other half, all of whom were smokers, had therapeutic failure. The average concentration of IL-12 (pg/ml) in the serum of patients who responded well to therapy was elevated from the 12th and 18th application of IFN-α 2b compared to patients who experienced therapeutic failure: 1804.0 ± 1020 vs 391.2 ± 722.3 and 1738.0 ± 2426.0 vs 448.5 ± 407.2, respectively, P <0.05. CIN II-III treated with intralesional IFN-α 2b achieved a good response in non-smoking patients and was associated with an increase in IL-12 serum levels.

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.

MicroRNA-375 as a potential serum biomarker for the diagnosis, prognosis, and chemosensitivity prediction of osteosarcoma.

ObjectiveThis study was performed to examine serum microRNA-375 (miR-375) expression in patients with osteosarcoma and determine its diagnostic and prognostic value.MethodsSerum samples were obtained from 95 patients with osteosarcoma and 95 healthy individuals. miR-375 expression was detected by real-time polymerase chain reaction. The associations of serum miR-375 expression with the patients’ clinicopathological characteristics and prognosis were then evaluated. Receiver operating characteristic curve analysis was performed to obtain the potential value of serum miR-375 as a biomarker for osteosarcoma diagnosis and chemosensitivity prediction.ResultsSerum miR-375 expression was significantly lower in patients with osteosarcoma than in healthy individuals. Low serum miR-375 levels were associated with advanced clinical stages, large tumor size, positive distant metastasis, and poor tumor response to preoperative chemotherapy. Receiver operating characteristic curve analysis illustrated that serum miR-375 could distinguish patients with osteosarcoma from healthy individuals and distinguish patients with a good pathologic response from those with a poor response. Multivariate analysis confirmed low serum miR-375 expression as a statistically significant independent unfavorable prognostic factor.ConclusionsSerum miR-375 expression was downregulated in patients with osteosarcoma and might serve as a biomarker for its diagnosis, prognosis, and chemosensitivity prediction.

The Prognostic Impact of the Pathological Response to Neoadjuvant Dose-Dense Therapy for Ovarian Carcinoma.

The aim of this study was to assess the use of the pathological response to neoadjuvant chemotherapy (NAC) for predicting disease prognosis in patients with advanced ovarian cancer who received neoadjuvant dose-dense weekly paclitaxel and carboplatin (dd-TC) therapy. We retrospectively investigated patients with advanced epithelial ovarian, tubal, or peritoneal carcinoma treated at our hospital from July 2004 to October 2014. Patients received dd-TC therapy as NAC followed by interval debulking surgery (IDS). Specimens resected during IDS were divided into 4 groups based on pathological response: grade 1, most tumor cells appeared to be viable; grade 2a, most tumor cells had disappeared, whereas the remaining tumor cells were vacuolated or degenerated; grade 2b, small numbers of viable tumor cells were observed; and grade 3, small aggregations of macrophages were seen. Sixty-eight patients were enrolled. The median number of NAC cycles was 3 (range, 2-6), and 51 patients (75.0%) achieved complete resection at IDS. Regarding pathological response, 7 (10.3%) patients were classified as grade 1, 11 (16.2%) as grade 2a, 46 (67.7%) as grade 2b, and 4 (5.9%) as grade 3. In univariate and multivariate analyses, grades 2b and 3 pathological responses were significant favorable prognostic factors for progression-free survival (P = 0.028; hazard ratio, 0.48; 95% confidence interval, 0.26-0.92). Although the pathological complete response rate to NAC was low in this study, both complete and good pathological responses to NAC might be favorable prognostic factors for PFS in patients with advanced ovarian cancer who receive dd-TC.

Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

BackgroundExpression of clusterin correlates with tumor progression and therapeutic response in several human malignancies, including breast cancer. However, its predictive value in the neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether clusterin expression in breast cancer correlated with clinical pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy (NAC). Materials and MethodsWe determined the clusterin expression pattern in 72 triple negative breast cancers (TNBC) treated with NAC before surgery. Clusterin expression was evaluated by immunohistochemistry and was correlated with pathologic characteristics and response to NAC using residual cancer burden score. ResultsImmunohistochemistry analysis revealed a differential pattern of expression between tumor and stroma. Clusterin expression in the tumor associated stroma as opposed to expression by the neoplastic epithelium was significantly associated with neoadjuvant-treated TNBC. Low stromal clusterin, low stromal content, and high tumor-infiltrating lymphocytes were associated with a significantly greater likelihood of achieving a good pathologic response as reflected by lower residual cancer burden scores (P = .002, P = .003, and P = .001, respectively). Tumor and/or stromal clusterin expression were not associated with patient age, tumor histologic grade, stage, and lymph node status. ConculsionThis study suggests a potential role for the assessment of stromal clusterin as a predictive biomarker for response of TNBC to neoadjuvant therapy. Further validation of this biomarker in a large study is needed.

Predictive factors in the evaluation of treatment response to neoadjuvant chemoradiotherapy in patients with advanced esophageal squamous cell cancer.

Neoadjuvant therapy before esophagectomy is evidence-based, and is a standard-of-care for locally advanced and operable esophageal cancer. However response to such treatment varies in individual patients, from no clinical response to pathological complete response. It has been consistently shown that a good pathological responses is of prognostic value, but perhaps in the expense of those who do not. It is important to identify suitable predictive factors for response, so that patients are not exposed to potentially harmful chemotherapy and/or radiotherapy without benefits. Alternative management strategies can be devised. Various clinical, radiological, serological and potential molecular markers have been studied. None has been shown to be sufficiently reliable to be used in daily practice. Certainly more understanding of the molecular basis for response to chemotherapy/radiotherapy is needed, so that patient treatment can be tailored and individualized.

Immune-infiltrate characterization in localized osteosarcoma patients treated within protocol ISG-OS1.

11025 Background: We hypothesized that immune-infiltrates were associated with survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. Methods: Biopsies of patients (pts) treated from 04/2001 to 11/2006 were analyzed. TMAs from representative areas were assembled. Clinical and pathological characteristics at diagnosis, expression of CD8, CD4, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage), Tia-1 (cytotoxic T cell), CD303 (plamacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immuno-cells (IC), and PD-L1 both on tumor cells (TC) and IC were correlated with patients outcome. A TMA of surgical specimens of the same cases also was assembled, and chemotherapy-induced changes analysis is ongoing. Results: 86 pts identified. Median age: 16 (range 4-39); high LDH: 36/86; high serum alkaline phosphatase (SAP): 18/86. All pts underwent neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis) was achieved by 45/86 pts. IHC results are displayed in the Table. With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-yr OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good responders (good 89% vs poor 57%, p=0.0001); b) pts with CD8/Tia1 tumoral infiltrates (+/+ 81% vs +/- 60% vs -/- 45% p=0.002); c) pts with normal SAP (normal 85% vs high 44%, p=0.04). A numerically lower 5-yr OS was found in PD-L1 (IC) positive (+ 58% vs - 77%, p=0.14) and CD163 negative (+ 81% vs - 56%, p=0.17) cases. After multivariate analysis, poor histologic response (p=0.007) and lack of CD8/Tia1 infiltration (p=0.02) were independently correlated with poorer survival. In the subset of CD8+ patients, poorer (p= 0.02) OS was observed for PD-L1 (IC) + cases. Conclusions: Our findings support the hypothesis that CD8/Tia1 (cytotoxic T cells) infiltrate in tumor microenvironment at diagnosis is associated with superior survival for patients with localized osteosarcoma, while PD-L1 expression is associated with poorer survival. [Table: see text]

A metabolomic signature for predicting chemosensitivity in gastric cancer.

e15504 Background: Perioperative chemotherapy (QT) with platinum and fluoropyrimidines with or without anthracyclines is recommended option in patients with resectable gastric cancer (GC) at least cT2 or nodal involvement. Another option is surgery followed by QT with radiotherapy (QT/RT) or QT without RT in patients with D2 lymphadenectomy. Unfortunately, a considerable percentage of patients progress during neoadjuvant-QT (neo-QT) and some cases become inoperable cancer. These patients could benefit from curative surgery after diagnosis without neo-QT. Currently, histological/molecular markers have not been established to predict which patients can benefit from neo-QT. As potent analysis method, study of blood metabolites of resectable GC patients to establish a profile to differentiate responder patients (R-P) or not-responder (NR-P) to neoadjuvant-QT is promising. To establish a metabolomic profile or metabolomic signature and correlate with chemosensitivity, defined as pathological and clinical response is our endpoint. Methods: To this end we performend an untargeted metabolomic analysis by LC-HRMS of serum samples from resectable GC patients before neo-QT (n = 20 vs n = 10 healthy controls). Chemosensitive tumors were defined as those with good pathological response (Mandard 1 or 2) and partial response by TAC and chemoresistance tumors, defined as those with poor pathological response (Mandard 5) or/and progression by TAC. Reverse phase and HILIC chromatographic modes were applied to deal with highly polar as well as hydrophobic as required for untargeted metabolomics. For identification of potential biomarkers, we used in combination 2 independent variable selection techniques: principal component analysis and Student t test. Results: 11 patients were R-P and 9 patients were NR-P. We observed differences in metabolic profile between patients with GC &amp; healthy controls and R-P &amp; NR-P to neo-QT. Seven identified metabolites contributed most to the differentiating between R-P and NR-P. Conclusions: There are different metabolomic phenotypes among patients R-P and NR-P to neo-QT. It is necessary to validate a metabolomic signature to allow effective chemosensitivity prediction in patients with resectable GC.

Trabectedin and radiotherapy in soft-tissue sarcoma (TRASTS) study: An international, prospective, phase I/II trial—A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) groups study.

11061 Background: Myxoid liposarcoma/round cell liposarcoma (ML) exhibits especial sensitivity to trabectedin (T). In prospective series, long-lasting T treatment showed responses in 44% of patients (pts) with ML. ML is also sensitive to radiation therapy (RT) and preclinical data suggested radiosensitizing properties of T. Preoperative short-course of T with concurrent low-dose RT was conducted in a multicenter, European, phase I/II trial. We present here data from the phase I part in pts with centralized diagnosis of locally advanced, resectable ML. Methods: Pts received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8Gy/fraction). The phase I had the classic 3+3 design. Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting &lt; 5 days and G3-4 nausea/vomiting due to inadequate prophylaxis. RECIST responses were evaluated preoperatively at week 10. Surgical specimens were processed for histologic changes and residual tumor. Results: From February 2015 to May 2016,14 pts (M/F 7/7) with median age 36y (24-71) and median tumor size 12.5 cm were enrolled. 7 pts received T at dose Level 1 and 7 pts at Level 2. One DLT (G3 transaminitis) occurred at Level 1 and another (sepsis due to catheter infection) at Level 2. Overall, grade G 3/4 AEs were: ALT elevation (n = 6, 43%), and GGT elevation, neutropenia, anemia, epithelitis and sepsis (n = 1, 7% each). There were no deaths. One pt developed metastasis after C3 and did not undergo surgery; another one had a sepsis after C1 and received definitive RT. All pts completed RT. 13 pts were evaluable for response: 5 achieved PR (38%), 7 SD (53%), 1 distant PD (8%). 12 pts underwent surgery (7 R0/5 R1). Median viable residual tumor was 5% (0-60) with 9/12 pts (75%) with ≤ 10% viable remaining tumor, 3/12 (25%) complete responses. Conclusions: T in combination with RT was feasible and well tolerated in the preoperative setting. T dose of 1.5 mg/m2 is the recommended phase II dose. A high proportion of patients achieved a good pathological response, with 3/12 (25%) complete responses. Clinical trial information: 2014-001549-26.

Serum miR-143 levels predict the pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

Recently, several circulating miRNAs have been reported as promising, minimally invasive biomarkers for the diagnosis or prediction of the prognosis in various types of cancer. However, the utility of circulating miRNAs as predictive markers of the cancer response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer is still unclear. To identify circulating serum miRNAs useful for predicting a pathological good response to nCRT, total 18 serum miRNAs of interest were analyzed by real-time polymerase chain reaction in 94 rectal cancer patients treated with nCRT and surgery. Pathological complete response (pCR; Dworak TRG4) and near-pCR (TRG3) were obtained in 12 (13%) and 9 (9%) patients respectively, and we regarded them as nCRT-responders. Of the 18 serum miRNAs, only the serum level of miR-143 was identified significantly associated with a pathological response to nCRT in 94 patients; the serum miR-143 level was significantly lower in nCRT-responders than in non-responders. A multivariate analysis incorporating other clinicopathological factors showed that only the serum miR-143 level was an independent predictor of a good pathological response. The circulating serum miR-143 level may be a novel, non-invasive predictive marker of a response to nCRT in locally advanced rectal cancer patients.

High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma

BackgroundLocoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum‐based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma.MethodsData of patients with cT2‐cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed.ResultsForty‐four patients were treated with intensity‐modulated radiation therapy, volumetric‐modulated arc therapy or three‐dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow‐up duration was 22.4 months and median survival was 25.6 months. Two‐year overall, progression‐free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3–4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3–4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%).ConclusionTrimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long‐term survival with low toxicities.

The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers.

The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients' blood neutrophils (n = 108), DCs (mDC1 and pDC), and their costimulatory molecules (n = 30) were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC.

The Pretreatment Systemic Inflammatory Response is an Important Determinant of Poor Pathologic Response for Patients Undergoing Neoadjuvant Therapy for Rectal Cancer

BackgroundNot all patients respond equally to neoadjuvant chemoradiotherapy (nCRT), with subsequent effects on survival. The systemic inflammatory response has been shown to predict long-term outcomes in colorectal cancer. The current study examined the association between systemic inflammation and nCRT in patients with rectal cancer.MethodsBetween 1999 and 2010, patients who underwent nCRT were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow prognostic score (mGPS), and differential white cell counts were obtained before and after nCRT. The Rödel scoring system measured pathologic tumor regression, and magnetic resonance imaging and computed tomography determined radiologic staging.ResultsThe study included 79 patients. Of these patients, 37% were radiologically downstaged, and 44% were categorized as showing a good pathologic response (Rödel scores 3 and 4). As a validated measure of the systemic inflammatory response, mGPS (P = 0.022) was associated with a poor pathologic response to nCRT. A radiologic response was associated with a good pathologic response to treatment (P = 0.003). A binary logistic regression model identified mGPS (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.07–0.96; P = 0.043) and radiologic response (OR 0.43; 95% CI 0.18–0.99; P = 0.048) as strong independent predictors of a pathologic response to treatment.ConclusionThe current study showed that a systemic inflammatory response before nCRT is associated with a poor pathologic response. Further study in a prospective controlled trial setting is warranted.

The Presence of Serum p53 Antibody Predicts the Pathological Tumor Response to Neoadjuvant Chemotherapy with Docetaxel, Cisplatin and Fluorouracil (DCF) in Esophageal Squamous Cell Carcinoma.

Docetaxel, cisplatin and fluorouracil (DCF) is a candidate neoadjuvant chemotherapy (NAC) regimen for esophageal squamous cell carcinoma (ESCC). Although the efficacy and safety of DCF have been reported, the markers that predict the patient's response are still unknown. The aim of this study was to identify the predictive markers for a response to NAC with DCF in patients with ESCC. A total of 79 patients who received preoperative DCF followed by esophagectomy between August 2008 and December 2014 were enrolled in this study. All of the patients completed 2 preoperative courses of DCF. The clinical and pathological responses to DCF were investigated, and the associations between the pathological response, the clinicopathological factors and the prognosis were retrospectively analyzed. Among the 79 patients, the pathological response to DCF (evaluated according to the Japanese Classification of Esophageal Cancer) was grade 3 (complete pathological response) in 7 patients (8.9%), grade 2 in 13 patients (16.5%), grade 1b in 8 patients (10.1%) and grade 1a in 51 patients (64.6%). A good pathological response (grade 2-3) was significantly associated with both favorable disease-free survival (P=0.0051) and favorable cancer-specific survival (P=0.0366). A multivariate analysis revealed that a good clinical response (HR 13.743, 95% CI 2.455-76.917) and the presence of serum p53 antibody before treatment (HR 3.987, 95% CI 1.103-14.416) were independent predictors of good pathological response. The presence of serum p53 antibody can be used as a novel, noninvasive predictor of the pathological tumor response to NAC with DCF in ESCC patients.

Abstract 4894: Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant chemotherapy

Abstract Background: Characterization of the immunological microenvironment has been demonstrated to be associated with prognosis and the effect of chemotherapy of various cancers. Then it has been shown by their role several studies in 5-FU-based neoadjuvant chemoradiotherapy for rectal cancer. However, their role in neoadjuvant chemotherapy (NAC) for rectal cancer remains unknown. The objective of this study was to examine the relationship between immune reactions and the pathological response to induction oxaliplatin-based NAC in patients with advanced rectal cancer. Methods: A total of 65 patients with advanced rectal cancer who underwent induction oxaliplatin-based NAC followed by surgical resection were enrolled. The resected tumor specimens were counted positive cell of tumor infiltrating lymphocytes (TILs) and macrophages by using immunohistochemical staining for CD3, CD8, Foxp3, CD86, CD206. We analyzed for the relationship between the numbers of TILs or macrophages at the stroma in resected specimens and the pathological response to induction oxaliplatin-based NAC. Results: The numbers of Foxp3+ TILs in resected specimens were strongly correlated with pathological response. Patients with higher number of Foxp3+ TILs showed poor pathological response (p&amp;lt;0.001). There were no statistically significant differences between the number of CD3+, CD8+ TILs and pathological response, but patients with higher ratio of CD8+/FOXP3+ TILs was associated with good pathological response (p = 0.023). No associations were observed between the numbers of CD86+, CD206+ macrophages and pathological response. Conclusions: In rectal cancer patients, T lymphocyte-mediated immune reactions significantly correlated with pathological response of oxaliplatin-based NAC for advanced rectal cancer. These were similar to the T lymphocyte-mediated immune responses in the neoadjuvant radiation therapy for rectal cancer. Citation Format: Kentaro Sekizawa, Yasushi Ichikawa, Atsushi Ishibe, Hirokazu Suwa, Masashi Momiyama, Ikuma Kato, Mitsuyoshi Ota, Itaru Endo. Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4894.

The effect of perioperative chemotherapy for patients with an adenocarcinoma of the gastroesophageal junction: A propensity score matched analysis

BackgroundThe optimal neoadjuvant approach for patients with adenocarcinomas of the gastroesophageal junction (GEJ) remains unclear. Aim of this study was to evaluate the usefulness of perioperative chemotherapy in these patients. MethodConsecutive patients with GEJ adenocarcinoma, treated with surgery alone or chemotherapy plus surgery, were included from a prospective database (2003–2013). Propensity score matching was used to build comparable groups. Response to chemotherapy was assessed according to standardized regression grading. ResultsAfter propensity score matching, 196 patients were included. Chemotherapy was administered in 124 patients (63%). There was no difference between the chemotherapy plus surgery and surgery-alone group regarding overall and disease-free survival (p = 0.351 and p = 0.529). Pathological good response (i.e. tumor regression grading [TRG] 1–3) was achieved in 32 patients (34%), whereas 81 (66%) had poor response (TRG 4). Good responders had lower ypT-stage (p < 0.001), lower ypN-stage (p < 0.001) and more R0-resections (100% vs. 78%, p = 0.016) compared to surgery-alone patients, which improved the 5-year survival from 35% to 67% (p = 0.002). They also developed less recurrences (35% vs. 57%, p = 0.048). In poor responders, histopathology did not differ compared to surgery-alone and more recurrences were found (73% vs. 57%, p = 0.037). Overall survival in poor responders was 21% compared to 35% in surgery-alone patients (p = 0.551). ConclusionPerioperative chemotherapy for GEJ adenocarcinoma leads to increased survival in good responders (34%) as compared to surgery alone. Poor responders had no survival benefit and developed more recurrences, which underlines the importance of the search for predictive biological or radiological markers to predict or assess chemotherapy sensitivity.