Degree Of Pathologic Response Research Articles

Neoadjuvant immune checkpoint blockade enhances local and systemic tumor immunity in head and neck cancer.

Neoadjuvant (presurgical) immune checkpoint blockade (ICB) has shown promising clinical activity in head and neck cancer and other cancers, including FDA approvals for neoadjuvant approaches for triple-negative breast cancer and nonsmall cell lung cancer. Here we will review recent data from clinical trials in head and neck squamous cell carcinoma (HNSCC), including mechanistic studies highlighting local and systemic effects on T cell-mediated immunity. A series of clinical trials of neoadjuvant ICB have documented evidence of clinical activity, including clinical to pathologic downstaging and pathologic response in a subset of patients. Also, emerging data suggest improved survival outcomes for patients with tumors responsive to neoadjuvant ICB. In depth mechanistic studies have documented intra-tumoral expansion of CD8 T cell populations characterized by tissue residency and cytotoxicity programs. Treatment also leads to expansion of activated CD8 T cells in the blood, many of which share TCR sequences with tumor-infiltrating T cells. The frequency of activated circulating CD8 T cell populations is correlated with the degree of pathologic response within tumors. Even a short duration of neoadjuvant immunotherapy can enhance local and systemic tumor-reactive T cell populations. Downstaging induced by neoadjuvant ICB can reduce the extent of surgical resection in this anatomically sensitive location.

Serum HIF-1α and TGF-β1 levels depending on the clinical and morphological characteristics of breast cancer and sensitivity of tumor to neoadjuvant chemotherapy

Purpose of the study. To assess the serum levels of HIF-1 α and TGF-β1 in patients with invasive breast cancer (BC) depending on the clinical and morphological characteristics, molecular biological subtypes and the degree of pathological response (PR) of the tumor and metastases in the regional lymph nodes.Materials and methods. 65 patients with newly diagnosed invasive BC, of whom 32 received from 6 to 8 courses of neoadjuvant chemotherapy (neo-A-CT) were included in this pilot study. The levels of TGF-β1 and HIF-1α were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed using the Statistica 12.0 software.Results. It was found that a high level of TGF-β1 was significantly more often observed in HER2-positive and I-IIa stages of luminal A and triple-negative BC (p = 0.01). HIF-1a levels were significantly higher in the presence of distant metastases (p = 0.04) and slightly higher in the presence of microcalcifications on mammograms (p = 0.07).The analysis showed that patients with grade III-IV of PR in tumor were significantly younger (p = 0.047). Grade III-IV of PR in tumor was significantly more often observed in G3 (p = 0.05), in Her2-positive and triple negative BC (p = 0.01), in the absence of perineural (p = 0.002) and lymphovascular invasion (LVI) (p = 0.045), in the presence of lymphoid infiltration (p = 0.011) and microcalcifications in the tumor (p = 0.043), and slightly higher in ductal BC (p = 0.08). No significant correlations were found between the levels of TGF-β1 and HIF-1a and tumor PR (p = 0.6 and p = 0.9, respectively). However, in patients with grade III-IV of PR in regional metastases, the level of TGF-β1 was significantly lower than in patients with grade I-II (p = 0.03).Conclusions. Thus, these data indicate the presence of correlations between the levels of HIF-1 α and TGF-β1 in the blood serum and a number of clinical characteristics of BC. The highest levels of HIF-1α are observed in the presence of distant metastases, and the highest levels of TGF-β1 are noted in HER2-positive and I-IIa stages of luminal A and triple-negative breast cancer. Given the presence of significant correlations between the level of TGF-β1 and the degree of PR in regional lymph nodes, its determination may be useful for assessing the sensitivity of metastases to regional lymph nodes to the neo-A-CT.

444 CORRELATION BETWEEN PATHOLOGIC COMPLETE RESPONSE TO NEOADJUVANT THERAPY AND RECURRENCE IN PATIENTS WITH ESOPHAGEAL CANCER

Abstract Multimodal treatment options in carcinoma esophagus include neoadjuvant chemoradiotherapy or chemotherapy followed by surgery. The degree of pathologic response to different neoadjuvant options and its impact on the oncologic outcome is a matter of debate. With this background we carried out this study to analyze the rate of pathologic complete re-sponse (pCR) and its effect on recurrence in patients with carcinoma esophagus treated with various combinations of neoadjuvant chemotherapy/radiotherapy and surgery. Methods The records of all patients with carcinoma esophagus registered in our clinics between June 2012 and December 2014 were retrieved from a prospectively maintained database and were analyzed. of the 70 patients with histologically proven esophageal cancer who were treated with curative intent during this period, those with pCR (15) were followed up for a minimum of 5 years. These 15 patients are the subjects of this study. Results Forty eight (48) patients received neoadjuvant chemotherapy (NACT), 16 were treated with short course radiotherapy (SRT), and 3 patients received neoadjuvant chemoradiation (CRT). Four patients developed metastatic disease on neoadjuvant therapy. 66 patients (63 after neoadjuvant therapy and 3 upfront) underwent transthoracic esophagect-omy. Pathological CR was seen 12 patients (25%) in NACT-surgery arm, 2 (12%) in SRT-surgery and 1 (33%) in CRT-surgery groups. Three patients had postoperative mortality due to pulmo-nary complications. At 5 yrs, 14 out of 15 patients with pathological CR are alive and disease free. One patient developed brain metastases after 3 years and died. Conclusion Neoadjuvant therapy followed by radical surgery is a safe and effective treatment option for the management of carcinoma esophagus. Pathologic CR strongly correlates with recurrence-free survival. The relative significance of pCR after different types of neoadjuvant therapies need to be tested in future studies.

Intratumoral HLA-DR-/CD33+/CD11b+ Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted model to predict tumor response, and allow for patient stratification. The level of circulating Myeloid-derived suppressor cells (MDSCs), a subpopulation of early myeloid cells (EMCs), has been shown to correlate with prognosis and response to therapy in advanced colon cancer, but their role in LARC is not clear. We sought to study the effect of intratumoral and circulating levels of different EMCs subpopulations including MDSCs on response to nCRT. We analyzed tumor, normal mucosa, and peripheral blood samples from 25 LARC patients for their different EMCs subpopulation before and after nCRT, and correlated them with degree of pathologic response, as determined postoperatively. In addition, we compared LARC patient to 10 healthy donors and 6 metastatic patients. CD33+HLA-DR−CD16−CD11b+EMCs in the circulation of LARC patients were found to inhibit T-cell activation. Furthermore, elevated levels of CD33+HLA-DR− myeloid cells were found in the tumor relative to normal mucosa, but not in the circulation when compared to healthy subjects. Moreover, intratumoral, but not circulating levels of MDSCs correlated with clinical stage and response to therapy in patients treated with nCRT, with high levels of MDSCs significantly predicting poor response to nCRT. Importantly, therapy by itself, had significant differential effects on MDSC levels, leading to increased circulating MDSCs, concomitantly with decreasing intratumoral MDSCs. Our results suggest that high levels of intratumoral, but not circulating MDSCs may confer drug resistance due to immunomodulatory effects, and serve as a biomarker for patient stratification and decision-making prior to nCRT.

Improved Outcomes for Responders After Treatment with Induction Chemotherapy and Chemo(re)irradiation for Locally Recurrent Rectal Cancer.

Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes. All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), diseasefree survival (DFS), local recurrencefree survival (LRFS), and metastasisfree survival (MFS). A pathologic complete response was observed in 22 patients (17%), a "good" response (Mandard 2-3) in 74 patients (56%), and a "poor" response (Mandard 4-5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (p = 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (p = 0.004, p = 0.003, and p = 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (p = 0.020 and p = 0.028, respectively). Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.

IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

Degree of Pathologic Response as Predictor of Recurrence, Metastasis, and Survival in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy and Total Mastectomy

Purpose: To determine easy-to-use predictors of overall survival (OS), locoregional recurrence (LRR), and distant metastasis (DM) in breast invasive ductal carcinoma (IDC) patients receiving neoadjuvant chemotherapy (NACT) and total mastectomy (TM), we used the degree of pathologic response (DPR) of primary breast diseases (T stages), nodal diseases (N stages), and combined primary and nodal diseases (American Joint Committee on Cancer [AJCC] stages) based on existing clinical and pathologic reports as predictors. Patients and Methods: We enrolled patients with IDC who received NACT followed by TM. Cox regression analysis was used to calculate hazard ratios (HRs) and confidence intervals (CIs) of DPR; other independent predictors were controlled for or stratified in the analysis. Results: We analyzed 3654 IDC patients (1031, 1215, 1003, and 405 patients with clinical stages IIB, IIIA, IIIB, and IIIC, respectively) receiving NACT and TM. After multivariate Cox regression analyses, the adjusted HRs (aHRs) (95% CI) for all-cause mortality, LRR, and DM were noted to be 0.21 (0.13–0.34), 0.19 (0.08–0.48), and 0.33 (0.23–0.47), respectively, for pCR; 0.56 (0.48–0.65), 0.67 (0.51–0.89), and 0.61 (0.52–0.70), respectively, for AJCC downstaging; and 1.85 (1.56–2.18), 1.17 (0.84–1.62), and 1.61 (1.36–1.90), respectively, for AJCC upstaging. Conclusion: The DPR parameters used in the study are easily applied because they are based on existing staging records, and they can strongly predict OS, LRR, and DM in IDC patients receiving NACT and TM, regardless of clinical stage. The results can be used to guide adjuvant treatment. Funding Statement: Lo-Hsu Medical Foundation, LotungPoh-Ai Hospital, supports SzuYuan Wu’s work (Funding Number: 10908 and 10909). Declaration of Interests: The authors have no potential conflicts of interest to declare. Ethics Approval Statement: Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. 201712019).

Abstract OT2-04-05: Phase II trial of pre-operative stereotactic ablative radiotherapy (SABR) in early-stage breast cancer

Abstract Background: Post-operative accelerated partial breast irradiation (APBI) has demonstrated efficacy in preventing in-breast tumor recurrence. Pre-operative administration of APBI may be advantageous as an intact breast tumor is smaller than its corresponding lumpectomy cavity, is easier to distinguish on treatment-planning images, and results in smaller and more accurately delineated target volumes. Pre-operative APBI may reduce the incidence of positive margins following breast-conserving surgery (BCS). Investigation is needed in the correlation of MR imaging with pathologic response 6 weeks after SABR. Also, evidence suggests that SABR induces immune activation in the tumor microenvironment; evaluation of excised tumor tissue will give insight into these processes. Trial Design: Treatment Planning and Delivery: CT simulation and treatment are performed in the prone position. Diagnostic MRI is fused to planning CT. GTV is delineated on registered breast MRI and includes the intact breast tumor. CTV is 15mm expansion of GTV. PTV is 3 mm expansion of CTV. VMAT or IMRT are permitted. Daily image-guidance aligning to tumor and biopsy-fiducial is mandatory. All subjects undergo pre-operative SABR to 28.5 Gy in 3 fractions of 9.5 Gy on different days separated by ≤48 hours. CTCAE v4 is used to assess toxicity 4-5 weeks after SABR. Pre-operative diagnostic MRI is performed 5-6 weeks following SABR. Imaging parameters to be evaluated include changes in tumor size, enhancement, and tumor margin description. BCS will be 6-8 weeks following SABR. Tissue pathology: Margin status and degree of pathologic response are recorded from breast-conserving excisions, specimens are archived for future analysis. Eligibility Criteria: Inclusion criteria are women age ≥50 with biopsy proven invasive breast adenocarcinoma with tumor size ≤2cm on MRI, cN0 M0, ER+/HER2-, without history of invasive malignancy or prior breast/thoracic radiotherapy. Exclusion criteria are active scleroderma or lupus erythematosus with skin involvement, MRI defined tumor within 10 mm of skin, implanted hardware prohibiting appropriate treatment planning or delivery, neoadjuvant chemotherapy, carrier of BRCA1 or 2 gene mutation, pregnancy. Specific Aims: The primary endpoint is pathologic complete response (pCR) in the breast tumor, secondary endpoints are incidence of adequate surgical margins (defined as “no tumor on ink”) and MRI response following SABR. Analyses of tumor immune response and microenvironment on pathologic specimens following SABR will also be performed. Statistical Methods: Fisher's exact test will be performed to examine associations between patient/tumor characteristics and pCR and surgical margins; these associations will be explored with multivariable logistic and linear regressions. Accrual: Present accrual is 9 subjects. Expected accrual is 22 subjects; if ≥3 pCR are noted in the initial cohort, accrual will be expanded to 40 subjects. Citation Format: Liveringhouse CL, Diaz R, Ahmed KA, Lee MC, Czerniecki B, Laronga C, Khakpour N, Weinfurtner RJ, Rosa M, Montejo ME. Phase II trial of pre-operative stereotactic ablative radiotherapy (SABR) in early-stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-04-05.

Hormone receptor-negative as a predictive factor for pathologic complete response to neoadjuvant therapy in breast cancer.

ABSTRACTObjectiveTo define a predictive factor for pathologic complete response, compare the oncologic outcomes associated with the degree of pathologic response after neoadjuvant chemotherapy, and to analyze pathologic complete response as a prognostic factor for overall survival and progression-free survival.MethodsA retrospective study of patients admitted to Hospital Estadual Mário Covas and Hospital Anchieta from 2008 to 2012, with locally advanced breast cancer. Hormone receptor status, HER2 status, histologic and nuclear grade, age upon diagnosis and histological type of the tumor were analyzed. Pathologic evaluation of the tumor was subdivided into pathologic complete response, defined by the absence of tumor; intermediate response, considered as a favorable stage; and poor response, considering low-responder patients. Data obtained were submitted to statistical analysis.ResultsThe study included 243 patients. There was an association of pathologic complete response with HER-2 negative, histological grade 3, stage III, hormone receptor negative, positive lymph node, older age and more advanced tumors. However, after multivariate analysis the only predictor of pathologic complete response was the presence of negative hormone receptor. By analyzing the prognostic factors, hormone receptor negative was considered as an independent risk factor, and pathologic complete response was considered as an independent protective factor.ConclusionHormone receptor negative is predictive of pathologic complete response and is an isolated risk factor for lower progression-free survival and overall survival. Pathologic complete response is a protective factor for these same survival analyses.

Neoadjuvant chemotherapy without radiotherapy for patients with locally advanced rectal cancer. Oncologic outcomes.

the standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy, surgery and adjuvant chemotherapy. Only 50% of patients receive the adjuvant treatment due to the surgical complications and toxicity of radiotherapy. Recently, neoadjuvant chemotherapy has been investigated in the locally advanced rectal cancer setting, with the aim of guaranteeing an uninterrupted systemic treatment. The objective of the present study was to assess the safety and efficacy of neoadjuvant chemotherapy in locally advanced rectal cancer. patients treated with neoadjuvant chemotherapy and surgery were identified from a prospective database of patients with rectal cancer (cII-III). The primary outcomes were the assessment of the number of R0 resections, the degree of pathologic response, patterns of recurrence and overall and disease-free survival. Treatment schedule: patients received 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy. twenty-seven patients who received neoadjuvant chemotherapy were identified. Twenty-six anterior resections and one Hartmann intervention were performed. An R0 resection was performed in 27 (100%) patients and no involvement of the circumferential margin was observed. Complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients. The median follow-up was 35 months (range: 10-81) and four distant recurrences were recorded. Overall and disease-free survival at five years was 85% and 84.7%, respectively. Twenty-seven (100%) patients received all the cycles of chemotherapy, with a mean of six cycles (range 5-8) per patient. neoadjuvant chemotherapy is a promising alternative in the locally advanced rectal cancer setting and further phase III clinical trials are clearly warranted.

Abstract CT181: Safety, activity, and biomarkers for neoadjuvant anti-PD-1 therapy in melanoma

Abstract Background: We have shown that the pharmacodynamic immune response to anti-PD1 therapy peaks at 3 weeks in the peripheral blood and correlates with tumor burden (Nature 2017). These observations suggest that the presence of antigen is important in the generation of an immune response to checkpoint blockade. We hypothesized that neoadjuvant administration of anti-PD1 therapy followed by complete resection at 3 weeks and adjuvant therapy would be a safe and clinically effective approach for patients with high risk resectable melanoma. Methods: We enrolled patients with resectable Stage IIIB/C or Stage IV melanoma, who received one 200mg dose of pembrolizumab followed by curative intent resection 3 weeks after Cycle 1 Day 1. Pathologic assessment was performed at the three-week resection timepoint. Patients continued to receive one year of adjuvant pembrolizumab. Results: 30 patients have been consented since study activation in 2015. 27 patients were eligible to be enrolled and have received treatment before a data cutoff of 12/21/17. 56% of patients were stage IIIC/IV; the remainder were IIIB. 59% were male. Grade 3 adverse events occurred in six patients, with no grade 4 events and no delays in surgical management. No patients were unresectable at the time of surgery. Among 20 patients with at least one year of follow-up or a recurrence event, the 1 year recurrence-free survival (RFS) was 55%. Of the 9 patients who had recurrences, 5 are now disease free after additional therapy or resection and 2 patients remain alive with disease. 2 patients have died. After one dose of pembrolizumab, 8 of 27 (30%) of patients had a complete or-near complete (<10% viable tumor) pathologic response, all of whom are currently recurrence-free. Patients with residual viable tumor of less than 50% at time of resection had a 1 year RFS of 88%, compared to 33% for those with greater than 50% residual viable tumor. Patients with brisk TILs had a 1 year RFS of 89% compared to 27% with non-brisk TILs. Clinical responses after one dose of therapy could also be observed by FDG PET/CT imaging by 3 weeks and correlated with the degree of pathologic response. In addition, a significant increase in CD8 T cells and PD-L1 expression was observed in paired pre and on treatment tissue specimens consistent with an adaptive immune response. Conclusion: Neoadjuvant anti-PD1 therapy is safe and active in patients with resectable high risk stage III and IV melanoma. Four of five patients with stage IIIB (80%) and seven of 14 with IIIC (50%) melanoma who received neoadjuvant and adjuvant pembrolizumab were recurrence free at 1 year suggesting promising clinical activity and further research is warranted. Consistent with our published data in the peripheral blood, the clinical activity of anti-PD-1 therapy occurs early in the tumor and can be detected by gross, histologic, radiographic, and immune changes after only 1 dose of therapy. Citation Format: Alexander C. Huang, Xiowei Xu, Robert J. Orlowski, Sangeeth M. George, Lakshmi Chilukuri, Andrew Kozlov, Mary Carberry, Lydia Giles, Suzanne McGettigan, Kristin Kreider, Jennifer H. Yearley, Lakshmanan Annamalai, Gerald Linette, Ravi K. Amaravadi, Lynn M. Schuchter, Michael Farwell, John Wherry, Giorgos Karakousis, Tara Gangadhar. Safety, activity, and biomarkers for neoadjuvant anti-PD-1 therapy in melanoma [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 CT181.

Abstract 3609: Differential gene expression is associated with response to chemoradiation and relapse-free and overall survival in rectal adenocarcinoma

Abstract Background: Neoadjuvant chemoradiation is a standard therapy for stage II-III rectal adenocarcinoma, and the degree of pathologic response observed upon resection informs prognosis. However, there is a need to identify novel biomarkers of response to chemoradiation and survival after chemoradiation, particularly using modern next-generation sequencing methods. Methods: We prospectively collected pretreatment endoscopic tumor biopsies from 43 patients with stage II-IV rectal adenocarcinoma prior to neoadjuvant chemoradiation with concurrent fluoropyrimidine. Tumor samples were fresh frozen, and subsequently RNA was extracted, paired end libraries for mRNA sequencing (RNASeq) were prepared using TruSeq RNA Access library prep kits (Illumina), and samples were sequenced on Illumina HiSeq. Differentially expressed genes were determined using DESeq2 and Ingenuity pathway analysis (Qiagen) was performed. Additionally, the association between “claudin-low”-like gene sets established in breast and bladder cancers and clinical outcomes was determined. Results: Among the 36 patients with adequate RNA quality, 7 had a pathologic complete response (pCR) and 29 did not, with 22 differentially expressed genes with false discovery rate (FDR) <0.1 between the two cohorts, including EME2 (2.0-fold change, FDR p-value 0.00627). At 5 years of follow-up, 11 patients had known relapse and 11 were known to be relapse-free, with 33 differentially expressed genes with FDR<0.1 between the two cohorts. Pathway analysis demonstrated that p53 signaling and Wnt/β-catenin signaling pathways were associated with relapse, while dendritic cell maturation and Toll-like receptor signaling pathways were associated with relapse-free survival. Rectal cancers with greater expression of a “claudin-low”-like signature had significantly inferior relapse-free survival (HR 1.79, 95% CI 1.07-3.00) and overall survival (HR 1.91, 95% CI 1.17-3.12) on univariate Cox proportional hazards model. Conclusions: There are multiple differentially expressed genes associated with response to neoadjuvant chemoradiation in rectal adenocarcinoma. EME2, which forms an endonuclease that cleaves stalled replication forks, was one of the most differentially expressed genes overexpressed in patients with pathologic complete response and thus is a rational target for further investigation. Extension of “claudin-low” gene expression signatures to rectal cancers may serve as a new prognostic biomarker. Further investigation into the association of gene expression subtypes and responses to neoadjuvant chemoradiation is warranted. Citation Format: Michael S. Lee, Cheryl Carlson, Benjamin F. Calvo, Bert H. O'Neil, Dante S. Bortone, Benjamin G. Vincent. Differential gene expression is associated with response to chemoradiation and relapse-free and overall survival in rectal adenocarcinoma [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 3609.

Dynamic Diffuse Optical Tomography for Monitoring Neoadjuvant Chemotherapy in Patients with Breast Cancer.

Purpose To identify dynamic optical imaging features that associate with the degree of pathologic response in patients with breast cancer during neoadjuvant chemotherapy (NAC). Materials and Methods Of 40 patients with breast cancer who participated in a longitudinal study between June 2011 and March 2016, 34 completed the study. There were 13 patients who obtained a pathologic complete response (pCR) and 21 patients who did not obtain a pCR. Imaging data from six subjects were excluded from the study because either the patients dropped out of the study before it was finished or there was an instrumentation malfunction. Two weeks into the treatment regimen, three-dimensional images of both breasts during a breath hold were acquired by using dynamic diffuse optical tomography. Features from the breath-hold traces were used to distinguish between response groups. Receiver operating characteristic (ROC) curves and sensitivity analysis were used to determine the degree of association with 5-month treatment outcome. Results An ROC curve analysis showed that this method could identify patients with a pCR with a positive predictive value of 70.6% (12 of 17), a negative predictive value of 94.1% (16 of 17), a sensitivity of 92.3% (12 of 13), a specificity of 76.2% (16 of 21), and an area under the ROC curve of 0.85. Conclusion Several dynamic optical imaging features obtained within 2 weeks of NAC initiation were identified that showed statistically significant differences between patients with pCR and patients without pCR as determined 5 months after treatment initiation. If confirmed in a larger cohort prospective study, these dynamic imaging features may be used to predict treatment outcome as early as 2 weeks after treatment initiation. © RSNA, 2018 Online supplemental material is available for this article.

Pathologic response following treatment for locally advanced rectal cancer: Does location matter?

BackgroundDespite advances in the treatment of rectal adenocarcinoma, the management of locally advanced disease remains a challenge. The standard of care for patients with stages II and III rectal cancer includes neoadjuvant chemoradiation followed by total mesorectal excision and postoperative chemotherapy. Much effort has been dedicated to the identification of predictive factors associated with pathologic complete response (pCR). The aim of our study was to examine our institutional experience and determine whether any association exists between anatomic tumor location and the rate of pCR. We hypothesized that lesions more than 6 cm from the anal verge are more likely to achieve a pCR. MethodsUsing data from our prospectively maintained tumor registry, a query was completed to identify all patients with locally advanced rectal adenocarcinoma who underwent treatment at Fox Chase Cancer Center from 2002 to 2015. Demographics, pretreatment, posttreatment, and final pathologic TNM staging data were collected as well as treatment intervals in days, recurrence status, overall survival, and disease-free survival. Patients with incomplete endoscopic data, staging information, survival, or recurrence status were excluded. The primary outcome measured was the degree of pathologic response. Logistic regression was used to adjust for covariates. ResultsOf the 135 patients eligible in the study cohort, 39% were female and 61% were male. Regarding initial clinical stage, 43% were stage II and 57% were stage III. A total of 29% had a pCR, 43% had partial pathologic response, and 28% had no response to neoadjuvant treatment. Tumor location ranged from 0 to 13 cm from the anal verge. Longitudinal tumor length was recorded in 111 patients, facilitating the calculation of mean tumor distance from the anal verge. This ranged from 0 to 15.5 cm. Univariate and multivariable analyses were completed using pCR as a primary outcome. No statistically significant difference was noted based on tumor location, regardless of measurement approach. ConclusionsAnatomic location of cancer of the rectum does not affect pCR after neoadjuvant therapy and subsequent surgical resection.

Esophageal adenocarcinoma stage III: Survival based on pathological response to neoadjuvant treatment

BackgroundNeoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal adenocarcinomas (EAC). Pathological response is thought to be a major prognostic factor. Aims of this study were to determine the frequency of complete response and to compare the survival of complete and incomplete responders in stage III EAC. MethodsA retrospective review was performed of all stage III patients that underwent neoadjuvant therapy followed by esophagectomy between 1999 and 2015. Patients were classified into complete (pCR) versus incomplete responders (pIR). Results110 patients were included. Neoadjuvant chemotherapy was applied in 25 (23%) and chemoradiotherapy in 85 (77%) patients. Pathologic response was complete in 25% (n = 27) and was more common after chemoradiotherapy. Mean F/U interval was 36 months (0.3–173). There was a significant difference in the overall survival between complete and incomplete responders (p = 0.036). Median survival in the pIR group was 24.4 months and the median survival was not reached during the observation time in pCR. The 3-year-survival-rate was 70% in pCR and 40% in pIR (p = 0.01). Positive lymph nodes (ypN+) were present in 56 patients (51%). The 3-year-survival-rate was 59% in pIR with ypN0 and 29% in pIR with ypN+ (p = 0.005). ConclusionsComplete response to neoadjuvant therapy has a significantly better overall and 3-year-survival after esophagectomy than incomplete response. In incomplete responders, residual lymph node disease was associated with a significantly worse survival. These findings suggest that the degree of pathologic response and lymph node status are major prognostic factors for survival in EAC patients with stage III disease.

Abstract ES6-2: ES6-2 Surgical considerations in patients receiving neoadjuvant therapy

Abstract Early randomized trials of neoadjuvant chemotherapy failed to show an improvement in overall survival compared to adjuvant therapy, yet it reduces the need for mastectomy and axillary lymph node dissection, thus decreasing the morbidity of surgery, without increasing the risk of locoregional recurrence. It is also now increasingly clear that the impact of neoadjuvant chemotherapy varies by molecular subtype; whereby patients with high-grade estrogen receptor negative and/or HER2 positive breast cancers are more likely to experience pathologic complete response to NAC that those with low-grade, estrogen receptor positive cancers. The increasing rates of pCR following neoadjuvant chemotherapy have had a significant impact on local-regional treatment considerations. However, patient selection for this approach remains critical. Sentinel node biopsy after neoadjuvant chemotherapy accurately stages the axilla and is associated with a low rate of nodal recurrence in patients presenting with a clinically negative axilla. Sentinel node biopsy after neoadjuvant chemotherapy in patients with proven axillary metastases prior to neoadjuvant chemotherapy who become clinically node negative has a false negative rate of less than 10% only when 3 or more sentinel nodes are identified and there are no data on nodal recurrence rates after sentinel node biopsy alone in this population. Hence, strategies to ensure a low false negative rate are critical if sentinel node biopsy is offered to patients with proven axillary metastases prior to neoadjuvant chemotherapy. The relative contribution of pre-treatment stage and post-treatment stage (degree of pathologic response) to local control is also uncertain and tailoring of local therapy based on the degree of response is the subject of ongoing trials. Citation Format: King TA. ES6-2 Surgical considerations in patients receiving neoadjuvant therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES6-2.

PD33-07 PARTIAL VS. COMPLETE RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN MUSCLE-INVASIVE BLADDER CANCER PATIENTS: A COMPARISON OF POST-CYSTECTOMY OUTCOMES

You have accessJournal of UrologyBladder Cancer: Invasive IV1 Apr 2016PD33-07 PARTIAL VS. COMPLETE RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN MUSCLE-INVASIVE BLADDER CANCER PATIENTS: A COMPARISON OF POST-CYSTECTOMY OUTCOMES Aaron Brant, Max Kates, Meera Chappidi, Hiten Patel, Nikolai Sopko, and Trinity Bivalacqua Aaron BrantAaron Brant More articles by this author , Max KatesMax Kates More articles by this author , Meera ChappidiMeera Chappidi More articles by this author , Hiten PatelHiten Patel More articles by this author , Nikolai SopkoNikolai Sopko More articles by this author , and Trinity BivalacquaTrinity Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.716AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Several randomized controlled trials have found that neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) provides a survival benefit to patients who achieve complete pathologic response. We compared survival and recurrence outcomes between partial and complete responders. METHODS We identified 225 consecutive patients with ≥cT2 urothelial carcinoma who received neoadjuvant chemotherapy prior to RC at our institution from 2005-2014. Partial response was defined as down-staging to pT1, pTis, or pTa at RC, and complete response was defined as down-staging to pT0. Characteristics between partial and complete responders were compared using Wilcoxon-Mann-Whitney for continuous and chi-squared for categorical variables. Cox regression was used to identify predictors of recurrence and survival in both partial and complete responders, adjusting for age, BMI, gender, race, smoking status, Charlson score, intravesical therapy, clinical stage, and degree of pathologic response. RESULTS In our cohort of 225 patients, 69 (30.7%) achieved partial response and 51 (22.7%) achieved complete response. The only significant difference between partial and complete responders was median days from NAC initiation to RC (160 vs. 140, p=.03). Cox regression found that partial and complete response were each independent predictors of decreased cancer recurrence (hazard ratio (HR)=.194 and .128, p<0.01) and overall mortality (HR=.140 and .129, p<0.01). Log-rank test found no difference in recurrence-free survival or overall survival between partial and complete responders. CONCLUSIONS The benefit of NAC is not limited to patients who achieve complete pathologic response. Complete and partial responders were each associated with improved recurrence-free survival and overall survival when compared to non-responders. There was no significant difference in recurrence-free survival or overall survival between partial and complete responders. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e768 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Aaron Brant More articles by this author Max Kates More articles by this author Meera Chappidi More articles by this author Hiten Patel More articles by this author Nikolai Sopko More articles by this author Trinity Bivalacqua More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

AKT expression is associated with degree of pathologic response in adenocarcinoma of the esophagus treated with neoadjuvant therapy.

Neoadjuvant chemoradiation (NCRT) has become standard in the treatment of locally advanced esophageal adenocarcinoma (EAC) with survival correlated to degree of pathologic response. The phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (AKT)/mTOR pathway plays an important role in tumorgenesis and resistance. We sought to elucidate the role of this pathway in patients with EAC who received NCRT. After IRB approval, a prospective trial was initiated in which patients with EAC underwent endoscopic biopsies of normal and tumor tissue prior to instituting NCRT. Patients then proceeded to esophagectomy. The pre-treatment tissues underwent gene expression profiling. SAM method was used to analyze expression of AKT within normal and tumor tissue. Expression was then correlated to degree of pathologic response. One-hundred patients were consented for the study, of which 67 met final eligibility. Nineteen patient's tumors ultimately underwent gene expression profiling via microarray. The differential expression of all AKT isoforms in tumor tissue was markedly overexpressed compared to normal tissue (P=6×10(-5)). There were 3 patients designated as pNR, 6 as pPR, and 10 as pCR. Partial and non-responders had higher expressions of AKT compared to pCR with the non-responders consistently illustrated the highest expression of AKT (P=0.02). There was a significant correlation between individual isoforms of AKT-1, AKT-2, and AKT-3 and degree of pathologic response (P=0.002, 0.04, and 0.04 respectively). AKT is overexpressed in patients with AC of the esophagus. Moreover, pathologic response to NCRT may be correlated with degree of AKT expression. Additional data is needed to clarify this relationship to potentially add targeted therapies to the neoadjuvant regimen.

Association of AKT expression with degree of pathologic response in patients with esophageal cancer undergoing neoadjuvant therapy.

89 Background: Neoadjuvant therapy (NCRT) has become standard in the treatment of locally advanced esophageal adenocarcinoma (EAC) with survival correlated to degree of pathologic response. The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorgenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of AKT in chemoresistance in patients with esophageal adenocarcinoma (AC) who received NCRT. Methods: After IRB approval, a prospective trial was initiated in which patients with EAC requiring NCRT were consented for endoscopic biopsies of normal and tumor tissue prior to instituting therapy. After completion of NCRT patients then proceeded to esophagectomy. The tissues obtained preoperatively underwent gene expression profiling using the Affymetrix 133 Plus 2.0 Gene chip. SAM method was used to analyze significant differentially expression of AKT within normal and tumor tissue. Expression was then correlated to degree of pathologic response. Results: One-hundred patients were consented for the study, of which 67 met final eligibility. Nineteen patient’s tumors ultimately underwent gene expression profiling via microarray. The differential expression of all AKT probesets in tumor tissue was markedly overexpressed compared to normal tissue (p=6x10-5). There were 3 patients designated as pNR, 5 as pPR, and 11 as pCR. Investigating the relationship between the degree of expression of AKT and pathologic response demonstrated a linear correlation between over-expression of AKT and degree of pathologic response. Partial and non-responders had higher expressions of AKT compared to pCR with the non-responders consistently illustrated the highest expression of AKT (p=0.02). There was a significant correlation between individual probesets AKT1, AKT2, and AKT3 and degree of pathologic response (p=0.002, 0.04, and 0.04 respectively). Conclusions: AKT is overexpressed in patients with AC of the esophagus. Moreover, pathologic response to NCRT may be correlated with degree of AKT expression. Additional data is needed to clarify this relationship further and add potential targeted therapies.

644P - Induction Chemotherapy Followed By Chemoradiotherapy in Locally Advanced Esophagogastric Adenocarcinoma. Has the Location of the Primary Tumor Any Influence on Patients' Outcome? a Retrospective Analysis

ABSTRACT Aim: Multimodal therapy is the standard of care in locally advanced esophagogastric adenocarcinoma. However, most trials include both, gastric (GC) and gastroesophageal junction (GEJ) cancers. We aimed to rule out whether patients (pts) with either locally advanced GEJ (group A) or GC (group B) have different outcomes when treated with a neoadjuvant approach based on induction chemotherapy (ICT), chemoradiotherapy (CRT) and surgery. Methods: EUS-T2-4 and/or N+ M0 GEJ or GC adenocarcinoma patients were scheduled to receive preoperative therapy (3-4 cycles of chemotherapy followed by concurrent CRT). Surgery was scheduled 4 to 6 weeks after the end of CRT. Pathological response was graded according to the Becker criteria. Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were also evaluated. Results: From november 2004 to July 2013, 87 pts (27 in group A, 60 in group B) met the specified criteria. Pts characteristics were; Group A; M/F; 23/4; EUS-T3 52%, T4 40,7%, N+ 95%, median age 56 (31-81); Diffuse/Intestinal 55%/44%. Group B; M/F; 42/18; EUS-T3 40%, T4 56%, N+ 95%; median age 60.5 (36-76); Diffuse/Intestinal 57%/42%. Seventy-four pts underwent surgery (group A/ B; 92.6%/82%). Pathological response (Group A/B); Grade Ia-Ib according to Becker criteria (72%/51%), pN0 (60.3%/53%). R0 resection (Group A/B); (96%/94%). Among resected pts we analysed the impact of tumor location (GC vs GEJ) on known prognostic factors such as Lauren classification and degree of pathological response regarding PFS and OS. In group A, median OS and PFS did not difer according to Lauren neither classification nor pN status. In contrast, median PFS varied according to Becker response (Ia-b: Not Reached; II-III: 13m; p = 0.02). In group B, we found differences in PFS and OS according to; a)- Lauren Classification; Intestinal GC vs Diffuse GC pts [median PFS; NR vs 13.6m; p = 0.028, median OS: NR vs 15.3m; p = 0.026]. b)pN status (-/+) [median PFS; NR vs 18m; p Conclusions: When treated with ICT followed by CRT, GEJ and GC pts have different outcomes in terms of pathological response degree, patterns of recurrence and survival times. Disclosure: All authors have declared no conflicts of interest.