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BACKGROUND - There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm.
PATIENTS AND METHODS - Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years.
RESULTS - Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015).
CONCLUSIONS - TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
BACKGROUND - Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection.
METHODS - We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis.
RESULTS - A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded.
CONCLUSIONS - AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.
© 2017 Wiley Periodicals, Inc.
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
Most gallbladder cancers (GBCs) are discovered incidentally after routine cholecystectomy. The influence of timing of diagnosis on disease stage, treatment, and prognosis is not known. Patients with GBC who underwent resection at 10 institutions from 2000 to 2015 were included. Patients diagnosed incidentally (IGBC) and nonincidentally (non-IGBC) were compared. Primary outcome was overall survival (OS). Of 445 patients with GBC, 266 (60%) were IGBC and 179 (40%) were non-IGBC. Compared with IGBC, non-IGBC patients were more likely to have R2 resections (43% vs 19%; P < 0.001), advanced T-stage (T3/T4: 70% vs 40%; P < 0.001), high-grade tumors (50% vs 31%; P < 0.001), lymphovascular invasion (64% vs 45%; P = 0.01), and positive lymph nodes (60% vs 43%; P = 0.009). Receipt of adjuvant chemotherapy was similar between groups (49% vs 49%). Non-IGBC was associated with worse median OS compared with IGBC (17 vs 32 months; P < 0.001), which persisted among stage III patients (12 vs 29 months; P < 0.001), but not stages I, II, or IV. Despite accounting for other adverse pathologic factors (grade, T-stage, lymphovascular invasion, margin, lymph node), adjuvant chemotherapy was associated with improved OS only in stage III IGBC, but not in non-IGBC. Compared with incidental discovery, non-IGBC is associated with reduced OS, which is most evident in stage III disease. Despite being well matched for other adverse pathologic factors, adjuvant chemotherapy was associated with improved survival only in stage III patients with incidentally discovered cancer. This underscores the importance of timing of diagnosis in GBC and suggests that these two groups may represent a distinct biology of disease, and the same treatment paradigm may not be appropriate.
BACKGROUND - The aim of this study was to compare patients with PHC with lymph node metastases (LN+) who underwent a resection with patients who did not undergo resection because of locally advanced disease at exploratory laparotomy.
METHODS - Consecutive LN+ patients who underwent a resection for PHC in 12 centers were compared with patients who did not undergo resection because of locally advanced disease at exploratory laparotomy in 2 centers.
RESULTS - In the resected cohort of 119 patients, the median overall survival (OS) was 19 months and the estimated 1-, 3- and 5-year OS was 69%, 27% and 13%, respectively. In the non-resected cohort of 113 patients, median OS was 12 months and the estimated 1-, 3- and 5-year OS was 49%, 7%, and 3%, respectively. OS was better in the resected LN+ cohort (p < 0.001). Positive resection margin (hazard ratio [HR]: 1.54; 95%CI: 0.97-2.45) and lymphovascular invasion (LVI) (HR: 1.71; 95%CI: 1.09-2.69) were independent poor prognostic factors in the resected cohort.
CONCLUSION - Patients with PHC who underwent a resection for LN+ disease had better OS than patients who did not undergo resection because of locally advanced disease at exploratory laparotomy. LN+ PHC does not preclude 5-year survival after resection.
Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31-1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis.
PURPOSE - Anorectal gastrointestinal stromal tumors (GISTs) are exceedingly rare, and management remains controversial in regard to local resection (LR) and preoperative chemotherapy.
METHODS - The National Cancer Data Base was queried from 1998 to 2012 for cases of GIST resection in the rectum or anus. Patient demographics, type of surgery (LR vs. radical excision [RE]), short-term outcomes, and overall survival (OS) were analyzed. Preoperative chemotherapy was recorded following the US FDA approval of imatinib in 2002.
RESULTS - Overall, 333 patients with resection of anorectal GISTs were included. Mean age at presentation was 62.3 years (range 22-90), and median tumor size was 4.0 cm (interquartile range 2.2-7.0). Five-year OS for all patients was 77.6%. In a multivariable survival analysis, only age and tumor size >5 cm (hazard ratio 2.48, 95% confidence interval 1.50-4.01; p = 0.004) were associated with increased mortality. One hundred and sixty-three (49.0%) patients underwent LR, compared with 158 (47.4%) who underwent RE. For tumors smaller than 5 cm, no difference in 5-year survival by surgical approach was observed (LR 82.3% vs. RE 82.6%; p = 0.71). Fifty-nine patients (17.7%) received preoperative chemotherapy; for patients undergoing RE with tumors >5 cm, there was decreased mortality in the group who received preoperative chemotherapy (5-year OS with chemotherapy 79.2% vs. no chemotherapy 51.2%; p = 0.03).
CONCLUSIONS - Size is the most important determinant in survival following resection. Local excision is common, with resection split between LR and RE. For smaller tumors, LR may be adequate therapy. Preoperative chemotherapy may result in improved survival for large tumors treated with radical resection, but the data are imperfect.
BACKGROUND - Adjuvant chemotherapy for T3N0 colon cancer is controversial. National guidelines recommend its use in patients with stage II with high-risk features, including lymph node harvest of less than 12, yet this treatment is underused.
OBJECTIVE - The purpose of this study was to demonstrate that the use of adjuvant chemotherapy in patients with T3N0 adenocarcinoma with inadequate lymph node harvest is beneficial.
DESIGN - This was a retrospective population-based study of patients with resected T3N0 adenocarcinoma of the colon.
SETTINGS - The National Cancer Database was queried from 2003 to 2012.
PATIENTS - A total of 134,567 patients with T3N0 colon cancer were included in this analysis.
MAIN OUTCOME MEASURES - The use of chemotherapy, short-term outcomes, and overall survival was evaluated. Clinicopathologic factors associated with omission of chemotherapy were also analyzed.
RESULTS - Inadequate lymph node harvest was observed in 23.3% of patients, and this rate decreased over the study period from 46.8% in 2003 to 12.5% in 2012 (p < 0.0001). Overall 5-year survival for patients with T3N0 cancer was 66.8%. Inadequate lymph node harvest among these patients was associated with lower overall 5-year survival (58.7% vs 69.8%; p < 0.001). The use of adjuvant chemotherapy among patients with T3N0 cancer after inadequate lymph node harvest was only 16.7%. In a multivariable analysis, factors associated with failure to receive chemotherapy included advanced age (OR = 0.44 (95% CI, 0.43-0.45)), increased comorbidities (OR = 0.7 (95% CI, 0.66-0.76)), and postoperative readmission (OR = 0.78 (95% CI, 0.67-0.91)). Patients with inadequate lymph node harvest who received adjuvant chemotherapy had improved 5-year survival (chemotherapy, 78.4% vs no chemotherapy, 54.7%; p < 0.001). Even when controlling for all of the significant variables, the administration of chemotherapy remained a predictor of decreased mortality (HR = 0.57 (95% CI, 0.54-0.60); p < 0.001).
LIMITATIONS - This study was limited by its retrospective, population-based design.
CONCLUSIONS - Patients with T3N0 colon cancer with inadequate lymph node harvest who receive adjuvant chemotherapy have increased overall survival. Despite this survival benefit, a fraction of these patients receive adjuvant chemotherapy. Barriers to chemotherapy are multifactorial.