Pretreatment Nodal Status Research Articles

Factors Associated with Nodal Pathologic Complete Response Among Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Results of CALGB 40601 (HER2+) and 40603 (Triple-Negative) (Alliance).

De-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) requires careful patient selection. We seek to determine predictors of nodal pathologic complete response (ypN0) among patients treated on CALGB 40601 or 40603, which tested NAC regimens in HER2+ and triple-negative breast cancer (TNBC), respectively. A total of 760 patients with stage II-III HER2+ or TNBC were analyzed. Those who had axillary surgery before NAC (N = 122), or who had missing pretreatment clinical nodal status (cN) (N = 58) or ypN status (N = 41) were excluded. The proportion of patients with ypN0 disease was estimated for those with and without breast pathologic complete response (pCR) according to pretreatment nodal status. In 539 patients, the overall ypN0 rate was 76.3% (411/539) to 93.2% (245/263) in patients with breast pCR and 60.1% (166/276) with residual breast disease (RD) (P < 0.0001). For patients who were cN0 pretreatment, the ypN0 rate was 88.8% (214/241), 96.3% (104/108) with breast pCR, and 82.7% (110/133) with RD. For patients who were cN1, 66.2% (157/237) converted to ypN0, 91.7% (111/121) with breast pCR and 39.7% (46/116) with RD. For patients who were cN2/3, 65.6% (40/61) converted to ypN0, 88.2% (30/34) with breast pCR and 37.0% (10/27) with RD. On multivariable analysis, only pretreatment clinical nodal status and breast pCR/RD were associated with ypN0 status (both P < 0.0001). Breast pCR and pretreatment nodal status are predictive of ypN0 axillary nodal involvement, with < 5% residual nodal disease among cN0 patients who experience breast pCR. These findings support the incorporation of axillary surgery de-escalation strategies into NAC trials.

BMI1-KLF4 axis deficiency improves responses to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer

PurposeNeoadjuvant concurrent chemoradiotherapy (CCRT) is a gold standard treatment for patients with stage II/III rectal cancer. B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) is a member of the polycomb group of proteins that are involved in regulating gene expression. High levels of BMI1 have been demonstrated to contribute to the malignant phenotypes of several cancers; however, its relevance in rectal cancer treated with CCRT is largely unknown. Methods and materialsWe used two patient cohorts to address the clinical relevance of BMI1 in human cancers. In addition, HT-29 and HCT-116 cells were chosen as our in vitro models to verify the role of BMI1 in cell response to ionizing radiation. Stemness-related proteins were analyzed by western blotting and cell survival was determined using clonogenic assays. ResultsBMI1 overexpression was found to significantly correlate with advanced pre-treatment nodal status (N1-N2; p < 0.001), post-treatment tumor stage (T1-T2; p = 0.015), inferior tumor regression grade (p = 0.001), and also an independent prognosis factor in 172 rectal cancer patients receiving CCRT. Serial cell-based functional examination indicated that BMI1 deficiency sensitized cells to radiation treatment by modulating the gene expression of Kruppel-like factor 4 (KLF4) and enhanced radiosensitivity in microsatellite stable (MSS) colorectal cancers. Overexpression of KLF4 partially overcame BMI1-deficiency-mediated γ-H2AX expression after ionizing radiation exposure. Consistent with in vitro data, an analysis of an additional 30 rectal cancer tissue specimens revealed a positive correlation between BMI1 and KLF4 (p = 0.02). ConclusionHigher levels of BMI1 are associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT.

The Impact of Pretreatment PET/CT Nodal Status on Esophageal Squamous Cell Carcinoma After Neoadjuvant Chemoradiation.

For advanced esophageal cancer, the clinical significance of pretreatment nodal status (cN) as determined by different examinations remains unclear. Patients with esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiation and surgery were analyzed in this study. Pretreatment cN status assessed by CT, EUS, and PET/CT and clinicopathological features were used to evaluate tumor recurrence and long-term survival. Two hundred and twenty-two patients were identified in this study. Pretreatment PET/CT cN0 [odds ratio (OR) cN0 versus cN+, 5.316, p < 0.001] and pretreatment CT cN0 (OR 1.957, p = 0.032) both independently predicted ypN0. Pretreatment PET/CT cN0 was also associated with a lower recurrence rate and longer survival across the entire study group. Among patients with ypN0, pretreatment PET/CT cN+ indicated poor disease-free survival [hazard ratio (HR) 2.777, p = 0.001] and overall survival (HR 2.211, p = 0.034) compared with pretreatment PET/CT cN0, which predicted a favorable prognosis. Data from the current study suggest that pretreatment lymph node status as assessed by PET/CT is strongly correlated with survival outcomes after neoadjuvant chemoradiation and surgery in patients with esophageal squamous cell carcinoma. ypN0 patients can achieve better survival outcomes when pretreatment cN0 is assessed by PET/CT.

PCSK1 Overexpression in Rectal Cancer Correlates with Poor Response to Preoperative Chemoradiotherapy and Prognosis.

BackgroundIn a data mining search for potential therapeutic targets to improve the outcome of rectal cancer, we identified PCSK1 as the cell–cell signaling gene most significantly associated with poor response to concurrent chemoradiotherapy (CCRT). This study aims to investigate the prognostic value of PCSK1 expression in rectal cancer patients who underwent neoadjuvant CCRT.MethodsEndoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery were assessed immunohistochemically for PCSK1 expression, and H-scores were determined. Expression levels of PCSK1 were further analyzed for correlations with clinicopathologic features, tumor regression grade, metastasis-free survival, disease-specific survival, and recurrence-free survival.ResultsPCKS1 overexpression was significantly associated with pretreatment tumor status (T3–4; p = 0.009), pretreatment nodal status (N1–2; p < 0.001), posttreatment tumor status (T3–4; p < 0.001), posttreatment nodal status (N1–2; p < 0.001), vascular invasion (p = 0.003), and perineurial invasion (p = 0.023). PCKS1 overexpression was also found to be significantly associated with a lower degree of tumor regression (p < 0.001). In the univariate analysis, PCSK1 overexpression was significantly associated with lower disease-specific survival, metastasis-free survival, and recurrence-free survival (p < 0.005). PCSK1 overexpression remained an independent prognostic factor of lower disease-specific survival (p = 0.003; hazard ratio, 5.478) in the multivariate analysis.ConclusionDetermination of PCSK1 overexpression may be useful for identifying rectal cancer patients at risk for a poor response and worse survival after CCRT.

Association Between Adjuvant Chemotherapy and Overall Survival in Patients With Rectal Cancer and Pathological Complete Response After Neoadjuvant Chemotherapy and Resection

Although American guidelines recommend use of adjuvant chemotherapy in patients with locally advanced rectal cancer, individuals who achieve a pathological complete response (pCR) following neoadjuvant chemoradiotherapy are less likely to receive adjuvant treatment than incomplete responders. The association and resection of adjuvant chemotherapy with survival in patients with pCR is unclear. To determine whether patients with locally advanced rectal cancer who achieve pCR after neoadjuvant chemoradiation therapy and resection benefit from the administration of adjuvant chemotherapy. This retrospective propensity score-matched cohort study identified patients with locally advanced rectal cancer from the National Cancer Database from 2006 through 2012. We selected patients with nonmetastatic invasive rectal cancer who achieved pCR after neoadjuvant chemoradiation therapy and resection. We matched patients who received adjuvant chemotherapy to patients who did not receive adjuvant treatment in a 1:1 ratio. We separately matched subgroups of patients with node-positive disease before treatment and node-negative disease before treatment to investigate for effect modification by pretreatment nodal status. We compared overall survival between groups using Kaplan-Meier survival methods and Cox proportional hazards models. We identified 2455 patients (mean age, 59.5 years; 59.8% men) with rectal cancer with pCR after neoadjuvant chemoradiation therapy and resection. We matched 667 patients with pCR who received adjuvant chemotherapy and at least 8 weeks of follow-up after surgery to patients with pCR who did not receive adjuvant treatment. Over a median follow-up of 3.1 years (interquartile range, 1.94-4.40 years), patients treated with adjuvant chemotherapy demonstrated better overall survival than those who did not receive adjuvant treatment (hazard ratio, 0.44; 95% CI, 0.28-0.70). When stratified by pretreatment nodal status, only those patients with pretreatment node-positive disease exhibited improved overall survival with administration of adjuvant chemotherapy (hazard ratio, 0.24; 95% CI, 0.10-0.58). The administration of adjuvant chemotherapy in patients with rectal cancer with pCR is associated with improved overall survival, particularly in patients with pretreatment node-positive disease. Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with pCR, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study.

Abstract ES6-3: ES6-3 Radiation implications post neoadjuvant therapy

Abstract Neoadjuvant therapy offers unique challenges and opportunities for the radiation oncologist. Classical indications for radiation have been rooted in the pathologic analysis of tissue resected prior to treating the patient with systemic therapy. However, in patients treated with neoadjuvant therapy, pathologic findings are frequently altered by the administration of systemic therapy, and thus classical indications for radiation may be clouded. Nevertheless, the degree of response to neoadjuvant therapy offers a novel prognostic factor which reflects intrinsic tumor biology and affords the opportunity for a new, precision approach to risk stratification and radiation therapy treatment decision making. To maximally capitalize on the information gained from treating a patient with neoadjuvant chemotherapy, patients must be meticulously staged, preferably by a multidisciplinary team, prior to initiation of systemic therapy. Ultrasound of the regional nodal basins including the low axillary, infraclavicular, supraclavicular, and internal mammary nodal chains with ultrasound-guided fine needle aspiration of radiographically abnormal nodes enables detailed mapping of the local-regional disease extent. Cross-sectional imaging with CT and/or PET/CT is also helpful to permit customized radiation field design after systemic therapy and surgery. These imaging studies are invaluable to the radiation oncologist and allow for optimal field design to facilitate cure. Additionally, nodal surgery prior to administration of systemic therapy, while helpful in documenting pre-treatment nodal status, results in loss of ability to accurately assess response to chemotherapy in the lymph nodes and is thus avoided in our practice. The available evidence indicates that patients experiencing a pathologic complete response have exceptional local-regional control. Accordingly, current randomized trials are exploring whether either radiation or surgery can be de-escalated within this context. In contrast, for patients with significant residual tumor burden following neoadjuvant chemotherapy, local-regional control outcomes are suboptimal for those with triple negative or HER2 positive disease. Novel strategies to escalate therapy with radiosensitizers or other biologic agents are needed for this population. Citation Format: Smith BD. ES6-3 Radiation implications post 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 ES6-3.

OC-101 Lymph node positivity in patients with anal cancer treated in the modern era: prognostic impact and patterns of locoregional relapse (L‐nuance)

Introduction Chemo-radiotherapy (CRT) is the first line treatment in patients with anal squamous cell carcinoma (ASCC). Clinical lymph node positivity (LN+) is considered an adverse prognosticator. Accurate lymph node staging impacts on treatment, such that in LN+ patients, lymphatic fields are treated with prophylactic phase I wide volume radiotherapy. Modern imaging modalities, namely magnetic resonance imaging (MRI) and PET-CT scanning increase sensitivity to detect LN+, but It is unclear whether enhanced pre-treatment staging impacts upon oncological outcome. Method From 1990 to 2014 we characterised the pattern of changes in the detection rates of LN+ in patients with ASCC through a dedicated anal cancer MDT serving a population of 3 million. We divided time periods as: (i) pre-MRI era; (ii) MRI era; and (iii) MRI + PET-CT era. In patients receiving curative CRT, we determined actuarial rates for loco-regional and inguinal relapses, and cancer-specific survival (CSS), using Kaplan-Meier curves. Imaging modalities were compared using log-rank tests, and Cox multivariate models that also conditioned for period and cohort effects. Results From 971 patients with new ASSC, 550 were treated with CRT [M, F: 207:343, median age (range): 61 (29–89)]. In the pre-MRI era (pre-2004), LN+ was identified in 18% (36/200); with the use of MRI the detection rate increased to 34% (62/185); and further increased to 48% (58/120) with the use of MRI and PET-CT in combination (post-2011) (p Conclusion MRI and PET scans improve pre-treatment staging in anal cancer although precise characterisation of the specific lymphatic fields involved needs further evaluation. Demonstration of the Will Roger’s effect challenges the prognostic value of pre-treatment nodal status in anal cancer and current treatment algorithms. This study was generously supported by the BDRF. Disclosure of interest None Declared.

PLA2G2A overexpression is associated with poor therapeutic response and inferior outcome in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy.

The aim of this study was to investigate the prognostic impact of group IIA phospholipase A2 (PLA2G2A) expression and its role in predicting the response to neoadjuvant concurrent cheomoradiotherapy (CCRT) in rectal cancer. Through analysing a public transcriptome of rectal cancers, the PLA2G2A gene was identified as a significant predictor for CCRT response. We validated the expression of PLA2G2A using immunohistochemistry in the pretreatment tumour specimens from 172 patients with rectal cancer. The results were correlated with clinicopathological features, tumour regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of PLA2G2A was associated with advanced pretreatment tumour status (P = 0.001), advanced pretreatment nodal status (P = 0.010), advanced post-treatment tumour status (P = 0.002) and lower tumour regression grade (P = 0.006). Furthermore, PLA2G2A expression was correlated negatively with gamma H2A histone family, member X (γ-H2AX) expression (P < 0.001, r = -0.580). More importantly, high expression of PLA2G2A emerged as an adverse prognostic factor for OS (P = 0.0190), DFS (P < 0.0001) and LRFS (P < 0.0001). In multivariate analysis, it remained independently prognostic for shorter DFS (P = 0.014) and LRFS (P = 0.012). High expression of PLA2G2A was associated with poor therapeutic response and worse survival in patients with rectal cancer receiving neoadjuvant CCRT, justifying PLA2G2A as an important marker to predict CCRT response and outcome.

Overexpression of REG4 confers an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy.

Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. Through data mining from published transcriptomic database, we identified Regenerating Gene Type IV (REG4) as the most significantly associated gene with resistance to CCRT. This study examined the prognostic impact of REG4 expression in patients with rectal cancer receiving neoadjuvant CCRT. REG4 immunohistochemistry was retrospectively assessed for pre-treatment biopsy specimens from 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery without initial distant metastasis. The results were correlated with the clinicopathological variables, disease-specific survival (DSS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), as well as γ-H2AX expression in post-treatment tumor samples. High expression of REG4 was associated with advanced pre-treatment nodal status (P = 0.026), advanced post-treatment tumor status (P = 0.006), advanced post-treatment nodal status (P = 0.001), advanced post-treatment tumor stage (P < 0.001), and inferior tumor regression grade (P = 0.001). Of note, high expression of REG4 emerged as an adverse prognosticator for DSS (P = 0.0004), LRFS (P = 0.0009), and MeFS (P = 0.0254). After multivariate comparisons, it remained independently prognostic for worse DSS (hazard ratio [HR] = 2.731; P = 0.025) and LRFS (HR = 2.676; P = 0.029). High expression of REG4 was also negatively associated with γ-H2AX expression (P < 0.0001, r = -0.708). High expression of REG4 is associated with poor therapeutic response, adverse outcome and an aggressive phenotype in rectal cancer patients treated with neoadjuvant CCRT, justifying REG4 is a surrogate marker to predict CCRT resistance.

Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy.

Neoadjuvant concurrent chemoradiation therapy (CCRT) is an increasingly common therapeutic strategy for rectal cancer. Clinically, it remains a major challenge to predict therapeutic response and patient outcomes after CCRT. Annexin I (ANXA1), encoded by ANXA1, is a Ca(2+)/phospholipid-binding protein that mediates actin dynamics and cellular proliferation, as well as suggesting tumor aggressiveness and predicting therapeutic response in certain malignancies. However, expression of ANXA1 has never been reported in rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of ANXA1 expression in patients with rectal cancer following neoadjuvant CCRT. We identified ANXA1 as associated with resistance to CCRT through data mining from a published transcriptomic dataset. Its immunoexpression was retrospectively assessed using H scores on pre-treatment biopsies from 172 rectal cancer patients treated with neoadjuvant CCRT followed by curative surgery. Results were correlated with clinicopathological features, therapeutic response, tumor regression grade (TRG), and metastasis-free survival (MeFS), as well as local recurrent-free survival (LRFS) and disease-specific survival (DSS). High expression of ANXA1 was associated with advanced pre-treatment tumor status (T3, T4, p = 0.022), advanced pre-treatment nodal status (N1, N2, p = 0.004), advanced post-treatment tumor status (T3, T4, p < 0.001), advanced post-treatment nodal status (N1, N2, p = 0.001) and inferior TRG (p = 0.009). In addition, high expression of ANXA1 emerged as an adverse prognosticator for DSS (p < 0.0001), LRFS (p = 0.0001) and MeFS (p = 0.0004). Moreover, high expression of ANXA1 also remained independently prognostic of worse DSS (hazard ratio [HR] = 3.998; p = 0.007), LRFS (HR = 3.206; p = 0.028) and MeFS (HR = 3.075; p = 0.017). This study concludes that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT.

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

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

High Negative Predictive Value of FDG-PET/CT in Assessment of Tumor Response Following Radiation Treatment for Head-and-Neck Carcinomas: Long-term update

High Negative Predictive Value of FDG-PET/CT in Assessment of Tumor Response Following Radiation Treatment for Head-and-Neck Carcinomas: Long-term update

Prognostic value of Smac expression in rectal cancer patients treated with neoadjuvant therapy

The objective was to evaluate expression of second mitochondria-derived activator of caspase (Smac) expression before and after treatment in patients treated with preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer and to correlate the clinicopathological characteristics and level of Smac expression with pathologic response and outcome. Expression of biomarker was evaluated by immunohistochemistry in tumor samples from 98 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy plus concurrent chemotherapy. All patients received a standardized total mesorectal excision procedure after a long interval of 4-6 weeks. For Smac, patients with a good response to neoadjuvant CRT tended to have higher pre-therapy levels (P = 0.007). The level of Smac expression decreased after neoadjuvant therapy (P = 0.016). High expression of Smac before CRT, and high Dworak's tumor regression grade (TRG) were significantly associated with improved 5-year disease-free survival (P < 0.05). Pretreatment nodal status also was significantly associated with 5-year disease-free survival and 5-year local relapse-free survival (P < 0.05). Multivariate analysis confirmed that the pretreatment expression of Smac and Lymph nodal status were independent prognostic factors. Our study suggests that high expression of Smac before neoadjuvant CRT could predict good outcome in locally advanced rectal cancer patients.