Worse Distant Recurrence-free Survival Research Articles

Abstract C042: TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer

Abstract Background: Endocrine therapy is the standard of care for ER+/HER- breast cancer; but some patients need additional adjuvant chemotherapy to counter the risk of metastasis. While chemotherapy can reduce metastasis, some patients still relapse. Tumor cells metastasize through TMEM (Tumor Microenvironment of Metastasis) Doorways, consisting of a Mena-expressing tumor cell, a macrophage, and a vascular endothelial cell, all in direct contact. High TMEM doorway scores correlate with increased dissemination in mice and metastatic outcomes in ER+/HER2- breast cancer patients. Recent studies show that adjuvant chemotherapy may activate growth in disseminated tumor cells (DTCs). Thus, we hypothesized that patients with high TMEM doorway scores who receive endocrine plus chemotherapy will have worse distant recurrence-free survival (DRFS) than those with lower TMEM Doorway scores, or those who receive endocrine therapy alone. Methods: We conducted a retrospective study on 119 patients with stage I-III, ER+/HER2- unilateral invasive ductal breast carcinoma (age≥18) from 2005- 2018. All underwent surgery and received adjuvant endocrine treatment alone or with chemotherapy. We excluded patients who had metastatic disease at diagnosis, received neoadjuvant chemotherapy, or lacked treatment data. Formalin-fixed paraffin-embedded primary tumor tissues were stained for TMEM doorways. A pathologist categorized the TMEM doorway scores as low, intermediate, or high. Kaplan-Meier curves and Cox-proportional hazard models compared DRFS based on treatment type and TMEM doorway scores. Multivariate logistic regression analyzed the association between macrophage density or TMEM Doorway Score and metastatic outcomes, adjusting for tumor size, grade, and node positivity. Results: Of all patients, 72 received endocrine plus chemotherapy and 47 endocrine therapy alone. In the chemotherapy group, 34 (47.2%) developed metastases, while 38 (52.8%) remained disease-free. In the endocrine alone group, 37 (78.7%) remained disease-free and 9 (19.1%) developed metastases. There was no significant difference in TMEM Doorway Scores between groups (p=0.07). In patients who received endocrine plus chemotherapy, a high TMEM Doorway Score was associated with greater odds of metastasis (OR 6.8; 95% CI 1.35–33.76; p=0.02), controlling for tumor size, grade, and node positivity but not when endocrine therapy was used alone (p=0.817). Patients with high TMEM Doorway Scores had worse DRFS in the endocrine plus chemotherapy group (HR 2.61; 95% CI 1.08–6.27; p=0.03), but not in the endocrine therapy alone group (p=0.77) adjusted similarly. Conclusions: This study highlights potential clinical utility of TMEM Doorway Scores as a predictive biomarker for chemotherapy selection in ER+/HER2- breast cancer patients. Larger trials are needed to confirm these findings and with confirmation, physicians considering giving chemotherapy to ER+/HER2- breast cancer patients might consider pre-treatment stratification using TMEM Doorway Scores to mitigate the risk of chemotherapy-induced metastasis. Citation Format: Priyanka Parmar, Andrew Miller, Burcu Karadal-Ferrena, Suryansh Shukla, Cien Huang, Mindy Ginsberg, Chedva Rosenbaum, Malka Felder, Chenxin Zhang, John S. Condeelis, Xiaonan Xue, Thomas E. Rohan, Joseph A. Sparano, Jesus D. Anampa, David Entenberg, Maja H. Oktay. TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C042.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer

There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Racial disparity in tumor microenvironment and distant recurrence in residual breast cancer after neoadjuvant chemotherapy

Black, compared to white, women with residual estrogen receptor-positive (ER+) breast cancer after neoadjuvant chemotherapy (NAC) have worse distant recurrence-free survival (DRFS). Such racial disparity may be due to difference in density of portals for systemic cancer cell dissemination, called TMEM doorways, and pro-metastatic tumor microenvironment (TME). Here, we evaluate residual cancer specimens after NAC from 96 Black and 87 white women. TMEM doorways are visualized by triple immunohistochemistry, and cancer stem cells by immunofluorescence for SOX9. The correlation between TMEM doorway score and pro-metastatic TME parameters with DRFS is examined using log-rank and multivariate Cox regression. Black, compared to white, patients are more likely to develop distant recurrence (49% vs 34.5%, p = 0.07), receive mastectomy (69.8% vs 54%, p = 0.04), and have higher grade tumors (p = 0.002). Tumors from Black patients have higher TMEM doorway and macrophages density overall (p = 0.002; p = 0.002, respectively) and in the ER+/HER2- (p = 0.02; p = 0.02, respectively), but not in the triple negative disease. Furthermore, high TMEM doorway score is associated with worse DRFS. TMEM doorway score is an independent prognostic factor in the entire study population (HR, 2.02; 95%CI, 1.18–3.46; p = 0.01), with a strong trend in ER+/HER2- disease (HR, 2.38; 95%CI, 0.96–5.95; p = 0.06). SOX9 expression is not associated with racial disparity in TME or outcome. In conclusion, higher TMEM doorway density in residual breast cancer after NAC is associated with higher distant recurrence risk, and Black patients are associated with higher TMEM doorway density, suggesting that TMEM doorway density may contribute to racial disparities in breast cancer.

Abstract GS1-02: Racial disparity in tumor microenvironment and outcomes in residual breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Black, compared to White women with localized breast cancer have higher mortality and worse distant recurrence free survival (DRFS). This has been attributed to social determinants of health and higher prevalence of triple negative breast cancer (TNBC) in Black compared to White women. Recent studies indicate that racial disparity in outcome is present in patients with estrogen receptor-positive (ER+), but not ER- disease, in particular in patients with residual disease after neoadjuvant chemotherapy (NAC). It has been shown that in some patients NAC may induce pro-metastatic changes in tumor microenvironment, such as increased density of tumor associated macrophages and portals for cancer cell dissemination to distant sites called TMEM doorways (TMEM score). TMEM score correlates with metastasis in patients with ER+/HER2- breast cancer. We hypothesized that racial disparity in DRFS in patients with residual ER+/HER2- disease is due to enhanced pro-metastatic components (macrophage and TMEM doorway density) in the tumor microenvironment post-chemotherapy in Black compared to White women. Methods: We performed a retrospective, multi-institutional study of TMEM score and macrophage density in the residual disease after NAC from 196 patients diagnosed with unilateral invasive ductal cancer of breast between 2004 and 2014. 99 patients self-identified as Black and 97 as White. TMEM doorways were visualized by triple immunohistochemistry for macrophages (CD68), tumor cells (panMena), and endothelial cells (CD31). The evaluation of TMEM score and macrophage density was done using automated image analysis. Tumor characteristics and patient survival were compared between Black and White patients. The relationship between TMEM score, macrophage density and DRFS was examined by log-rank test and multivariate Cox regression model. The covariates in Cox model included TMEM score, age (continuous), race (Black vs White), surgery type (mastectomy vs lumpectomy), tumor stage (T3 vs T1; T2 vs T1), lymph node status (positive vs negative), and tumor subtype (triple negative [TN] vs ER+/HER2-; other vs ER+/HER2-). Results: Black compared to White women were more likely to develop distant recurrence (49.5% vs 34%, p=0.04), receive mastectomy (69.7% vs 51.5%, p=0.014), and have higher grade (p=0.001). Tumors from Black patients had more macrophages and a higher TMEM score in the entire cohort (p=0.004; p=0.001 respectively) and in the ER+/HER2- subset (p=0.008; p=0.008 respectively), but not in the TNBC subset. High TMEM score was associated with worse DRFS in all patients (p=0.004) and in the ER+/HER2- (p=0.03), but not in TNBC. In multivariate Cox model, TMEM score was an independent prognostic factor in the entire cohort (HR, 1.92; 95%CI, 1.15-3.22; p=0.01) and trended towards significance in ER+/HER2- disease (HR, 2.13; 95%CI, 0.96-4.71; p=0.06). TN, compared to ER+/HER2- cancers had higher TMEM score (p=0.01), and macrophage density (p=0.001). Conclusion: Racial disparity in outcome in patients with localized breast cancer may be due to a more pronounced pro-metastatic response to chemotherapy in Black, compared to White patients with ER+/HER2- disease. Thus, higher prevalence of TNBC in Black patients may not be the controlling factor in racial disparity. Citation Format: Burcu Karadal, Gina Kim, Ved Sharma, Jessica Pastoriza, Isabelle Oktay, Yu Lin, Xianjun Ye, Jiyue Qin, Esther Cheng, Nurfiza Ladak, John Condeelis, Esther Adler, Paula Ginter, Timothy D’Alfonso, Xiaonan Xue, David Enterberg, Joseph Sparano, Maja Oktay. Racial disparity in tumor microenvironment and outcomes in residual breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-02.

Risk Factors Associated With Recurrence and Death in Patients With Tall Cell Papillary Thyroid Cancer

Tall cell morphology (TCM) is a rare and aggressive variant of papillary thyroid carcinoma (PTC) that has been associated with poor outcomes; however, the risk factors for worse survival are not well characterized. To identify prognostic factors associated with cancer recurrence and death in patients with PTC-TCM. All patients treated for PTC-TCM at a single tertiary-level academic health care institution from January 1, 1997, through July 31, 2018, were included. Tall cell variant (TCV) was defined as PTC with TCM of 30% or more; and tall cell features (TCF) was defined as PTC with TCM of less than 30%. Patients with other coexisting histologic findings and/or nonsurgical management were excluded. Clinicopathologic features associated with worse outcomes were identified using Kaplan-Meier and Cox proportional-hazards model. Data were analyzed from March 1, 2018, to August 15, 2018. Locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and overall survival (OS) after surgery. A total of 365 patients (median [range] age, 51.8 [15.9-91.6] years; 242 [66.3%] female) with PTC-TCM (TCV, 32%; TCF, 68%) were evaluable. Total thyroidectomy was performed in 336 (92%) patients; 19 (5.2%) received radiotherapy; and 15 (4.1%) received radioactive iodine. Clinical features were pT3 or T4, 65%; node-positive, 53%; and positive surgical margins, 24%. LRRFS at 1-, 3-, 5-, and 10-year was 95%, 87%, 82%, and 73%, respectively. On multivariable analysis, male sex and age were not independent predictors of inferior 5-year LRRFS, whereas positive surgical margins (HR, 3.5; 95% CI, 2.0-6.3), positive lymph nodes (HR, 2.8; 95% CI, 1.4-5.8), and primary tumor size of 3 cm or more (HR, 3.3; 95% CI, 1.4-7.8) were strongly associated with worse LRRFS. Age 55 years or older (HR, 3.2; 95% CI, 1.5-7.0), male sex (HR 4.5; 95% CI, 2.1-10.0), positive surgical margins (HR, 2.7; 95% CI, 1.2-6.0), nodal positivity (HR, 3.1; 95% CI, 1.3-7.7), tumor diameter of 1.5 cm or more (HR, 20.6; 95% CI, 2.8-152.1), and TCV vs TCF (HR, 3.1; 95% CI, 1.5-6.7) were associated with worse DRFS. Male sex (HR, 3.1; 95% 1.4-6.8) and tumor diameter of 1.5 cm or more (HR, 2.8; 95% CI, 1.0-7.4) were associated with worse OS. A findings-based nomogram was constructed to predict 10-year LRRFS (C index, 0.8). This retrospective cohort study found that in patients with PTC-TCM, positive surgical margins, node positive disease, and tumor size of 3 cm or more were risk factors for worse LRRFS. Intensified locoregional therapy, including adjuvant radiation, may be considered for treating these patients.

Abstract P2-08-19: Prognostic significance of Hounsfield unit of tumor in patients with breast cancer

Abstract Background: Angiogenesis is known to be related with poor survival. However, previous clinical studies with anti-angiogenetic agents failed to show a clear overall survival benefit and one of the reasons was lack of appropriate biomarker. Therefore, the identification of biomarkers that may identify patients who might benefit from target agents against angiogenesis may be the key to determining which patients would benefit from these therapies. This study aimed to find biomarker which can reflect angiogenesis of the tumor and serve as a prognostic factor. Methods: Patients with stage I-III breast cancer who completed planned treatment were included. Data were retrospectively collected from the Wonju Severance Christian Hospital database of Yonsei University and the Korean National Cancer Center database. Results: 534 patients were enrolled in this study. Patients were divided into two groups according to the cut-off value (31.4) of proportional ratio between maximum Hounsfield unit (HU) of tumor and maximum HU of aortic arch (maximum tumor - aorta ratio, TAR), and analyzed with clinico-pathological factors. Tumor stage was significantly related with higher TAR [TI vs T2-T3, 29.5% vs 50.6%, p < 0.001]. While estrogen receptor positivity was not related with TAR. Human Epiermal growth factor Rceptor-2 showed higher frequency in high TAR [high TAR vs. low TAR, 17.6% vs. 28.1%, p = 0.006]. Kaplan-Meier curve with log rank test showed significantly worse distant recurrence free survival in high TAR group (p < 0.001) Cox proportional hazard model indicated that age, ER negativity, and high TAR were significant risk factors for distant relapse. Conclusion: TAR measured by CT performed before treatment can be used as a prognostic factor for overall and distant relapse-free survival in patients with breast cancer. We believe TAR could be a potential biomarker to select patients who will benefit from target agents based on anti-angiogenesis. Key words: breast neoplasms, computed tomography, Hounsfield unit, survival analysis. Table 1.Baseline characteristics of patientsCharacteristicsNumber (n = 534) (%)Age54.4 ± 11.5HistopathologyInfiltrating ductal carcinoma498 (93.3)Infiltrating lobular carcinoma19 (3.6)Others17 (3.2)T stageT025 (4.7)T1280 (52.4)T2198 (37.1)T331 (5.8)Tumor size (cm)2.4 ± 1.8N stageN0356 (66.5)N1116 (20.6)N249 (9.2)N319 (3.6)Unknown1 (0.2)ER (+) *297 (55.6)PR (+) **274 (51.3)HER 2 (+) ***128 (24.0)ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; * Data were missing in 3 patients ** Data were missing in 2 patients *** Data were missing in 4 patients. Table 2.Relationship between TAR and clinico-histologic factorsClinico-pathologic factorsLower TAR(< 31.4 %) (n = 200)Higher TAR(≥ 31.4) (n = 334)p-valueAge56.2 ± 11.253.4 ± 11.60.007T stage (2 – 3)59 (29.5 %)169 (50.6 %)< 0.001Present lymph node metastasis62 (31.0 %)116 (34.7 %)0.395ER (+) *122 (61.3 %)175 (52.7 %)0.053PR (+) **109 (54.8 %)165 (49.5%)0.243HER – 2 (+) ***35 (17.6 %)93 (28.1 %)0.006TAR, Maximum Hounsfield unit of tumor aorta ratio; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2* Data were missing in 3 patients ** Data were missing in 2 patients *** Data were missing in 4 patients Citation Format: Kwangmin Kim, In-Jeong Cho, Hany Noh, Hyangsook Choi, Seok Hahn, Seung Taek Lim, Jong-In Lee, Airi Han. Prognostic significance of Hounsfield unit of tumor in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-19.

Abstract P1-08-36: Racial disparity in post-neoadjuvant chemotherapy residual breast tumor microenvironment

Abstract Background: Black women with residual estrogen receptor (ER)-positive breast cancer after neoadjuvant chemotherapy (NAC) have worse distant recurrence free survival (DRFS) compared to White women. Distant metastases result from motile breast cancer stem cells (BCSCs) disseminating through intravasation portals on blood vessels called tumor microenvironment of metastasis (TMEM) doorways. Each TMEM doorway is composed of an actin-regulatory protein (Mena) expressing cancer cell, a macrophage expressing high levels of receptor tyrosine kinase TIE2, and an angiopoietin-expressing endothelial cell. High TMEM doorway density predicts metastatic potential in patients with ER+/HER2- breast cancer. The function of TMEM doorways can be pharmacologically blocked using TIE2 inhibitors. We hypothesized that racial disparity in DRFS in patients with residual ER-positive disease post-NAC is due to difference in density of TMEM doorways, BCSCs, and motile cells in the residual breast tumor microenvironment (TME). Methods: We performed a retrospective, multi-institutional study of the TME in the residual disease post-NAC from 200 patients. Triple immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) tissue sections was used to visualize TMEM doorways. Immunofluorescent staining of FFPE tissue sections for SOX9 and MenaINV was used to visualize BCSCs and motile cells, respectively. The density of TMEM doorways, BCSC and motile cells was determined by automated image analysis. The relationship between the density of TMEM doorways, stem and motile cells, and DRFS was examined using Kaplan Meier log-rank test. Comparisons were made for the entire cohort, and separately for the two most prevalent molecular subtypes: ER+/HER2- and triple negative (TN). The analysis included 200 samples of residual breast cancer post-NAC: 100 from Black and 100 from White women. Results: Black compared to White women were more likely to develop distant recurrence (49% vs 34%, p=0.04), to receive mastectomy (70% vs 51%, p=0.009), and to have TN subtype (35% vs 21%, p<0.0001). Median time-to-follow-up was 70 months (range 2.8-160.7), and was similar between Black and White patients (67.7 vs 71.0 months, p=0.7). There was no racial disparity in DRFS in the overall cohort or TN subtype, but there was a trend towards worse survival in Black women in the ER+/HER2- subtype (Log-Rank p=0.09). TMEM doorway density was higher in Black women in the entire cohort (p=0.001) and in the ER+/HER2- subtype (p=0.01), while there was no difference in the TN subtype. TMEM doorway density was prognostic for DRFS in all patients (Log-Rank p=0.009) and the ER+/HER2- subtype (Log-Rank p=0.001), but not in the TN subtype. There was a trend towards higher BCSC density in the entire cohort (p=0.06) and the ER+/HER2- subtype (p=0.09), but there was no difference in the TN subtype. There was no racial disparity in motile cell density in the entire cohort as well as in the two subtypes. BCSC density and motile cell density were not prognostic for DRFS. Conclusion: Worse DRFS in Black, compared to White, women with ER-positive residual breast cancer post-NAC may be due to differences in TMEM doorway and BCSC density. Further studies are necessary to determine if the outcome of patients with residual disease and high TMEM doorway density post-NAC could be improved by blocking TMEM doorway function with TIE2 inhibitors. Citation Format: Gina Kim, Saeed Asiry, Isabelle Oktay, Yu Lin, Xianjun Ye, Esther Cheng, Nurfiza Ladak, John Condeelis, Esther Adler, Paula Ginter, Timothy D'Alfonso, David Entenberg, Maja Oktay. Racial disparity in post-neoadjuvant chemotherapy residual breast tumor microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-36.

The beneficial role of Asian-based RecurIndex test in the prognostic prediction in Chinese male breast cancer patients

RecurIndex, a multigene profiling assay, can predict the risk of local recurrence and distant metastasis in female breast cancer (FBC), but its role in male breast cancer (MBC) remains unclear. In this study, the clinicopathological data of 43 consecutive MBC patients undergoing surgeries between 2009 and 2018 were retrospectively analysed. Their paraffin-embedded tissue sections were examined by RecurIndex test which comprised 2 models: recurrence index for local recurrence (RI-LR) and recurrence index for distant recurrence (RI-DR). Of 43 patients, there were 26 low-risk and 17 high-risk patients assessed by RI-LR, while 17 low-risk and 26 high-risk patients by RI-DR. For RI-LR, tumor N stage showed statistically significant (P < 0.001) between low- and high-risk patients; for RI-DR, differences were pronounced in tumor grade (P = 0.033), T stage (P = 0.043) and N stage (P = 0.003). In terms of clinical outcomes, the overall survival (OS) of low- and high-risk patients stratified by RI-LR showed no statistically significant differences (P = 0.460), while high-risk patients identified by RI-DR had a significantly worse distant recurrence-free survival (DRFS) (P = 0.035), progression-free survival (PFS) (P = 0.019) and OS (P = 0.044) than low-risk patients. Overall, RI-DR can effectively predict the DRFS, PFS and OS of MBC patients and identify those at low risk of recurrence, which may serve as a potential prognostic tool for MBC.

Muscle Loss after Chemoradiotherapy as a Biomarker of Distant Failures in Locally Advanced Cervical Cancer.

This study aimed to evaluate whether computed tomography (CT)-based muscle measurement predicts distant failure in patients with locally advanced cervical cancer (LACC). Data from 278 patients with LACC who underwent chemoradiation therapy (CCRT) between 2004 and 2017 were analysed. Changes in the skeletal muscle index (SMI), skeletal muscle density, and total adipose tissue index during CCRT were calculated from CT images taken at the baseline and after CCRT. The predictive capability of CT-based muscle measurement for distant failure was evaluated using Cox proportional hazards regression, Harrell’s concordance index (C-index), and time-dependent receiver operating characteristic curves. SMI loss ≥ 5% was independently associated with worse distant recurrence-free survival (DRFS) (HR: 6.31, 95% CI: 3.18–12.53; p < 0.001). The addition of muscle change to clinical models, including International Federation of Gynaecology and Obstetrics (FIGO) stage, lymph nodes, pathology, and squamous cell carcinoma-antigen, achieved higher C-indices (0.824 vs. 0.756; p < 0.001). Models including muscle change had superior C-indices than those including weight change (0.824 vs. 0.758; p < 0.001). The area under the curve for predicting 3-year DRFS was the highest for the muscle-loss model (0.802, muscle-loss model; 0.635, clinical model; and 0.646, weight-loss model). Our study demonstrated that muscle loss after CCRT was independently associated with worse DRFS and that integrating muscle loss into models including classical prognostic factors improved the prediction of distant failure.

Abstract P4-12-19: Impact of delaying initiation of RT following definitive surgery or following adjuvant chemotherapy on survival outcomes in breast cancer patients

Abstract Purpose: For breast cancer (BC) patients treated with adjuvant chemotherapy (CT), the optimal time to initiation of adjuvant radiotherapy (TTR) from definitive surgery is still controversial especially with modern systemic therapy, while the impact of TTR from completion of CT has not been reported to date. The current study aims to evaluate the impact of TTR from surgery and from completion of CT on survival outcomes in non-metastatic BC patients according to BC subtype. Methods and Materials: BC patients who were treated with definitive surgery followed by adjuvant CT and received adjuvant radiotherapy (RT) from January 2009 through December 2015 in a single institution were included in this study. Patients receiving neoadjuvant therapy were not enrolled. According to our clinical practice, if adjuvant treatments were well organized, RT could be initiated within 180 days following surgery and with completion of most up-to-date CT regimens. As a result, patients were categorized into two groups according to TTR from surgery as ≤180 and &amp;gt;180 days and according to TTR from CT as ≤12 and &amp;gt;12 weeks. The survival curves were estimated by the Kaplan-Meier method and compared by log-rank test. The independent effect of TTR from surgery and TTR from CT were separately tested using a Cox proportional hazards model for multivariate analysis after adjusting for these variables that were statistically significant on univariate analysis. Results: In total, 989 patients were enrolled. The number of patients with HR-positive, triple-negative (TN) and HER2-positive BC was 590, 196, and 203, respectively. The median follow-up was 43 (range: 4 to 117) months. The median TTR from surgery was 180 (range: 24 to 117) days and from completion of CT was 29 (range: 7 to 247) days. The 5-year recurrence-free survival (RFS), locoregional RFS (LRRFS), distant RFS (DRFS) and overall survival (OS) were 88.0%, 96.9%, 89.3% and 93.5%, respectively. The 5-year OS was 94.7%, 88.3% and 95.2% in patients with HR-positive, TN and HER-2 positive BC, respectively (P&amp;lt;0.01). Initiation of RT &amp;gt;12 weeks after completion of CT was associated with worse OS (5-year 94.0% vs 85.1%, p=0.006), &amp;gt;180 days after surgery was associated with worse DRFS (5-y 91.7% vs 86.9%, p=0.004) and worse RFS (5-y 90.7% vs 85.4%, p=0.003). In the multivariable analysis, TTR after completion of CT remained independent prognostic factor for OS (hazard ratio [HR], 2.81; 95% CI, 1.17 to 6.74; P=0.02) and TTR &amp;gt;180 days after surgery was also significantly associated with worse DRFS (HR, 1.79; 95% CI, 1.09 to 2.93; P=0.02) and RFS (HR, 1.71; 95% CI, 1.09 to 2.69; P=0.02). In patients with HR-positive BC, TTR &amp;gt;12 weeks after completion of CT was significantly associated with worse OS, while &amp;gt;180 days after surgery was with adverse DRFS (5-y 91.0% vs. 83.8%, p=0.004), RFS (5-y 89.8% vs. 82.8%, p=0.003), and OS (5-y96.6% vs 91.8%, p=0.026). However, these associations between TTRs and survival outcomes were not found in patients with HER2-positive BC or TNBC. Conclusion: In BC patients indicated for CT, delaying initiation of RT after definitive surgery or after completion of CT both adversely impact on survival outcomes. Efforts should be made to minimize delays in the initiation of RT in the above two TTR settings. Citation Format: Lu Cao, Jia-Yi Chen. Impact of delaying initiation of RT following definitive surgery or following adjuvant chemotherapy on survival outcomes in breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-19.

Abstract P2-07-03: Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden

Abstract Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p&amp;lt;0.00001), and more effective at predicting pCR/RCB-I than predicting pCR alone (AUC: 0.72 vs. 0.65). Larger pre-surgical FTV remains associated with worse DRFS adjusting for subtype (Wald p &amp;lt;0.00001). The RCB index is also significantly associated with DRFS adjusting for subtype (Wald p&amp;lt;0.00001). Adding FTV to a model containing RCB and subtype further improves association with DRFS (LR p=0.0007). RCB-I patients have excellent DRFS (94% at 3 years compared to 95% in the pCR group). Efforts are underway to identify an optimal threshold for dichotomizing pre-surgical FTV and FTV change measures for use in combination with pCR/RCB-I class to generate integrated RCB (iRCB) groups as a composite predictor of DRFS. Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [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 P2-07-03.

Abstract A92: Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy

Abstract Background: Compared to white women, black women with operable breast cancer treated with primary surgical therapy and adjuvant or neoadjuvant systemic chemotherapy have higher recurrence rates and breast cancer mortality. Large randomized prospective studies did not find significant differences in distant-recurrence-free survival (DRFS) and overall survival (OS) between breast cancer patients treated in the adjuvant and neoadjuvant setting for predominantly white populations. However, data indicating that neoadjuvant treatment is equivalent to adjuvant treatment for black breast cancer patients are missing. Here, we first examined racial differences in DRFS among breast cancer patients treated in the neoadjuvant setting at Einstein-Montefiore Center for Cancer Care (EMCCC) in the Bronx, and then investigated if DRFS in black patients treated in the neoadjuvant setting is comparable to DRFS in the adjuvant setting. Methods: We evaluated DRFS in 241 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant chemotherapy between January 2000 and December 2016. In addition, we evaluated DRFS in 474 white and 701 black patients with localized or regionally advanced breast cancer treated with systemic adjuvant (N=432 [whites], 596 [blacks]) or neoadjuvant (N=42 [whites], 105 [blacks]) chemotherapy. Using multivariate Cox proportional hazard models, we generated hazard ratios (HRs) (95% confidence intervals [CI]) for risk of distant recurrence, with adjustment for age (&amp;lt;50 vs &amp;gt;/50 years), stage (I/II vs III), estrogen receptor (ER) status (+ vs -), HER2/neu overexpression (+ vs -/equivocal/unknown), triple-negative (TN) status (yes vs no), and type of systemic chemotherapy (adjuvant vs neoadjuvant). Results: Black patients treated with neoadjuvant systemic chemotherapy had significantly worse DRFS than white patients (HR=2.29; 95%CI=1.02-5.15, p=0.04). DRFS in non-black Hispanics and patients from racial backgrounds other than Hispanic or black compared to whites was not statistically different. Neoadjuvant chemotherapy was associated with worse DRFS compared to adjuvant chemotherapy in black (HR=3.72; 95%CI=4.03-5.81; p=&amp;lt;0.0001), but not in white women. Conclusion: Black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical covariates. This observation needs to be confirmed in further prospective studies, and biologic factors contributing to this finding need to be evaluated. Citation Format: Jessica M. Pastoriza, George S. Karagiannis, Xiaonan Xue, Juan Lin, John S. Condeelis, Joseph A. Sparano, Thomas E. Rohan, Maja H. Oktay. Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A92.

Abstract 67: Chemotherapy induced pro-metastatic changes in the primary breast tumors of racially diverse patients

Abstract Neoadjuvant chemotherapy (NAC) induces influx of bone marrow-derived proangiogenic Tie2hi monocytes into the primary tumor, resulting in increased density of perivascular Tie2hi macrophages (1). Perivascular Tie2hi/Vegfhi macrophages in physical contact with Mena expressing cancer cells create micro-anatomic sites of transient vascular permeability called TMEM, which mediate cancer cell intravasation and dissemination (2). Cancer cells capable of intravasation via TMEM sites express high level of MenaINV, an isoform of Mena, induced by macrophage contact, which renders tumor cells intravasation-competent (3, 4). Consequently, breast cancers from mice and patients treated with NAC have increased density of TMEM sites and show increased expression of MenaINV (1) Moreover, in PyMT mouse mammary carcinoma and patient derived xenografts, NAC increases the number of circulating tumor cells and lung metastasis (1). The Tie2-inhibitor rebastinib, which inhibits TMEM function, can reverse chemotherapy-induced increases in the number of CTCs and lung metastasis in mouse mammary carcinoma (1, 5). Although NAC induces pro-metastatic changes in breast cancer microenvironment, large randomized prospective studies did not find significant differences in distant-recurrence free survival (DRFS) and overall survival (OS) between breast cancer patients treated with adjuvant and neoadjuvant chemotherapy in predominantly white populations. Since the breast cancer microenvironment in black women has higher microvascular density and density of Tie2hi macrophages, suggesting that black women may be more prone to develop TMEM-associated pro-metastatic changes in response to NAC, we questioned if there is a difference in DRFS in black women treated with NAC compared to AC. We evaluated DRFS in 1,211 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant or adjuvant chemotherapy between January 2000 and December 2016 and found that black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical covariates in multivariate analysis. The biologic factors contributing to this finding, in particular TMEM-mediated pro-metastatic changes have been evaluated and will be discussed. 1. Karagiannis et al, Sci Transl Med. 2017;9:397. 2. Harney et al, Cancer discovery. 2015;5:932. 3. Pignatelli J et al, Sci Rep. 2016;6:37874. 4. Pignatelli J et al, Sci Signal. 2014;7:353. 5. Harney et al, Mol Cancer Ther. 2017;16:2486. Citation Format: George S. Karagiannis, Jessica M. Pastoriza, Sonali Lanjawar, Yarong Wang, David Entenberg, Esther Cheng, Timothy M. Dalfonso, Joan G. Jones, Jesus Anampa, Thomas E. Rohan, Joseph A. Sparano, John S. Condeelis, Maja H. Oktay. Chemotherapy induced pro-metastatic changes in the primary breast tumors of racially diverse patients [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 67.

Patterns of recurrence in oral tongue cancer with perineural invasion.

Although perineural invasion (PNI) is recognized as an adverse prognostic factor in oral tongue squamous cell carcinoma (SCC), the patterns of failure are poorly defined. Patients with oral tongue SCC who received primary surgical treatment were identified. Specimens were reviewed by head and neck pathologists. Disease-specific survival (DSS) and locoregional recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS) were calculated. The PNI and PNI characteristics were analyzed as predictors of outcome. The utility of grading the extent of PNI was assessed by quantifying the number of PNI foci per slide reviewed, nerve caliber, and percent circumference involved. Patients with PNI had a decreased DSS; however, PNI was not predictive of LRFS or RRFS. Patients with PNI were more likely to develop a distant recurrence and 19.40 (confidence interval [CI] 6.70-56.14; P < .001) times more likely to develop a distant recurrence if PNI foci density was >1. The presence of PNI in oral tongue SCC predicts worse DSS, with distant recurrence as the most common pattern of failure. High PNI foci density is associated with worse DRFS.

Abstract P6-10-02: Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy

Abstract Background: Compared to white women, black women with operable breast cancer treated with primary surgical therapy and adjuvant or neoadjuvant systemic chemotherapy have higher recurrence rates and breast cancer mortality. Large randomized prospective studies did not find significant differences in distant-recurrence free survival (DRFS) and overall survival (OS) between breast cancer patients treated in the adjuvant and neoadjuvant setting for predominantly white populations. However, data indicating that neoadjuvant treatment is equivalent to adjuvant treatment for black breast cancer patients are missing. Here, we first examined racial differences in DRFS among breast cancer patients treated in the neoadjuvant setting at Einstein-Montefiore Center for Cancer Care (EMCCC) in the Bronx, and then investigated if DRFS in black patients treated in the neoadjuvant setting is comparable to DRFS in the adjuvant setting. Methods: We evaluated DRFS in 241 racially diverse patients with localized or regionally advanced breast cancer treated with neoadjuvant chemotherapy between January 2000 and December 2016. In addition, we evaluated DRFS in 474 white and 701 black patients with localized or regionally advanced breast cancer treated with systemic adjuvant (432 whites, 596 blacks) or neoadjuvant (42 whites, 105 blacks) chemotherapy. Using multivariate Cox proportional hazard models, we generated hazard ratios (HR) and 95% confidence intervals (95%CI) for risk of distant recurrence, with adjustment for age (&amp;lt;50 vs &amp;gt;/50 years), stage (I/II vs III), estrogen receptor (ER) status (+ vs -), HER2/neu overexpression (+ vs. -/equivocal/unknown), triple negative (TN) status (yes vs no), and type of systemic chemotherapy (adjuvant vs. neoadjuvant). Results: Black patients treated with neoadjuvant systemic chemotherapy had significantly worse DRFS than white patients (HR=2.29; 95%CI=1.02-5.15, p=0.04). DRFS in non-black Hispanics and patients from racial backgrounds other than Hispanic or black compared to whites was not statistically different. Neoadjuvant chemotherapy was associated with worse DRFS compared to adjuvant chemotherapy in black (HR=3.72; 95%CI=4.03-5.81; p=&amp;lt;0.0001), but not in white women. Conclusion: Black patients with localized breast cancer treated with systemic neoadjuvant chemotherapy not only have inferior DRFS compared to white patients, but also worse DRFS when compared to black patients treated with adjuvant chemotherapy, after adjustment for clinical and pathological covariates. This observation needs to be confirmed in further prospective studies and biologic factors contributing to this finding need to be evaluated. Citation Format: Pastoriza JM, Karagiannis GS, Xue X, Lin J, Condeelis JS, Sparanno JA, Rohan TE, Oktay MH. Black race is associated with worse distant relapse-free survival in breast cancer patients treated with neoadjuvant compared to adjuvant systemic chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-10-02.

Symptomatic presentation as a predictor of recurrence in gastroenteropancreatic neuroendocrine tumors: A single institution experience over 15 years.

228 Background: The prognostic implications on outcomes of symptomatic presentation of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) remains unclear. Methods: Patients who underwent curative-intent resection of nonfunctional, well-differentiated GEP NETs from 2000-2014 at a single institution were analyzed. Patients were classified as symptomatic if clinical symptoms were present at diagnosis. Primary end points were distant recurrence-free survival (DRFS) and overall survival (OS). Results: A total of 339pts were identified, of which 208pts (61%) were symptomatic at presentation. Symptomatic presentation was associated with younger age at presentation (55vs59yrs, p = 0.001), higher tumor grade (38vs21%, p = 0.027), LVI (58vs33%, p &lt; 0.001), PNI (53vs30%, p = 0.002), and advanced disease (T3/T4/N1/M1 63vs44%, p = 0.002), but not tumor size (2.6vs2.5cm, p = 0.74). Symptomatic presentation was associated with decreased DRFS but not OS. When accounting for race, tumor size, positive resection margins, presence of metastatic disease, and positive lymph nodes on multivariate analysis (MVA), symptomatic presentation remained independently associated with reduced DRFS (HR 3.51, p = 0.007). On subgroup analysis of patients only with advanced disease (T3/T4/N1/M1), symptomatic presentation was still associated with decreased 3-yr DRFS (67vs79%, p = 0.012), but not OS. On MVA, symptomatic presentation persisted as an independent factor associated with decreased DRFS in patients with advanced disease (HR 2.89, p = 0.014). Conclusions: Symptomatic presentation of GEP NETs is associated with more aggressive pathologic features and worse DRFS than incidentally diagnosed NETs irrespective of tumor size. As our armamentarium of therapeutic agents for NETs expands and improves, trials assessing the value of adjuvant therapy for advanced GEP NETs are needed, and symptomatic presentation may be considered as one inclusion criterion. Following resection, symptomatic presentation should be taken into account when planning follow-up strategies, as these patients may require closer surveillance than their incidentally diagnosed counterparts.

Prognosis following local recurrence after breast conserving treatment in young women with early breast cancer

Few studies have focussed on the prognosis of young women with local recurrence (LR) after breast-conserving therapy and the factors that can be used to predict their prognosis. We studied the outcome and related prognostic factors in 124 patients with an isolated local recurrence in the breast following breast-conserving surgery and radiotherapy for early stage breast cancer diagnosed at the age of 40 years or younger. The median follow-up of the patients after diagnosis of LR was 7.0 years. At 10 years from the date of salvage treatment, the overall survival rate was 73% (95% CI, 63-83), the distant recurrence-free survival rate was 61% (95% CI, 53-73), and the local control rate (i.e. survival without subsequent LR or local progression) was 95% (95% CI, 91-99). In the multivariate analysis, the risk of distant metastases also tended to be higher for patients with LR occurring within 5 years after BCT, as compared to patients with LR more than 5 years after BCT (Hazard ratio [HR], 1.89; p=0.09). A worse distant recurrence-free survival was also observed for patients with a LR measuring more than 2cm in diameter, compared to those with a LR of 2cm or smaller (HR, 2.88; p=0.007), and for patients with a LR causing symptoms or suspicious findings at clinical breast examination, compared to those with a LR detected by breast imaging only (HR 3.70; p=0.03). These results suggest that early detection of LR after BCT in young women can improve treatment outcome.

Abstract 81: Role of GRM1 in breast cancer

Abstract Despite epidemiologic studies suggesting a link between melanoma and breast cancer, molecular mechanisms leading to these associations have not been elucidated. Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in melanomagenesis. Its primary action occurs through activation of the MAPK signaling pathway and other pathways through intracellular calcium release. A recent study implicated GRM1 as playing a role in angiogenesis in hormone receptor negative breast cancer. However, the role of GRM1 in hormone receptor positive disease is yet to be described. Given the associations between melanoma and breast cancer, we evaluated three SNPs in GRM1 for genotype associations with breast cancer clinicopathologic variables using DNA isolated from peripheral blood of 1,096 breast cancer patients. Our study found that a SNP in GRM1 resulting in a proline to serine substitution correlates with age at diagnosis of breast cancer and reflects the receptor status of the breast cancer, e.g. for progesterone receptor positive (PR+) disease, proline carriers were diagnosed 8 years earlier than serine carriers. Genotype-specific associations with risk of developing specific molecular subtypes of breast cancer were observed, i.e. serine carriers were twice as likely to develop estrogen receptor positive (ER+) and PR+ disease. Furthermore, carrying the proline isoform also correlated with higher risk of recurrence of breast cancer and shorter time to recurrence. Immunohistochemical evaluation of breast microarrays showed that GRM1 expression is higher in breast cancers as compared to normal tissue and is higher in ER+ as compared to ER- breast cancers. This parallels higher expression observed in ER+ breast cancer cells lines in comparison to ER- lines. In vitro studies with breast cancer cell lines were also performed to evaluate the expression of GRM1 as a function of hormone exposure and cell line receptor status. Treatment of ER+ cell lines with estradiol resulted in increased GRM1, while tamoxifen decreased expression. Gene expression data on ER+ breast cancers treated with tamoxifen were reanalyzed for association between GRM1 expression and recurrence. Analysis of breast cancers treated with tamoxifen from an independent cohort demonstrated that high expressors of GRM1 have a worse distant recurrence free survival. The results of these studies implicate GRM1 in hormone receptor positive breast cancer biology. Additional knowledge regarding the interaction between GRM1 and hormone signaling could have significant implications in breast cancer risk, prevention, and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 81. doi:1538-7445.AM2012-81

Abstract 5061: Genomic and functional analysis of Myxofibrosarcoma identifies novel prognostic markers and promising therapeutic targets

Abstract Introduction: Myxofibrosarcoma (MXF), which primarily affects the limbs of older patients, has few effective systemic therapies. Little is known about the MXF genome or the genes that drive tumorigenesis. We sought to identify subgroups and to identify genes that associate with outcome and could serve as therapeutic targets. Methods: Copy number alterations (CNAs) and gene expression profiles were measured in 73 MXF, 11 normal muscle, and 22 normal fat samples using Agilent 1M CGH and Affymetrix U133A arrays. Profiles were analyzed by unsupervised clustering and correlated with disease-specific survival (DSS) and distant recurrence-free survival (DRFS). Associations with disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed for the 68 patients with primary disease; this cohort included 21 patients who had distant recurrence and 15 who died of disease during follow-up (mean, 2.7 years). [ss1] Genes of interest were assayed using shRNA knockdown (for ITGA10) or serum ELISA levels (for HGF). Results: MXF samples had highly complex CNAs, some spanning entire chromosome arms. Unsupervised clustering based on CGH divided samples into 4 main groups driven by a loss at 1q and a gain at 5p. Unsupervised clustering based on U133A profiles divided samples into 3 main groups, 2 of which had a 3-year DSS of 85% while the third had a DSS of 31% (p&amp;lt;0.02). This third group was defined in part by high expression of integrin alpha-10 (ITGA10) and hepatocyte growth factor (HGF). Expression of ITGA10 was associated with worse DRFS (HR=2.7, p=0.03), and particularly strongly associated with worse DSS (HR=8.2, p=0.006). HGF expression was also associated with worse outcomes for both DRFS (HR=3.2, p=0.01) and DSS (HR=3.5, p=0.01). Knockdown of ITGA10 inhibited proliferation and induced apoptosis in an MXF cell line, but not in a normal fat cell line. Patients with high expression of both HGF and its receptor MET had a 3-year DRFS of 25%, vs approximately 60% for those with low expression of one of these genes and 85% for those with low expression of both genes (p=0.0016). Serum HGF was elevated in preoperative patients with MXF (n=38) compared to healthy volunteers (n=8): mean ± SD 1626 pg/mL ± 725 vs. 771 ± 110 (p=0.002). Patients with low serum HGF (≤mean +3 SD of normal [1101 pg/mL], n=10) tended to have better DSS (100% vs. 64%, p=0.14) and better DRFS (83% vs. 55%, p=0.08). Conclusions: MXF is genomically complex and diverse, but gene expression profiles cluster patients into groups associated with outcome. Levels of ITGA10, HGF and MET associate with outcome, and ITGA10 overexpression in a MXF cell line contributes to cell proliferation and survival. All three of these genes may be useful as therapeutic targets. Preoperative serum HGF levels may be a useful prognostic indicator in patients with MXF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5061. doi:1538-7445.AM2012-5061

P2-12-14: Prognostic Value of HER2 Positivity and Negative Hormonal Status in Patients with Small Tumor (&amp;lt;1cm) and Node-Negative Breast Cancer.

Abstract Introduction. Human epidermal growth factor receptor 2 (HER2) amplification has become the prototype biomarker to develop tailored biological treatment. Many studies suggested that HER2 positivity is an independent predictor of disease recurrence and breast cancer mortality. Trastuzumab has been introduced into clinical practice for high-risk HER2−positive patients who have completed the standard adjuvant treatment. However, small (&amp;lt;1cm), node-negative tumors remain a subgroup of HER2−positive patients who are currently ineligible for trastuzumab treatment, as clinically they have been deemed to have no requirement for standard adjuvant chemotherapy. The aim of our analysis was to evaluate the prognostic factors of local and distant recurrence in patients diagnosed with T1a-b, node-negative, HER-2 positive breast cancer. Materials and methods. A total of 704 patients were diagnosed at Florence University between November 1999 and December 2008 with node-negative, invasive BC that were 1 cm or smaller. Patients with ductal carcinoma in situ, with recurrent BC at presentation and patients that received adjuvant chemotherapy were excluded from analysis. Results. Mean follow-up was 4.9 years (0.5−10.8 years); we recorded a total of 19 recurrences, including 10 distant recurrences. Mean time to local relapse occurrence was 3.8 years (0.4−7.3 years); mean time to distant metastases diagnosis was 4.4 years (1.4−7.6 years). Among all patients, the recurrence-free survival (RFS) was 93.7%. The only parameter that emerged as significant predictor of events is the age (p=0.02). The distant recurrence-free survival (DRFS) rate was 96.5%. Patients who had HER2−positive BC had worse DRFS than patients who had HER2−negative BC (92.0% v 96.9%; p=0.045). In addition to HER2, also HR status was significantly associated with DRFS (p=0.026). Patients who had HR negative status had worse DRFS than patients who had HR positive status (91.4% v 97.4%; p=0.045). Conclusions. Patients with T1a-b, node-negative, breast cancer have a low risk of distant and local recurrence. Women with HER2−positive and negative hormonal status have a significant risk of distant recurrence and should be considered for anti-HER2 adjuvant therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-14.