PR-negative Status Research Articles

Characterization of estrogen receptor-low-positive breast cancer.

The biology of breast cancer with a low expression level (1-10%) of estrogen receptor (ER) remains a matter of confusion. The recent American Society of Oncology/College of American Pathologist Guidelines have recommended reporting such tumors as a new "ER-low-positive" category with a recommended comment to emphasize the possible overall benefit of endocrine therapies in these patients. The aim of the study was to analyze the clinicopathologic features and clinical outcomes of ER-low-positive breast cancers. We characterized the clinicopathologic features and survival outcomes of ER-low-positive breast cancers in our 4179 patients diagnosed from 1998 to 2018. The ER-positive, ER-low-positive, and ER-negative cases in our cohort were 2982 (71.4%), 97 (2.3%), and 1100 (26.3%), respectively. ER-low-positive tumors showed similar clinicopathologic characteristics yet significantly superior prognosis when compared to ER-negative tumors, while demonstrated largely overlapping survival outcomes with ER-positive tumors in the entire cohort. In the subcohort of tumors with a PR-positive phenotype, the prognosis of ER-low-positive tumors was intermediate between that of the ER-positive and ER-negative groups. ER-low-positive/PR-positive tumors had a significantly worse prognosis than ER-positive tumors, and a trend toward favorable survival outcomes when compared to ER-negative tumors, although no significant difference was identified for the latter. In contrast, the ER-positive and ER-low-positive groups showed similar survival outcomes in the subset of tumors with a PR-negative status, both being significantly better than ER-negative tumors. PR status as a surrogate marker of functional ER signaling provides critical information in this regard. These findings suggest that while ER-low-positive tumors are themselves heterogeneous, they often respond to endocrine treatment. Analysis of molecular signatures and standardization of therapeutic strategies are important to understand the biology of ER-low-positive tumors and to enable optimal treatment in the pursuit of individualized medicine.

Effects of clinicopathological factors on prognosis of young patients with resected breast cancer.

This study aims to analyze the relationship between clinicopathological characteristics and survival in young patients (≤35 years old) with resected breast cancer.A total of 173 cases were included in this study. The clinicopathological factors potentially associated with prognosis were evaluated. Furthermore, we categorized patients into different groups to evaluate the prognosis according to hormone receptor status or important risk factors.Younger age (≤30 years) was an independent predictor for poor disease-free survival (DFS) and overall survival (OS). Besides, PR negative status, tumor grade, and advanced lymph nodes postsurgery were independent prognostic factors of DFS, while PR negative status and advanced lymph nodes postsurgery were independent prognostic factors of OS. For hormone receptor-positive patients, people with ER+ or PR+ and HER2−/+ showed poorer prognosis than the other 2 levels. Risk factor grouping based on the ER, PR, HER2, Ki-67 status, tumor grade, and lymph nodes postsurgery showed that patients in highest score group received the poorest prognosis. Grading system based on the hormone status or the risk factor grouping may offer a useful approach to assess which subgroups of young breast cancer present poorer prognosis.

Clinical significance of serum 25 hydroxyvitamin D in breast cancer: An Indian scenario

Recent evidences suggest a protective mechanism of vitamin D signaling against breast cancer by the autocrine/paracrine manner and may modestly reduce the risk of breast cancer. Despite lots of sunshine, vitamin D deficiency is widespread in India. Moreover, there are limited studies from Indian population regarding circulatory 25(OH) D and breast cancer risk. Thus, the aim of the present study is to investigate circulatory 25(OH) D in relation to breast cancer risk and its association with various clinico-pathological parameters from Indian population. Total 297 subjects, comprising of 157 controls and 140 breast cancer patients were enrolled for the study. Circulatory 25(OH) D was analyzed by HPLC. Statistical analysis was carried out by SPSS software version 15. Further, subjects were categorized into severe, moderate, mild vitamin D deficiency and sufficiency. The prevalence of severe and moderate 25(OH) D deficiency was higher in breast cancer patients as compared to controls. Mean values of 25(OH) D were lower in breast cancer patients as compared to controls in mild, moderate and severe deficient groups (p = 0.07, p = 0.003 and p = 0.001). Moreover, 25(OH) D was significantly lower in postmenopausal breast cancer patients as compared to premenopausal breast cancer patients, particularly in severe deficient group. The levels of 25(OH) D were lower in ER and PR negative receptor status as compared to the positive receptor in severe deficient category (p = 0.06 and p = 0.09 respectively). Whereas, the mean values of 25(OH) D were lower in HER 2 negative receptor status as compared to positive receptor status in the moderate deficient category (p = 0.09). Further, severe deficient group showed significantly lower levels of 25(OH) Din TNBC as compared to luminal A subtype (p = 0.01). Thus, Results indicate that 25(OH) D deficiency might be associated with increased risk of breast cancer. Moreover, severe 25(OH) D deficiency is associated with aggressive behavior of breast cancer.

Pathologic complete response rate according to HER2 detection methods in HER2-positive breast cancer treated with neoadjuvant systemic therapy.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are known to have significant clinical and pathological response to neoadjuvant systemic therapy (NST). The aim of this study was to identify factors associated with pathological complete response (pCR), defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is ypN0), among patients with HER2-positive breast cancer and to compare pCR rates between breast cancers with HER2 protein overexpression by immunohistochemistry (IHC) versus HER2 gene amplification by fluorescence in situ hybridization (FISH) in the absence of protein overexpression by IHC. We conducted a retrospective review of HER2-positive breast cancer patients treated with NST and surgery at Memorial Sloan Kettering Cancer Center between January 2013 and May 2018. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were assessed according to the 2018 ASCO/CAP guidelines. During the study period, 560 patients were identified. Of 531 patients with IHC results available, 455 patients had HER2 IHC 3+, and 76 had IHC < 3+ but HER2 amplification detected by FISH. The overall pCR rate was 59% (330/560). The pCR rate among patients with HER2 protein overexpression (IHC 3+) was 67%, compared to 17% among patients with HER2 amplification by FISH (IHC < 3+). On univariate and multivariate analyses, HER2 protein overexpression by IHC (IHC 3+) was a significant predictor of pCR, along with grade 3 histology, PR-negative status, and dual anti-HER2 therapy. Although both HER2 IHC and FISH are standard HER2 testing methods in breast cancer, achievement of pCR is associated with HER2 IHC expression level, among other factors.

Abstract PD8-02: Residual axillary involvement in early breast cancer in patients with positive sentinel nodes after neoadjuvant chemotherapy (NACT)

Abstract Background:The association between pathological complete remission (pCR) in the breast and clinical/pathological parameters is well established, whereas the role of these parameters in the prediction of residual axillary involvement after NACT is unclear. The goal is to identify a subset of patients who do not need axillary treatment. We used data from Arm B of the SENTINA trial to analyze this association. Methods:Patients from arm B of the SENTINA trial with clinically and sonographically unsuspicious axillary nodes but with histologically proven involvement of SLNs prior to NACT were analyzed. All patients had SLNB and axillary dissection after NACT. Univariate analyses were performed to evaluate the association between clinical/pathological parameters and axillary involvement after NACT. Results:Arm B of the SENTINA study contained 360 patients, 318 of which were evaluable with respect to the above parameters. After NACT 71/318 (22.3%) patients had involved SLNs or non-SLNs; 71/318 (22.3%) had a pCR in the breast. We observed a significant association between pCR in the breast and negative ER status, negative PR status, positive HER2 status, triple negative (TN) status, tumor size before and after NACT, multifocality, lobular morphology and axillary involvement after NACT. Regarding residual axillary burden only the associations with lobular morphology, extracapsular invasion, multifocality, positive HER2 status and pCR in the breast were statistically significant. Conclusion:Our analysis demonstrates that patients enrolled in the SENTINA trial with clinically and sonographically unsuspicious axillary nodes but proven histological involvement of SLNs prior to NACT have positive axillary nodes in 22.3 % after NACT. This rate is confirming similar results from other groups. Although we found statistically significant associations between pCR in the breast and clinical/pathological parameters, only the association between lobular type, extracapsular invasion, positive HER2 status and pCR in the breast and residual axillary involvement after NACT were statistically significant. We cannot clearly identify a subset of patients for whom axillary treatment after NACT could be safely omitted if SLNs were positive. Our data are well in line with recently presented data demonstrating that the association between pCR in the breast and free axillary nodes after NACT is particularly strong in patients with TN and HER2 positive tumors. This question will be addressed in future trials currently under development. Citation Format: Kolberg H-C, Liedtke C, Bauerfeind I, Fehm T, Fleige B, Hauschild M, Helms G, Lebeau A, Schmatloch S, Schrenk P, Schwentner L, Stäbler A, Loibl S, Untch M, Kühn T. Residual axillary involvement in early breast cancer in patients with positive sentinel nodes after neoadjuvant chemotherapy (NACT) [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 PD8-02.

Abstract P2-08-02: Interaction of PIK3CA mutation subclasses with response to preoperative treatment with the PI3K inhibitor pictilisib in patients with estrogen receptor-positive breast cancer

Abstract Background: Although preclinical data suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance, results from randomized clinical trials have failed to identify a subgroup of patients that derive a substantial benefit. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib can increase the anti-tumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Methods: In this randomized, open-label, phase 2 study, 167 postmenopausal women with newly diagnosed, operable, ER-positive, HER2-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to two-weeks of preoperative treatment with anastrozole 1 mg once daily or the combination of anastrozole 1mg with pictilisib 260 mg once daily. The primary endpoint was inhibition of tumor cell proliferation, as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses included targeted NGS of a comprehensive cancer panel of &amp;gt;400 genes (Ampliseq Comprehensive Cancer panel), copy number variation analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling (NanoString nCounter platform). Results:There was significantly greater geometric mean Ki67 suppression of 82.5% (90% CI, 78.3%-85.8%) for the combination vs 70.7% (61.0%-78.0%) for anastrozole [geometric mean ratio (combination/ anastrozole) 0.60 (0.58-0.85);p=0.01]. Higher baseline Ki67, Luminal B status and/or negative PR status were associated with increased benefit from adding pictilisib. A significant interaction was observed between PIK3CA mutation subtypes [helical domain mutations (HD), kinase domain mutations (KD), wildtype (WT)] and mean Ki67 suppression; the combination/anastrozole geometric mean ratio of Ki67 suppression was 0.48 (0.27-0.84; p=0.02) for patients with HD mutations and 0.63 (0.39–1.0; p=0.05) for patients with PIK3Ca WT, compared to 1.17 (0.57–2.41; p=0.64) for patients with KD mutations. This was largely due to patients with HD mutations showing a particularly poor response to anastrozole alone [mean Ki67 suppression 53.9% (9.5%-76.5%)], that was reversed by the addition of pictilisib [mean Ki-67 suppression 78.1% (71.0%-83.4%)]. On the other hand, patients with KD mutations responded well to anastrozole alone [mean Ki-67 suppression 77.7% (57.0%-88.4%)] and showed no benefit from the addition of pictilisib [mean Ki-67 suppression 73.9% (59.8%-83.0%)]. There was no significant difference in induction of apoptosis between treatment groups. Comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: Adding pictilisib to anastrozole significantly increases the anti-proliferative response to preoperative treatment with anastrozole. A significant interaction was observed between PIK3CA mutation subtypes, with patients with helical domain mutations showing a particularly poor response to anastrozole alone that was reversed by the addition of pictilisib. Citation Format: Schmid P, Pinder S, Wheatley D, Zummit C, Macaskill EJ, Hu J, Price R, Bundred N, Hadad S, Shia A, Sarker S-J, Lim L, Mousa K, O'Brien C, Wilson TR, Lackner MR, Gendreau S, Gazinska P, Korbie D, Trau M, Mainwaring P, Thompson A, Purushotham A. Interaction of PIK3CA mutation subclasses with response to preoperative treatment with the PI3K inhibitor pictilisib in patients with estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-02.

Abstract P1-01-01: Systemic imaging fails to detect metastasis in early stage breast cancer

Abstract Background: Current NCCN guidelines for early stage breast cancer (Stage I and II) do not recommend routine systemic imaging in the absence of symptoms or abnormal labs suggestive of distant metastasis. This study aims to determine the frequency and appropriateness of these imaging studies performed, its impact on staging and the factors that influence physicians in ordering these imaging studies. Methods: Patients with stage I and II breast cancer at initial presentation were retrospectively identified between years 2011-2015 from the tumor registry. Charts were reviewed to determine patients who got systemic imaging (CT scan, non-breast MRI, bone scan or PET scan) within 6 months of diagnosis. Provider notes and laboratory data were analyzed to establish the appropriateness of ordered imaging studies and if the imaging altered the stage. For each patient in the study, age at diagnosis, the grade of the breast tumor, hormonal receptor status and HER-2 status was documented. Statistical analysis was done using appropriate tests. Results: A total of 1067 patient charts were screened, of which 882 were identified for inclusion in the study (544 stage I, 338 stage II). Amongst the cohort, 18.57% (101) of patients with stage I and 50.89% (172) of patients with stage II cancer received imaging studies within the first 6 months of diagnosis. Only 12.68% (69) of stage I patients and 18.24% (62) of stage II patients were judged appropriate for imaging based on symptoms and lab results suggesting metastasis. In the imaged cohort of Stage I patients, only 4.35% (3) of the appropriately imaged group and 13.33% (4) of the inappropriately imaged group had a change in stage. Similarly, in the Stage II cohort, only 4.84% (3) of the appropriately imaged group and 8.18% (9) of the inappropriately imaged group saw a change in state. The difference in stage change in the appropriately and inappropriately imaged groups was not statistically significant. (p = 0.11 for Stage I, p=0.41 for Stage II). Only 5.9% of Stage I and 2.9% of Stage II imaged patients changed to stage IV. Grade 1 patients were less likely to receive systemic imaging than grade 2 and 3 patients ((p &amp;lt;0.001). Similarly, the difference in imaging rates ordered in patients with ER and/or PR negative status versus ER and PR positive status was significant (p=0.0004). Triple negative (p &amp;lt;0.001) status and age≤ 50 years were statistically significant predictors of patients receiving imaging (p = 0.014). HER-2 status alone was not a significant predictor of getting imaged (p= 0.527). Conclusions: We performed the first ever study to investigate a correlation between the appropriateness of ordered imaging studies in early stage breast cancer and its ability to detect a change in stage. Distant metastasis identification among stage I &amp; II patients was extremely rare among both appropriately and inappropriately imaged groups. Our findings suggest a wide prevalence of inappropriately ordered imaging studies in Stage I and II breast cancer as well as limited utility for even appropriately ordered ones. Further, other factors such as grade of the tumor, ER/PR/HER2 status and age were found to be statistically significant predictors of whether patients received imaging studies. Citation Format: Gaba AG, Kraft R, Stjern BK, Monu M, Gunderson MA, Hanish C, Samreen A, Paladugu G. Systemic imaging fails to detect metastasis in early stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-01-01.

Prognostic effects of abnormal DNA damage response protein expression in breast cancer.

We aimed to explore the expression of DNA damage response machinery proteins and their integrated prognostic value in different subgroups of breast cancer. Expression of NBS1, BRCA1, BRCA2, ATM, and p53 was determined by immunohistochemistry in 419 surgically resected breast tumors. Loss of NBS1, BRCA1, ATM, and abnormal p53 expression was significantly associated with lower disease-free survival rates. Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status. Most patients with luminal B (86.1%), HER2-enriched (94.4%), and triple-negative (86.8%) breast cancers had abnormal DNA damage response protein expression. In contrast, abnormal DNA damage response protein expression was found in only 53.8% of luminal A tumors. Abnormal DNA damage response protein expression was associated with significantly lower 5-year disease-free survival rates in all patients (95.6% vs. 84.8%, p = 0.001), as well as in the luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DNA damage response protein expression remained an independent predictor of shorter disease-free survival for luminal A subtype (hazard ratio 3.14, 95% confidence interval 1.16-8.47; p = 0.024). Abnormal DNA damage response protein expression is found in most luminal B and HER2-enriched breast cancers as frequently as in triple-negative breast cancer. In the luminal A subtype, abnormal DNA damage response protein expression is an independent prognostic marker.

KLP-PI: a new prognostic index for luminal B HER-2-negative breast cancer.

Luminal B HER-2-negative (LBHN) subtype is one of the major subtypes of breast cancer according to different features, clinical behaviors, and treatment response. The LBHN subtype shows a poor prognosis and is insensitive to endocrine therapy. Our work aim is to investigate the prognostic factor in the LBHN subgroup and, meanwhile, try to obtain an optimal prognostic index (PI) contrapose LBHN subgroup which helps to guide chemotherapy. A total of 515 female LBNH patients who underwent diagnosis and surgery at our hospitals from August 2008 to August 2018 were enrolled. Clinical-pathological information was obtained and immunohistochemistry result was available. From these cases, a 30% Ki-67 LI was employed to divide LBHN into two groups with low and high levels; high Ki-67 LI was associated with GIII tumor grade (P < 0.001), positive axillary lymph nodes (ALN) status (P = 0.018) and negative PR status (P = 0.016), and also seemed to be related to T2-T3 tumor size (P = 0.058). High Ki-67 level (HR = 3.30; P < 0.011), positive ALN (HR = 7.29; P < 0.001) and PR negative (HR = 2.63; P = 0.034) significantly associated with poor 5-year DFS in multivariate Cox's proportional hazard regression model. A novel prognosis prediction model (KLP-PI), based on Ki-67 LI, ALN and PR status, showed a better discriminatory ability compared with traditional Nottingham prognostic index targeted to LBHN breast cancer. Our study highlights that high Ki-67 LI, positive ALN and negative PR status were associated with poor outcome in LBHN patients, and composed by these prognostic factors, KLP-PI improves the prognostic assessment using the Nottingham Prognostic Index when aiming at LBHN subtype.

Clinicopathological and prognostic significance of GLUT1 in breast cancer: A meta-analysis.

Background:Previous studies examining the prognostic value of glucose transporter 1 in breast cancer have yielded inconsistent results. We, therefore, performed a meta-analysis to clarify this issue.Methods:The research was reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Relevant studies were retrieved from PubMed, Web of Science, EMBASE, and Cochrane library.Results:A total of 7 reports with 1861 patients were finally chosen. GLUT1 overexpression was found to be associated with high histological grade (OR = 3.74, 95% CI = 2.45–5.69, P < .001), negative PR status (OR = 0.33, 95% CI = 0.22–0.49, P < .001), and negative estrogen receptor (ER) status (OR = 0.27, 95% CI = 0.17–0.42, P < .001). However, no significant correlation was seen between GLUT1 levels and presence of lymph node metastasis, tumor size or the status of human epidermal growth factor receptor 2 (HER2). Overexpression of GLUT1 also correlated with a poor overall survival (hazard ratio [HR] = 1.65, 95% confidence interval [CI] = 1.17–2.31, P = .004) and disease-free survival (HR = 2.35, 95% CI = 1.4–3.94, P < .001). No evidence of significant publication bias was found.Conclusion:This meta-analysis indicates that GLUT1 expression is associated with poor prognostic and a series of clinicopathological features in breast cancer. GLUT1 might be a potential biomarker and therapeutic target in breast cancer.

MYC amplification in subtypes of breast cancers in African American women

BackgroundMYC overexpression is associated with poor prognosis in breast tumors (BCa). The objective of this study was to determine the prevalence of MYC amplification and associated markers in BCa tumors from African American (AA) women and determine the associations between MYC amplification and clinico-pathological characteristics.MethodsWe analyzed 70 cases of well characterized archival breast ductal carcinoma specimens from AA women for MYC oncogene amplification. Utilizing immune histochemical analysis estrogen receptor (ER), progesterone receptor (PR), and (HER2/neu), were assessed. Cases were Luminal A (ER or PR+, Ki-67 < 14%), Luminal B (ER or PR+, Ki-67 = > 14% or ER or PR+ HER2+), HER2 (ER-, PR-, HER2+), and Triple Negative (ER-, PR-, HER2-) with basal-like phenotype. The relationship between MYC amplification and prognostic clinico-pathological characteristics was determined using chi square and logistic regression modeling.ResultsSixty-five (97%) of the tumors showed MYC gene amplification (MYC: CEP8 > 1). Statistically significant associations were found between MYC amplification and HER2-amplified BCa, and Luminal B subtypes of BCa (p < 0.0001), stage (p < 0.001), metastasis (p < 0.001), and positive lymph node status (p = 0.039). MYC amplification was associated with HER2 status (p = 0.01) and tumor size (p = 0.01). High MYC amplification was seen in grade III carcinomas (MYC: CEP8 = 2.42), pre-menopausal women (MYC: CEP8 = 2.49), PR-negative status (MYC: CEP8 = 2.42), and ER-positive status (MYC: CEP8 = 2.4).ConclusionsHER2 positive BCas in AA women are likely to exhibit MYC amplification. High amplification ratios suggest that MYC drives HER2 amplification, especially in HER2 positive, Luminal B, and subtypes of BCa.

Abstract P2-11-22: Adjuvant radiation is associated with decreased risk of locoregional recurrence in patients with micrometastatic invasive breast cancer

Abstract Purpose: Determining the appropriate adjuvant treatment in patients with micrometastatic disease remains a considerable challenge in the treatment of breast cancer. Recent data suggests patients with micrometastatic disease have an intermediate risk of locoregional recurrence between patients with macrometastatic disease and patients with no evidence of axillary disease. Further work is needed to tailor treatment strategies to individual patients based on tumor characteristics. Here, we reviewed the outcomes of patients with N1mic axillary disease treated at the University of Wisconsin to assess the risk of locoregional recurrence in patients with micrometastases to determine risk factors associated with increased risk of LRR. Methods: We identified patients with pathologic T1-T3, N1mic invasive breast cancers treated at the University of Wisconsin between 01/01/2004 and 07/01/2015. The patients were identified within the UW breast cancer registry and by query of pathologic records. We utilized the Kaplan-Meier method to determine the rate of locoregional recurrence free survival and overall survival. Multivariate analysis of patient and tumor characteristics was performed using the Cox proportional hazards model using locoregional recurrence as an outcome. Results: 154 patients were identified with micrometastatic disease with a median follow-up of 4.1 years. The 5 year locoregional recurrence free survival and overall survival for all patients was 92.6% and 88.9%, respectively. On univariate analysisl, ER negative status (HR 8.03, p&amp;lt;0.001), PR negative status (HR 3.18, p =0.49), Her2 amplification (HR 5.02, p=0.005), and tumor grade (HR 2.96, p=0.005) were all significantly associated with increased risk of locoregional recurrence (LRR). Radiation therapy (HR 0.174, p=0.005) was the only therapeutic variable associated with decreased risk of LRR. Lymphovascular space invasion, close or positive margins, extranodal extension, and tumor stage were not associated with risk of LRR. Additionally, the type of axillary surgery, the type of breast surgery, the use of chemotherapy, and the use of endocrine therapy were not associated with risk of LRR. On multivariate analysis, ER negative status (HR 6.39, p=0.004), Her2 amplification (HR 5.53, p=0.006), and treatment with radiation (HR 0.14, p=0.004) remained significantly associated with risk of LRR. Conclusion: The data presented suggest that treatment with radiation is associated with decreased LRR in patients with micrometastatic disease. Patients with Her2 amplification or ER negative status are also found to be at particularly high risk of recurrence. Future work is needed to determine strategies to decrease the rates of recurrence in these high risk groups and to define subgroups of patients with micrometastatic disease for whom radiation is particularly beneficial. Citation Format: Burr AR, Brickson CR, Anderson BM. Adjuvant radiation is associated with decreased risk of locoregional recurrence in patients with micrometastatic invasive breast cancer [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 P2-11-22.

Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification.

Molecular subclassification of endometrial carcinoma (EC) with Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifies four subtypes [DNA polymerase epsilon (POLE) mutant, mismatch repair‐deficient, p53 wild‐type (wt), and p53 abnormal]. The aim of this study was to evaluate additional EC biomarkers in the context of these subtypes. Tissue microarrays encompassing 460 previously characterized ECs were assessed for L1‐cell adhesion molecule (L1CAM), progesterone receptor (PR), estrogen receptor (ER) alpha, stathmin, and phosphatase and tensin homolog (PTEN), by immunohistochemistry (IHC). Associations with clinicopathological parameters, molecular subtype, and outcomes were determined. About 413 ECs (75% endometrioid, >15% serous) had complete data. L1CAM overexpression was found in 16%, associated with older age, lower body mass index (BMI), advanced stage, grade 3 (97%), non‐endometrioid histology (84%), deep myometrial invasion, lymphovascular space invasion (LVSI), and ER‐negative, PR‐negative status. Tumours overexpressing L1CAM were associated with poor outcomes {hazard ratio (HR) [95% confidence interval (CI)] 3.35 [2.10–5.23] for disease‐specific survival [DSS], p < 0.0001}. PR positivity was associated with younger women, higher BMI, early stage (77% stage I), low grade (61%), endometrioid histology (90%) without LVSI or nodal disease, ER positivity (90%), p53wt tumours (55%), and favourable outcomes [HR (CI) 0.39 (0.25–0.62) for DSS, p < 0.0001]. ER positive tumours were early stage (73%), low grade, endometrioid histology, with improved DSS. Stathmin and PTEN IHC were not associated with outcomes. There was minimal agreement between IHC and mutation status for PTEN. L1CAM overexpression was significantly associated with the p53 abnormal molecular subtype, which accounted for more than 70% of the tumours overexpressing L1CAM. PR expression also correlated with molecular subtype, with most PR negative tumours being p53 abnormal. Multivariable analysis demonstrated that only ProMisE subtype [overall survival (OS), DSS, and progression‐free survival] and age (OS only) maintained an association with outcomes. The prognostic significance of the single biomarkers tested could be explained based on their being covariable with the ProMisE molecular subtype.

Abstract 4739: Prognostic impact of abnormal DNA damage response protein expression in breast cancer

Abstract Purpose Defects of DNA damage repair are known to be associated with the efficacy of anthracycline or platinum-based chemotherapy as well as poly[ADP-ribose] polymerase (PARP) inhibitors (PARPi) and PD-1/PD-L1 checkpoint inhibitors. Since multiple proteins are involved in DNA-damage response (DDR) and operate collectively, our main aim was to better understand the expression of proteins in DDR machinery and their integrated prognostic value in the different subtypes of breast cancer. Methods A total of 419 consecutive breast cancer patients who underwent curative resection in 2008 were enrolled in the study. Tissue microarray has been constructed, and NBS1, BRCA1, BRCA2, ATM and p53 expression were determined by immunohistochemistry. Results All patients were female, with a median age of 47 years; 280 (67%) had luminal A, 36 (9%) had luminal B, 37 (9%) had HER2-enriched, and 56 (13%) had triple-negative breast cancer (TNBC). Loss of NBS1, BRCA1, BRCA2, and ATM expression was observed in 6.7%, 33.7%, 89.9%, and 30.8% of breast cancer patients, respectively, and abnormal p53 expression was observed in 39.3% of patients. Loss of NBS1, BRCA1, ATM and abnormal p53 expression was associated with significantly lower disease-free survival (DFS) rates, respectively. “Abnormal DDR protein expression”, defined as loss of any one of NBS1, BRCA1, ATM and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER- and/or PR-negative status. Majority of patients with luminal B (31/36, 86.1%), HER2-enriched (34/35, 94.4%), and TNBC (46/53, 86.8%) subtype showed abnormal DDR protein expression. In comparison, 136/264 patients (53.8%) with luminal A subtype had abnormal DDR protein expression. Abnormal DDR protein expression was associated with significantly lower 5-year DFS rate than those in patients with normal DDR protein expression in all patients (95.6% vs. 84.8%, p = 0.001), as well as in luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DDR protein expression remained as an independent predictor of shorter DFS for luminal A subtype tumors (hazard ratio 3.14; 95% confidence interval, 1.16 – 8.47, p = 0.024). Conclusion We demonstrated differential expression of proteins in DDR machinery according to breast cancer subtypes and its prognostic implication. Most of luminal B and HER2-enriched tumors has abnormal DDR expression as frequently as triple negative tumors. Less but significant proportion of luminal A tumors also shows abnormal DDR protein expression, which is an independent poor prognostic factor. Citation Format: Koung Jin Suh, Han Suk Ryu, Kyung-Hun Lee, Hyojin Kim, Ahrum Min, Tae-Yong Kim, Hyeong-Gon Moon, Sae-Won Han, Do-Youn Oh, Wonshik Han, In Ae Park, Dong-Young Noh, Seock-Ah Im. Prognostic impact of abnormal DNA damage response protein expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2017-4739

Time-dependent risk and predictors of venous thromboembolism in breast cancer patients: A population-based cohort study.

Venous thromboembolism (VTE) is a serious complication of cancer and its treatment. The current study assessed the risk and clinical predictors of VTE in breast cancer patients by time since diagnosis. This Swedish population-based study included 8338 breast cancer patients diagnosed from 2001 to 2008 in the Stockholm-Gotland region with complete follow-up until 2012. Their incidence of VTE was compared with the incidence among 39,013 age-matched reference individuals from the general population. Cox and flexible parametric models were used to examine associations with patient, tumor, and treatment characteristics, accounting for time-dependent effects. Over a median follow-up of 7.2 years, 426 breast cancer patients experienced a VTE event (cumulative incidence, 5.1%). The VTE incidence was 3-fold increased (hazard ratio [HR], 3.28; 95% confidence interval [CI], 2.87-3.74) in comparison with the incidence in the general population and was highest 6 months after diagnosis (HR, 8.62; 95% CI, 6.56-11.33) with a sustained increase in risk thereafter (HR at 5 years, 2.19; 95% CI, 1.80-2.67). Independent predictors of VTE included the following: older age, being overweight, preexisting VTE, comorbid disease, tumor size > 40 mm, progesterone receptor (PR)-negative status, more than 4 affected lymph nodes, and receipt of chemo- and endocrine therapy. The impact of chemotherapy was limited to early-onset VTE, whereas comorbid disease and PR-negative status were more strongly associated with late-onset events. This study confirms the long-term risk of VTE in breast cancer patients and identifies a comprehensive set of clinical risk predictors. Temporal associations with patient, tumor, and treatment characteristics provide insight into the time-dependent etiology of VTE. Cancer 2017;123:468-475. © 2016 American Cancer Society.

BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy.

Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment. We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR. In the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS. We confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

Prognostic Role of Programmed Death Ligand-1 Expression in Breast Cancer: A Systematic Review and Meta-Analysis.

Cancer therapies that target the PD-1/PD-L1 pathway are in ongoing phase I/II clinical trials for several tumor types. However, the prognostic value of PD-L1 expression in breast cancer is unclear. We assessed the prognostic role of PD-L1 expression in breast cancer. We searched Medline/PubMed for eligible studies of the association between PD-L1 expression and patient survival in breast cancer published before 7 December 2015. The effect size was the hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS), recurrence-free survival (RFS) and metastasis-free survival (MFS). Odds ratios (OR) with 95% CIs were also extracted to evaluate associations between PD-L1 expression and patient clinicopathological features. We included five studies with 7,802 total patients in this meta-analysis. The pooled OR associated high PD-L1 expression with predictors of poor-prognosis: high tumor grade, negative ER status, negative PR status, positive HER2 status and lymphovascular invasion. High PD-L1 protein expression was associated with shorter OS (HR = 3.22, 95% CI: 1.86-5.59; P < 0.0001), shorter RFS (HR = 1.38, 95% CI: 1.03-1.86; P = 0.03) and shorter MFS (HR = 3.33, 95% CI: 2.30-4.82; P < 0.00001); whereas high PD-L1 mRNA expression was associated with longer OS (HR = 0.86, 95% CI: 0.75-1.00; P = 0.05) and longer RFS (HR = 0.57, 95% CI: 0.36-0.91; P = 0.02). The findings of these studies were significantly heterogeneous; the results should be interpreted cautiously. In breast cancer, high PD-L1 protein expression appears to be a negative prognostic factor, whereas high PD-L1 mRNA expression appears to be a favorable prognostic factor.

Loss of ataxia-telangiectasia-mutated protein expression correlates with poor prognosis but benefits from anthracycline-containing adjuvant chemotherapy in breast cancer

We investigated the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors. ATM loss was observed in 126/407 evaluable cases (31.0%), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival rates than those in patients with intact ATM (5-year disease-free survival rate 81.2 vs. 90.7%, p=0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter disease-free survival [hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.48-8.17, p=0.004]. A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached (HR 1.74; 95% CI 0.95-3.20; p=0.075). In subgroup analysis, ATM loss was associated with shorter disease-free survival in patients who did not receive adjuvant anthracycline chemotherapy (5-year disease-free survival rate 92.7% in intact ATM group vs. 68.1% in ATM loss group, p=0.002), but this poor prognosis was overcome in patients who did (5-year disease-free survival rate 89.8 vs. 84.4%, p=0.243), suggesting more benefit from anthracycline-based chemotherapy. Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy.

Abstract P2-12-15: The role of neck dissection in breast cancer patients with synchronous and metachronous ipsilateral supraclavicular lymph node metastasis

Abstract Purpose: To evaluate the effect of neck dissection in breast cancer patients who present with ipsilateral supraclavicular lymphnode metastasis (ISLM) without distant metastasis and to reveal the outcomes of neck dissection in different molecular subtypes. Methods: A total of 90 patients with synchronous ISLM and 36 patients with metachronous ISLM without distant metastasis between 2000 and 2009 were retrospectively analyzed. Combined-modality treatments were performed, and patients were respectively divided into two parts according to whether they received neck dissection or not. Results: In the synchronous ISLM group, there was no significant difference between the neck dissection and non-dissection group with respect to age, menstrual status, tumour size, and histological type, PR and HER2 status. Patients with negative ER status and a higher number of positive axillary nodes were more common in the neck dissection group. The five-year locoregional relapse free survival (LRFS) was 63.6% in the neck dissection group VS. 48.9% in the non-dissection group, respectively (P=0.359). The 5-year distant metastasis free survival (DMFS) was 37.3% in the neck dissection group VS. 38.5% in the non-dissection group, respectively (P=0.882). Further analyses were performed by the site of metastases. Results showed that the incidence of bone metastasis was lower in neck dissection patients (14.7% vs. 28.6%, P=0.132). Due to the limited amount of patients, subgroup analysis was just performed in the subtypes with negative ER status, negative PR status and negative HER2 status, respectively. The five-year LRFS of patients receiving neck dissection in the subtypes with negative ER status, negative PR status and negative HER2 status was 63.7%, 59.8%and 61.2%, which was much better than their matched non-dissection group, respectively. However, the difference was not statistically significant. The 5-year overall survival (OS) was similar between the neck dissection and non-dissection group in the subtypes of negative ER status and negative PR status, respectively. However, the 5-year OS of HER2 negative subtype significantly decreased in the neck dissection group (37.2% vs. 65.4%, P=0.032). Besides, it's worth mentioning that in the HER2 positive subtype, the mean time to relapse, metastasis and death was shorter in the neck dissection subgroup compared with the non-dissection subgroup. In the metachronous ISLM group, a trend of better regional control, with similar PFS and OS, was achieved in the neck dissection group. Discussion: Neck dissection is an effective approach to improve the regional control for the patients with ISLM, especially for the subtypes with negative ER status, negative PR status and probably positive HER2 status in the synchronous ISLM. But, it might not be comfortable for the patients with negative HER2 status, because of the unfavorable effect on its overall survival. In addition, neck dissection, with better regional control, might be helpful for the control of bone metastasis, which is beneficial for long term survival. Citation Format: Xiao C, Qi X, Chen A, Zhang W, Zhang P, Cao X. The role of neck dissection in breast cancer patients with synchronous and metachronous ipsilateral supraclavicular lymph node metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-15.

Adiposity is associated with p53 gene mutations in breast cancer.

Mutations in the p53 gene are among the most frequent genetic events in human cancer and may be triggered by environmental and occupational exposures. We examined the association of clinical and pathological characteristics of breast tumors and breast cancer risk factors according to the prevalence and type of p53 mutations. Using tumor blocks from incident cases from a case-control study in western New York, we screened for p53 mutations in exons 2-11 using the Affymetrix p53 Gene Chip array and analyzed case-case comparisons using logistic regression. The p53 mutation frequency among cases was 28.1 %; 95 % were point mutations (13 % of which were silent) and the remainder were single base pair deletions. Sixty seven percent of all point mutations were transitions; 24 % of them are G:C>A:T at CpG sites. Positive p53 mutation status was associated with poorer differentiation (OR, 95 % CI 2.29, 1.21-4.32), higher nuclear grade (OR, 95 % CI 1.99, 1.22-3.25), and increased Ki-67 status (OR, 95 % CI 1.81, 1.10-2.98). Cases with P53 mutations were more likely to have a combined ER-positive and PR-negative status (OR, 95 % CI 1.65, 1.01-2.71), and a combined ER-negative and PR-negative status (OR, 95 % CI 2.18, 1.47-3.23). Body mass index >30 kg/m(2), waist circumference >79 cm, and waist-to-hip ratio >0.86 were also associated with p53 status; obese breast cancer cases are more likely to have p53 mutations (OR, 95 % CI 1.78, 1.19-2.68). We confirmed that p53 mutations are associated with less favorable tumor characteristics and identified an association of p53 mutation status and adiposity.