Negative Hormone Receptor Status Research Articles

Prognostic implications of HER2Neu-low in metastatic breast cancer.

1044 Background: HER2-Low (or HER2-equivocal, FISH negative) breast cancer has historically been treated as HER2-negative; however, recent evidence suggests that there may be prognostic and/or predictive differences between the two. We explore demographic characteristics and clinical outcomes of HER2-negative and HER2-low metastatic breast cancer (MBC) patients using real world data. Methods: We queried the National Cancer Database to identify MBC patients that were HER2 0, HER2 1+, or HER2 2+ per immunohistochemical staining, with the latter two defined as HER2-low and the former HER2-negative. A multivariable binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA), propensity matched to HER2 status, was performed to identify correlates of survival. Results: After excluding missing data, 24,636 MBC patients diagnosed between 2008-2015 were identified, 6,865 (27.9%) of whom were HER2-negative and 17,771(72.1%) of whom were HER2-low. There were no differences between the two groups with respect to age, race, year treated, location, income, insurance status, Charles Deyo comorbidity score, laterality, T stage, N stage, or use of systemic therapy. HER2-low tumors were half as likely to have concomitant hormone receptor-negative status (OR = 0.49, 95% CI 0.46-0.53). The 3-year survival rate among hormone receptor-negative patients was 33.8% for HER2-low and 32.2% for HER2-negative, and 60.9% and 55.6% in HER2-low and HER2-negative cases among hormone receptor-positive patients, respectively. HER2-low cases were associated with better survival on MVA (HR = 0.91, 95% CI 0.87-0.95), and remained superior with propensity-matching (HR = 0.92, 95% CI 0.89-0.96). In a subset analysis isolated to hormone receptor-positive cases, HER2-low remained correlated with improved survival (HR = 0.93, 95% CI 0.89-0.98) with propensity-matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02), Black race (HR = 1.13), uninsured (HR = 1.18), comorbidity score > 0 (HR = 1.28), higher T stage (HR = 1.17 to 2.34), node positivity (HR = 1.17) and, as the most influential, hormone receptor-negative status (HR = 1.94) [all P < 0.01]. Conclusions: Consistent with recent data in non-MBC, our study demonstrates a small but statistically significant association with improved survival for HER2-low tumors compared to HER2-negative tumors in MBC. Randomized data are necessary to further validate this discrepancy and determine if different management is warranted for each subtype.

Abstract P3-14-14: A mediation analysis of racial disparity in breast cancer survival

Abstract Introduction: Non-Hispanic Black (African American, AA) women have the worst breast cancer outcomes of any racial/ethnic group. In comparison to non-Hispanic white (white) women, disparities in breast cancer survival for AA women have persisted over the past several decades, although there has been some recent improvement both at the national level and for AA women in Florida. However, we recently reported that AA women in Florida still have twice the rate of breast cancer death compared to their white counterparts. Therefore, more targeted approaches are needed to eliminate survival disparities for AA women diagnosed with breast cancer. The purpose of this study was to conduct a multiple mediation analysis to identify the most important factors causing the disparity in breast cancer survival for AA women. Identifying the most important mediators will provide opportunities for targeted policies, programs, and interventions to ultimately eliminate the prognostic effect of race/ethnicity for Florida women diagnosed with breast cancer. Methods: The study population is comprised of women in Florida diagnosed with breast cancer between 2004 and 2015 who were reported to the Florida Cancer Data System. The following putative mediators were analyzed in this study: residence in high poverty neighborhoods, having Medicaid or no insurance, advanced disease stage at diagnosis, high tumor grade, negative hormone receptor status, and receipt of surgery, based on our causal diagram. The outcome of interest was 5-year breast cancer-specific death. Sociodemographic and clinical characteristics were compared between African American and white women. The Cox model was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the direct effect of AA race/ethnicity and indirect effects via mediators. Age was treated as a confounder in the model and mediators were treated as independent. The relative effect for African American ethnicity and each mediator, which is the percentage of the total effect of AA race/ethnicity explained (directly and indirectly) on breast cancer survival, are also provided. Results: African American women were more likely to be younger at diagnosis, living in high poverty neighborhoods, to be insured via Medicaid or uninsured, to have more advanced disease (stage, grade) with hormone receptor negative tumors, and less likely to receive surgery as treatment. From our mediation model, after accounting for all potential mediators, the direct effect associated with African American ethnicity was a 17% (HR = 1.17: 95% CI, 1.11-1.23) increased rate of breast cancer death, which represented 3.9% of the total racial/ethnic effect. The indirect and relative effects of mediators are provided in Table 1. Conclusions: This analysis identified receipt of surgery, advanced disease stage, hormone receptor negative disease, insurance status, and high tumor grade as the most important mediators of the racial/ethnic disparity in breast cancer survival for African American women in Florida. These results have ramifications for increasing access to screening services, providing options for health insurance, and ensuring prompt receipt of curative surgery to eliminate the prognostic effect of race/ethnicity for African American women diagnosed with breast cancer in the Florida. Study limitations are that these results are hypothesis generating based on the current status of methodology to examine multiple mediators in survival models. Table 1.Direct and Indirect Effects for the Association of African American Race/Ethnicity with 5-year Breast Cancer-Specific SurvivalDirect & indirect effectsCox Proportional Hazard ModelHR95%. CIrel effAA race/ethnicity (Direct Effect)1.171.11, 1.233.9%Surgery3.182.93, 3.4728.3%Advanced stage3.092.84, 3.3627.5%Hormone receptor negative1.581.51, 1.6511.1%Medicaid-Uninsured1.481.40, 1.579.6%High grade1.471.42, 1.539.4%High poverty1.341.23, 1.477.2%Hormone treatment1.111.09, 1.142.5%Immunotherapy1.081.02, 1.151.9%Radiation1.041.03, 1.051.0%Chemotherapy0.910.89, 0.92Total Effect60.1050.8, 71.1100.0%Abbreviations: AA, African American; HR, hazard ratio; CI, confidence interval. Citation Format: Robert B. Hines, Xiang Zhu, Eunkyung Lee, Carolyn Rapp, Albert Volk, Asal M. Johnson. A mediation analysis of racial disparity in breast cancer survival [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 P3-14-14.

Abstract P1-05-01: The tumor immune microenvironment and HER2 landscape of high-risk ductal carcinoma in situ: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology from indolent to aggressive. A minority of women present with clinically high-risk features associated with poor outcome. Yet even in patients with biologically aggressive DCIS, the risk of breast cancer mortality is only 3.3% compared to 30-40% in patients with biologically aggressive invasive cancer of the same size.1 We hypothesize that the tumor immune microenvironment could play a proactive role in preventing invasion in high grade clinically high-risk DCIS and that HER2 status, including specific HER2 isoform expression and post-translational modification of HER2, could impact progression. Methods: DCIS: Elaboration of Factors from Enlarged lesions that Nevertheless remain Stage 0 Entities (DEFENSE) is a study of high-risk DCIS, defined as having at least two of the following characteristics: large (>5cm), high grade, hormone receptor-negative status and/or HER2+ status. Slides obtained from FFPE tissue blocks were stained with fluorescence-based multiplex immunohistochemistry (mIHC) panels and imaged to characterize immune infiltrate within the ducts and the stromal compartments. mIHC was also used to detect extracellular and intracellular domains of HER2 with imaging analysis performed to identify HER2 isoforms of HER2+ specimens. Isoforms were characterized as 1) full-length/extracellular domain (ECD) intact, 2) pure/complete loss of ECD (p95 isoform), 3) subclonal populations of both full-length ECD and p95 and 4) gradient/representing partial loss of ECD per cell (reflecting post-translational cleavage). Clinical characteristics were correlated with molecular profile, tumor immune infiltrates, and HER2 isoform. Finally, expression profiling with a 44k array was conducted by Agendia, and MammaPrint and BluePrint results were generated. Results: Of 92 total patients, median age is 46 years. The average DCIS lesion size is 8.2cm, and 33% are hormone receptor negative (HR-). Based upon initial analysis, mIHC demonstrates significant heterogeneity in immune infiltrate populations of pathologically identical DCIS specimens and within regions of the same specimen. High-grade HR- disease has highly reactive stroma, characterized by dense CD3+, CD34+, and CD68+ infiltrate within the stromal compartment. HER2 testing of the first 51 cases demonstrates a high rate of positivity of 67% (34/51). Of those tested for HER2 isoform expression (n=21), none had homogeneous intact full-length HER2. Six (29%) demonstrate the pure p95 isoform, 3 (14%) demonstrate the subclonal isoform, and 12 (57%) demonstrate a gradient HER2 isoform phenotype. Preliminary data from expression profiling shows that the HER2+ cases are also HER2 intrinsic sub-type by BluePrint. Across all of the high-risk DCIS cases, all were scored as MammaPrint high risk, either Luminal B or HER2-type, with only 1 basal and no Luminal A. Additional analyses are ongoing, including completion of testing for the whole data set as well whole exome DNA sequencing and SMART-3SEQ RNA sequencing. Conclusions: Clinically high-risk and pathologically homogenous DCIS lesions demonstrate significant immune infiltrate heterogeneity. Nearly 70% of these large clinically high-risk DCIS lesions are HER2+ with HER2 isoforms most commonly representing either partial or complete loss of the HER2 ECD. This is significantly higher than what is reported for invasive HER2+ breast cancer. A comparison to size and molecularly matched invasive cancers, including from the I-SPY 2 trial, is underway in an effort to elucidate how molecularly aggressive lesions remain in situ despite their large size.

Disease Free Survival in Locally Advanced Breast Cancer: An Analysis of Clinical and Pathological Factors

Background: The TNM stage is the widely accepted tool to predict prognosis in breast cancer cases, but it deals with a limited range of factors and ignores patient-specific conditions, pathological or genotype characteristics and treatments. The purpose of this study was to evaluate if and how different clinical (tobacco chewing, age etc) and pathological (lymphovascular and perineural invasion etc) variables influence the disease free survival. Material and Methods: This study involves North Eastern Indian population. Data of 101 patients with locally advanced breast cancer diagnosed in the time period of January to December 2018 was probed and they were followed up till March 2020. Association between various clinicopathological risk factors and disease free survival was assessed using univariate and multivariate models. Survival estimates were computed using the Kaplan-Meier method and differences between survival times were assessed by means of the Log rank test. Multivariate analyses were carried out using Cox’s proportional hazards model. Results: During follow up period 14 patients developed metastasis. There was significantly reduced disease free survival seen trough Kaplan Meier plots in patients having tumor size >6 cm, N2/ N3 stage, triple negative receptor status, tobacco chewing and positive perineural invasion. Multivariate analysis revealed that stage (N2, N3) and positive perineural invasion are two independent variables which adversely affect the survival. Conclusion: Bottom line of the study is that, disease free survival in LABC patients is significantly reduced with higher stage (N2, N3) and positive perineural invasion as revealed by multivariate analysis. Three other factors which adversely affect DFS are tobacco chewing, tumor size > 6cm and triple negative hormone receptor status according to univariate analysis.

Evaluation of forkhead-box C1 expression in breast cancer

Background Forkhead box C1 (FOXC1) is considered an important member of forkhead-box transcription factors. Previous studies have shown that FOXC1 is associated with tumor progression and represents a poor prognostic indicator in triple-negative basal-like breast cancer. Method This is a retrospective study conducted on 187 cases of invasive breast carcinoma obtained from Histopathology Laboratory in Oncology Center, Faculty of Medicine, Mansoura University, starting from 2012. Aim and objectives In this study, we aimed to study FOXC1 protein expression in molecular subtypes of breast cancer and to correlate its expression with other prognostic parameters using immunohistochemistry and tissue microarrays. Results FOXC1-positive expression was seen in 26.7% of cases. Positive FOXC1 expression was most common in triple-negative basal-like breast cancer and HER2-enriched subtypes. Positive FOXC1 expression was higher in ER-negative cases than ER-positive cases (39 vs. 21%) with statistical significance (P = 0.01). Similarly, positive FOXC1 was higher in PR-negative cases than PR-positive cases (37.5 vs. 20%), this was statistically significant (P = 0.009). In our series, FOXC1 expression was not associated with survival. Conclusion FOXC1 expression is associated with negative hormonal-receptor status in breast cancer. FOCX1 is not a prognostic indicator of disease-free survival in our patient series.

Evaluation of the impact of serum lipid levels in breast cancer patients in a Moroccan cardio-oncology unit

Breast cancer (BC) is the most frequent cancer in women with a high morbidity and mortality. The identification of risk factors can improve BC prevention of cancer, especially modifiable ones such as obesity and hypercholesterolemia. The association between serum lipid level and BC prognosis is controversial. The purpose of this study was to evaluate the impact of serum lipid level in breast cancer prognosis. We conducted a prospective observational study from June 2018 to March 2021 in the cardio-oncology unit of Casablanca, Morocco. We analyzed a total of 684 patients with BC who had baseline serum lipid profiles; total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C), and divided them into 2 groups: group 1 ( n = 178) defined by lipid abnormalities at admission (CT > 2 g/L, HDL > 0.65, LDL > 1.8 or TG > 2) and group 2 ( n = 506) defined by normal values of lipid parameters. Patients were grouped on the basis of tumor grade, tumor size, lymph node metastasis and disease free survival. In comparison with the second group, group 1 patients had worse prognosis factors related to their BC such as higher nuclear grade ( P = 0.041), negative hormone receptor status ( P = 0.036), positive HER2 expression ( P = 0.024), and higher BC recurrence ( P = 0.047). Our study also showed that low levels of HDL cholesterol (≤ 0.65 g/L) were mainly present in BC patients with lymph node metastasis ( P = 0.024) and negative progesterone receptor ( P = 0.041). However, this study revealed no association between hyperlipemia and patients overall survival. Our study showed that baseline hyperlipemia is associated with a worse prognosis in BC patients and that a low level of HDL cholesterol may impact clinical outcome but not overall survival.

Ki67 and P53 expression in breast cancer and their correlation with clinicopathological parameters

Breast carcinoma is the most common malignancy in females and is a leading cause of death. Treatment depends upon various pathological and prognostic markers like lymph node status, size, type and grade of the tumour which influences the outcome of breast cancer. Markers like Ki-67 and p53 have been studied extensively and their roles in breast cancer are yet to be established.We evaluated the expression of Ki67 and P53 in breast cancer and their association with other clinico-pathological factors was studied. Ki67 and P53 expression was assessed in 60 breast cancer cases admitted to our hospital over a period of one year. Association with other prognostic parameters was evaluated. Statistical analysis was done by Chi square test and a p value of <0.05 was taken as significant. 43.33% cases had low proliferative Ki-67 score whereas 56.67% of the cases were highly proliferative. p53 expression was seen in 41.66% cases. Ki-67 and p53 expression were not significantly related to age, menopausal status, and tumour size whereas a significant correlation was seen with positive axillary lymph node status, high histological grade, negative hormone receptor status (ER, PR) and positive HER2/neu expression. Significant association was seen between Ki-67 and p53 expression.Ki67 and P53 may be considered as a valuable biomarker in breast cancer patients which can help in planning treatment strategies.

Ki67 as Proliferative Marker in Patients with Early Breast Cancer and Its Association with Clinicopathological Factors

Introduction: Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. Material and Methods: Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (n = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. Results: 595 (64.9%) patients had a Ki67 <20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1–90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2−) disease (n = 717), 20% for HR+/HER2+ (n = 76), 30% for HR−/HER2+ (n = 45), and 60% for HR−/HER2− (n = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (<20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). Conclusion: This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.

Prognostic factors of brain metastasis and survival among HER2-positive metastatic breast \ufeffcancer patients: a systematic literature review

BackgroundPatients with breast cancer who overexpress the human epidermal growth factor receptor 2 (HER2) and subsequently develop brain metastasis (BM) typically experience poor quality of life and low survival. We conducted a comprehensive literature review to identify prognostic factors for BM and predictors of survival after developing BM, and the effects of therapies with different mechanisms of action among patients with HER2+ breast cancer (BC).MethodsA prespecified search strategy was used to identify research studies investigating BM in patients with HER2+ BC published in English during January 1, 2009–to June 25, 2021. Articles were screened using a two-phase process, and data from selected articles were extracted.ResultsWe identified 25 published articles including 4097 patients with HER2+ BC and BM. Prognostic factors associated with shorter time to BM diagnosis after initial BC diagnosis included younger age, hormone receptor negative status, larger tumor size or higher tumor grade, and lack of treatment with anti-HER2 therapy. Factors predictive of longer survival after BM included having fewer brain lesions (< 3 or a single lesion) and receipt of any treatment after BM, including radiosurgery, neurosurgery and/or systemic therapy. Patients receiving combination trastuzumab and lapatinib therapy or trastuzumab and pertuzumab therapy had the longest median survival compared with other therapies assessed in this review.ConclusionsMore research is needed to better understand risk factors for BM and survival after BM in the context of HER2+ BC, as well as the assessment of new anti-HER2 therapy regimens that may provide additional therapeutic options for BM in these patients.

Abstract 3181: Nicotine promotes pre-metastatic niche formation in hormone receptor negative breast cancer through paracrine signaling in the tumor microenvironment

Abstract Hormone receptor negative breast cancer is responsible for a majority of the mortalities through aggressive metastatic spread, which accounts for a poor patient survival. Increasing epidemiological evidence indicates significant risk of pulmonary metastasis among smokers in breast cancer. However, little is known whether smoking or cessation affects clinical outcomes in breast cancer with pulmonary metastasis particularly in patients with hormone receptor negative status. To address this question, we employed spontaneous and experimental pre-metastasis in syngeneic mice model with or without i.p. injection of nicotine in line with human blood cotinine level and measured metastatic progression. We found that nicotine promoted the pulmonary metastasis burden by 100-fold in vivo. Immune profiling of the pulmonary metastatic lesions showed predominant infiltration of neutrophils compared to primary tumors. Notably, mice pre-exposed to nicotine showed a significantly increased number of neutrophils in the lungs even before injection of cancer cells (pre-metastatic lung). Remarkably, neutrophil depletion during metastatic colonization caused a decrease of spontaneous metastasis. Furthermore, infiltrated neutrophils in the pulmonary metastasis lesions under nicotine treatment selectively overexpressed N2-polarization phenotype in a STAT3-dependent manner. We then examined secretory factor(s) from nicotine-treated primary neutrophils using a qPCR array system. We found that the expression of LCN2 was significantly augmented in the conditioned medium of nicotine treated primary neutrophils. Next, we investigated functional contribution of neutrophil-secreted factors on tumor metastasis. MCF10CA cells were cultured with the conditioned medium (CM) of primary neutrophils that were treated with or without nicotine. Importantly, mesenchymal-like MCF10CA cells displayed epithelial phenotype with increase in the expression of epithelial markers when they were treated with the CM. These results strongly implies that nicotine-induced polarization of N2-neutrophils plays a critical role in regulating cancer cell plasticity. In addition, levels of LCN2 were significantly higher in the serum and urine of cancer patients and cancer-free healthy subjects who were smokers compared to non-smokers. Collectively, our results suggest a novel pro-metastatic role of nicotine-induced N2-neutrophils via secretion of LCN2 that facilitate metastatic colonization of hormone receptor negative breast cancer cells by supporting MET transition. Citation Format: Abhishek Tyagi, Sambad Sharma, Kerui Wu, Shih-Ying Wu, Dan Zhao, Ravindra Deshpande, Kounosuke Watabe. Nicotine promotes pre-metastatic niche formation in hormone receptor negative breast cancer through paracrine signaling in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3181.

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear. To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer. The SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014). Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size ≥ pT2, histologic grade 3, negative hormone receptor status, or age ≤35 years) primary invasive breast cancer. Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years). The primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis). Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P = .81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P = .90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%). The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced. ClinicalTrials.gov Identifier: NCT02181101.

Tall cell carcinoma with reversed polarity – a case report

Tall cell carcinoma with reversed polarity is a rare subtype of invasive breast carcinoma. Immunohistochemical and molecular research show that it is a distinct entity. It is negative for thyroid specific markers.1 It also has its own unique molecular mutations (IDH2 hotspot mutations and PI3K pathway mutations).2 We present a case of tall cell carcinoma with reversed polarity in the breast of an 81-year-old woman. The lesion showed papillary morphology and columnar cells exhibiting reversed nuclear polarity. Immunohistochemistry showed the tumour cells were positive for CK5/6. They showed weak positivity for GATA3 and GCDFP and were negative for TTF-1. Stains for p63 and p40 showed an absence of myoepithelial cells around tumour nests. The core biopsy showed triple negative hormone receptor status. Further molecular testing was performed which showed a mutation in the PIK3CA gene. An activating mutation in the IDH2 gene was also detected. The combination of morphologic, immunohistochemical and molecular findings are diagnostic of tall cell carcinoma with reverse polarity. It can present a diagnostic challenge when encountered. IDH2 and PI3K mutation testing may provide more confidence with diagnosing these lesions and to help distinguish it from other breast neoplasms. 1.WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Breast Tumours. 5th ed. Lyon: IARC, 2019.2.Zhong E, Scognamiglio T, D'Alfonso T, et al. Breast tumour resembling the tall cell variant of papillary thyroid carcinoma: molecular characterization by next-generation sequencing and histopathological comparison with tall cell papillary carcinoma of thyroid. Int J Surg Pathol 2019; 27: 134–41.

Optimal Duration of Neoadjuvant Taxane and Carboplatin Combined With Anti-HER2 Targeted Therapy for HER2-Positive Breast Cancer.

BackgroundTaxane, carboplatin and trastuzumab (TCH) is an effective neoadjuvant regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer with high pathologic complete response (pCR) rate. The KATHERINE trial changes the outlook for high-risk HER2-positive breast cancer, which suggests that escalation treatment for patients with residual disease after neoadjuvant anti-HER2 therapy may improve survival. The major objective of this study was to investigate the fewest cycles of neoadjuvant TCH therapy needed to screen out non-pCR patients.MethodsThis retrospective study included patients with HER2-positive breast cancer who received either four or six cycles of TCH preoperatively at Fudan University Shanghai Cancer Center between 2008 and 2019. The pCR status was evaluated, and relevant factors associated with pCR were identified using univariate and multivariable analyses. The pathological results of core needle biopsy (CNB) in the breast tumor after two cycles of neoadjuvant chemotherapy were also collected. Kaplan-Meier curve was used to estimate the event-free survival (EFS).ResultsOf 758 eligible patients, 303 were included and analyzed in the four-cycle group and 455 in the six-cycle group. There was no significant difference between the two groups in terms of the pCR rate (46.5% [95% CI 40.9% - 52.2%] in the four-cycle group and 49.9% [95% CI 45.3% - 54.5%] in the six-cycle group, p = 0.365) or the four-year EFS (90.8% in four-cycle group and 93.8% in six-cycle group; p = 0.264). Multivariable analysis indicated that a negative hormone receptor status and the weekly paclitaxel were independent factors for predicting pCR. After adjusting for factors in the multivariable analysis, there was still no significant difference between four and six cycles of neoadjuvant TCH (OR = 1.252, 95% CI 0.904 - 1.733, p = 0.176). Furthermore, 17.9% patients with invasive carcinoma on CNB after two cycles of TCH ultimately achieved pCR in the breast after the completion of neoadjuvant treatment.ConclusionFour cycles of taxane/carboplatin-based neoadjuvant anti-HER2 therapy may be applied as an optimal treatment duration for screening high-risk HER2-positive breast cancer patients for escalation treatment. Further prospective study is warranted.

Survival in male breast cancer (MaBC) over the past three decades.

569 Background: Breast cancer mortality in women has declined significantly over the past several years. In men, it is unclear whether survival has changed over time. The aim of this study was to evaluate changes in breast cancer-specific survival (BCSS) and overall survival (OS) in MaBC over the past three decades. Methods: We evaluated men diagnosed with breast cancer between 1988 and 2017, with known cause of death reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007 and 2008-2017. BCSS and OS were estimated by Kaplan-Meier and differences between groups were compared by log-rank test. Cox proportional hazards regression was used to evaluate the independent association of tumor and patient characteristics with BCSS and OS. Results: We included 8,412 men diagnosed between 1988-1997 (N = 1,033), 1998-2007 (N = 2,938) and 2008-2017 (N = 4,441). Median age for the overall population and within each decade of diagnosis was 68 years. Median follow-up was 23.6 years, 14.3 years and 4.5 years in periods 1988-1997, 1998-2007 and 2008-2017, respectively. Overall, BCSS at 5 years was 83.5%, 83.6% and 84.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.8. There was no significant difference in BCSS between the three periods of diagnosis within each stage of breast cancer (stage I, II, III and IV). Among all patients, OS at 5 years was 64.7%, 67.2% and 69.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.01. In multivariate Cox models, older age at diagnosis, black race, grade 3 disease, increasing stage, hormone receptor negative status and no surgery were all independently associated with worse BCSS and OS. In these adjusted Cox models, each additional year of diagnosis had no significant association with BCSS (hazard ratio, 1.0; 95% CI, 0.99 – 1.01; p = 0.78), and a significant improvement in OS (hazard ratio, 0.99; 95% CI, 0.98 – 0.99; p = 0.01). Conclusions: Over the past three decades, there has been no significant improvement in BCSS in MaBC. The changes in OS over time suggest increasing life expectancy. Efforts to improve BCSS in MaBC are warranted.

Disparities in Guideline-Concordant Initial Systemic Treatment in Women with HER2-Negative Metastatic Breast Cancer: A SEER-Medicare Analysis

BackgroundData on guideline-concordant initial systemic treatment among women with HER2-negative metastatic breast cancer (MBC) are limited. We determined the proportion of women with HER2-negative MBC who received guideline-concordant treatment and the extent to which independent variables explained differences in guideline-concordant treatment by hormone receptor (HR) status.MethodsWe conducted a retrospective cohort study using the SEER-Medicare database. We included women age >65 years diagnosed with HER2-negative MBC during 2010–2013. We used the National Comprehensive Cancer Network treatment guidelines to determine guideline-concordant initial treatment within the first 6 months of a cancer diagnosis. We conducted a multivariable logistic regression to identify the significant predictors of guideline-concordant treatment and a non-linear decomposition method to examine disparities by HR status.ResultsAmong 1089 eligible women, 72.3% received guideline-concordant treatment. Compared to women who did not receive guideline-concordant treatment, women who received guideline-concordant treatment were more like to be comparatively older (p<0.05), married (p=0.0171), resided in areas with higher proportion of people age ≥25 years with at least four years of college education, and had positive HR status (p<0.0001). Approximately 8% of the disparity in guideline-concordant treatment by HR status was explained by their observed characteristics. Need-related factors explained the highest proportion (66.9%) of the disparity.ConclusionOur findings indicate improvement of care for older women, who are single/divorced, have negative HR status, and who live in area with lower education levels. Unexplained disparities in guideline-concordant treatment by HR status can be attributed to patient preferences for treatment, physician-level factors, and perceptions.

Abstract PS18-14: Elucidating the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and immunohistochemical profiling of the tumor microenvironment: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 The DEFENSE study, supported with funding from the NCI Molecular Characterization of Screen-Detected Lesions (MCL) consortium, was designed to identify molecular, immunological, and stromal-related factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: The overall objective of the DEFENSE study is to compare 100 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile (Mammaprint) to 100 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (&amp;gt;5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients are divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunofluoresence (mIF) for immune cell infiltrates, and stromal profiling by IHC. Each profiling modality is performed by a different institution included in the MCL consortium (UCSF, UCD, UCSD, Stanford, and UVM). In order to evaluate the logistic and financial feasibility of our multi-institution protocol prior to expanding to our proposed full-scale study, we are conducting a pilot study of 11 high-risk DCIS specimens. Results: The 11 pilot specimens have been successfully sent and received by each institution. H&amp;E images from the sectioned specimens have been uploaded to the NASA Jet Propulsion Lab (JPL) cloud-based platform and shared for pathologic annotation among institutions. mIF of the pilot cohort has been completed, but interpretation of associations between tumor subtype and immune cell infiltrate is limited by the small sample size. Whole exome DNA sequencing, SMART-3SEQ RNA sequencing, and stromal profiling of the pilot cohort are each ongoing. We anticipate being able to provide full results from each profiling modality performed from the pilot cohort, as well as results from an expanded cohort of 40 additional specimens, by December 2020. Conclusions: We have successfully shown that a multi-institution collaboration can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that data from our expanded cohort will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention.

Abstract PD10-04: Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens

Abstract Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warranted. Citation Format: Alessandro Viansone, Claudia Omarini, Daniela Boggiani, Angelica Sikokis, Vera Uliana, Benedetta Pellegrino, Federico Piacentini, Maria Michiara, Antonino Musolino. Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-04.

The implications of a pathological complete response of the primary tumour after neoadjuvant chemotherapy for breast cancer on axillary surgery

BackgroundManagement of the node-positive axilla after neoadjuvant chemotherapy is controversial. The aim of this study is to predict the group of patients who may require a less invasive approach for axillary management. One possible group are patients with pathological complete response of the primary after chemotherapy.ResultsA unicentral retrospective cohort study including all breast cancer patients with axillary node metastases at presentation who received neoadjuvant chemotherapy resulting in pathological complete response. Pathological complete response in the axillary lymph nodes was recorded. A correlation between the response in the primary tumour and the lymph nodes was assessed. A subgroup analysis was conducted for different biological groups.Complete response was seen in the axillary nodes in 80.5% of patients. Patients with lobular cancer were less likely to show a similar response in the axilla as the primary tumour (p = 0.077). A higher incidence of axillary response was observed in HER2-positive tumours (p = 0.082). All patients with grade 3 tumours achieved complete response in the axilla (p = 0.094). Patients with negative or weak positive hormone receptor status had a significantly higher rate of complete response in the axilla compared to strongly positive hormone receptor status (OR, 7.8; 95% CI, 1.7–34.5; p = 0.007).ConclusionA less invasive axillary surgery may be safely recommended in selected group of node-positive patients after neoadjuvant chemotherapy when the primary tumour shows complete response. This group may include HER2-positive, ER-negative and grade 3 tumours. Less response is expected in ER-positive and lobular carcinoma even with complete response in the primary.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer\u2014results from the randomized phase III SUCCESS-A trial

BackgroundWhen chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients.MethodsA total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety.ResultsNo differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively.ConclusionAdding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting.Trial registrationClinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Membrane mesothelin expression positivity is associated with poor clinical outcome of luminal-type breast cancer.

Mesothelin is expressed in various types of malignant tumors. The present study immunohistochemically investigated mesothelin expression and its clinicopathological significance in each subtype of breast cancer, with special reference to its cellular localization, in particular, membrane mesothelin expression. Using tissue specimens from 482 patients with breast cancer, immunohistochemistry was used to study mesothelin expression and help classify its localization as membrane or cytoplasmic expression. Mesothelin expression was detected in 77 (16.0%) cases and was the highest in triple-negative breast cancer (31/75; 41.3%), followed by human epithelial growth factor receptor type 2 type (6/33, 18.2%) and luminal type (36/374; 9.6%). Among the 482 cases, membrane mesothelin expression was detected in 73 cases and was significantly associated with a negative hormone receptor status, higher Ki-67 labeling index, nuclear grade 3 and a lower relapse-free survival rate. Cytoplasmic mesothelin expression was not significantly associated with a lower relapse-free survival rate (P=0.058). In the 343 cases of luminal type, the membrane mesothelin expression-positive group had significantly worse prognosis than the membrane mesothelin-expression-negative group (P=0.042). There was no significant difference in the relapse-free survival rate according to the membrane mesothelin expression status in the triple-negative type and other types. It was suggested that membrane mesothelin expression in luminal type breast cancer is associated with a lower rate of relapse-free survival.