Progesterone Receptor Positive Tumors Research Articles

Abstract 3971: Progesterone impacts regulatory T cell activity to promote immunosuppression in the mammary gland

Abstract Estrogen and progesterone signaling together drive hormone-receptor positive breast cancer growth and progression. However, there have been limited studies on the independent role that progesterone and its receptor, the progesterone receptor (PR), play in the development of breast cancer. Studies in the Hagan lab have shown that progesterone signaling promotes mammary tumor growth and changes the immune landscape of the mammary gland towards immunosuppression. Regulatory T-cells (Tregs) are immune cells known to promote immunosuppression in the tumor microenvironment. The data from our lab shows that among hormone receptor positive breast cancers, higher levels of PR expression correlates to higher levels of Tregs in the tumor microenvironment. To determine if progesterone signaling increases the number of Tregs in the tumor-bearing mammary gland, we used a syngeneic orthotopic murine tumor model, E0771 cells, engineered to express mouse PR or control empty vector. Mice were treated with progesterone or placebo for 7 days before implantation of the modified E0771 cells. The results of this study show that progesterone promoted tumor growth, and flow cytometry analysis at tumor endpoint showed that PR-positive tumors treated with progesterone harbored more Tregs than mice treated with placebo. Additionally, initial studies using flow cytometry and RNA-seq indicate increased Treg activity following progesterone treatment in PR+ tumor-bearing mice. As progesterone treatment promoted tumor growth and Treg recruitment in progesterone receptor-positive tumors, these data imply that progesterone treatment may promote the release of secreted factors impacting the immune cells in the mammary microenvironment. To determine if progesterone treatment results in cytokine or chemokine changes that may affect Treg recruitment, cytokine arrays and enzyme-linked immunosorbent assays (ELISAs) were performed using cell culture supernatant from murine mammary tumor cells expressing progesterone receptor (E0771-PR) treated with progesterone (0-72 hours). E0771-PR cells treated with progesterone showed higher levels of cytokines and chemokines that have been linked to Treg recruitment and differentiation, such as MCSF. Our findings demonstrate that progesterone signaling promotes an immune suppressed microenvironment in the mammary gland through an increase in Tregs. This evidence provides rationale to investigate the use of anti-progestins as a mechanism to overcome the immune-cold tumor microenvironment seen in progesterone receptor positive breast tumors. Citation Format: Eilidh I. Chowanec, Lauryn R. Werner, Christy R. Hagan. Progesterone impacts regulatory T cell activity to promote immunosuppression in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3971.

Clinicopathological features, psychological status, and prognosis of 33 patients with occult breast cancer.

Occult breast cancer (OBC) has traditionally been considered to be a carcinoma of unknown primary origin with a favorable prognosis and can be treated as stage II-III breast cancer. Due to the small number of cases and limited clinical ex-perience, treatments vary greatly around the world and no standardized treat-ment has yet been established. To investigate the clinicopathological features, psychological status and prog-nostic features of patients with OBC. The clinicopathological data of 33 OBC patients diagnosed and treated in the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital from November 2015 to November 2022 were retrospectively analyzed. The psychological status of OBC patients was evaluated by the Self-rating Anxiety Scale and Self-rating Depression Scale. Patients' emotions, stress perception and psychological resilience were evaluated by the Positive and Negative Affect Schedule, the Chinese Perceived Stress Scale, and the Connor-Davidson Resilience Scale (CD-RISC), respectively. Patient survival was calculated using the Kaplan-Meier method, and survival curves were plotted for analysis with the log-rank test. Univariate and multivariate survival analyses were performed using the Cox regression model. The 33 OBC patients included 32 females and 1 male. Of the 33 patients, 30 (91%) had axillary tumors, 3 (9%) had a neck mass as the primary symptom; 18 (54.5%) had estrogen receptor-positive tumors, 17 (51.5%) had progesterone receptor-positive tumors, and 18 (54.5%) had Her-2-positive tumors; 24 (72.7%) received surgical treatment, including 18 patients who underwent modified radical mastectomy, 1 patient who underwent breast-conserving surgery plus axillary lymph node dissection (ALND), and 5 patients who underwent ALND alone; 12 patients received preoperative neoadjuvant therapy. All 30 patients developed anxiety and depression, with low positive affect scores and high negative affect scores, accompanied by a high stress level and poor psychological resilience. There were no differences in the psychological status of patients according to age, body mass index, or menopausal status. The overall survival and disease-free survival (DFS) of all the patients were 83.3% and 55.7%, respectively. Univariate analysis demonstrated that the initial tumor site (P = 0.021) and node stage (P = 0.020) were factors that may affect patient prognosis. The 5-year DFS rate of OBC patients who received radiotherapy was greater (P < 0.001), while the use of different surgical methods (P = 0.687) had no statistically significant effect on patient outcomes. Multivariate analysis revealed that radiotherapy (P = 0.031) was an independent prognostic factor. Receiving radiotherapy had a significant effect on the CD-RISC score (P = 0.02). OBC is a rare breast disease whose diagnosis and treatment are currently controversial. There was no significant difference in the efficacy of other less invasive surgical procedures compared to those of modified radical mastectomy. In addition, radiotherapy can significantly improve patient outcomes. We should pay attention to the psychological state of patients while they receive antitumor therapy.

Pregnancy-related breast cancer: 14-year experience in a tertiary institution in Hong Kong

BackgroundThe incidence of pregnancy-associated breast cancer (PABC) is increasing. Its tumor characteristics and overall survival compared with those in nonpregnant patients remain controversial. While there have been suggestions that PABC patients have a 40 % increase in the risk of death compared to non-pregnant patients, other studies suggested similar disease outcomes. This study aims to review our local experience with PABC. MethodsTwenty-eight patients diagnosed with PABC and twenty-eight patients diagnosed at premenopausal age randomly selected by a computer-generated system during the same period were recruited. Background characteristics, tumor features, and survival were compared. ResultsAmong the twenty-eight pregnant patients, seventeen were diagnosed during pregnancy, and eleven were diagnosed in the postpartum period. Compared to the non-pregnant breast cancer patients, they presented with less progesterone receptor-positive tumor (35.7 % vs. 64.2 %, p = 0.03). Although there was no statistically significant difference in tumor size (p = 0.44) and nodal status (p = 0.16), the tumor tended to be larger in size (2.94 +/− 1.82 vs 2.40 +/− 1.69 cm) and with more nodal involvement (35.7 % vs 25.0 %). There was also a trend of delayed presentation to medical attention, with a mean duration of 13.1 weeks in the PABC group and 8.6 weeks in the control group. However, the overall survival did not differ (p = 0.63). ConclusionPABC is increasing in incidence. They tend to have more aggressive features, but overall survival remains similar. A multidisciplinary approach is beneficial for providing the most appropriate care.

Tumor Ki-67, ER and PR, and antibodies against estradiol and progesterone in breast cancer patients

Aim. To investigate the associations of cell proliferation marker Ki-67 in estrogen receptor (ER) and progesterone receptor (PR) positive (ER+/ PR+) and negative (ER-/PR-) tumors with the ratio of antibodies against estradiol and progesterone (IgA1-E2/IgA1-Pg) in the serum of breast cancer (BC) patients.Materials and Methods. Antibodies against steroid hormones were analyzed by ELISA in the serum of 432 healthy women and 1212 patients with BC (573 patients with I stage and 639 patients with II–IV stages). Expression of Ki-67, ER and PR in tumors was determined by immunohistochemical staining. Serum estradiol and progesterone were measured by enzyme-linked immunosorbent assay.Results. In total, low IgA1-E2/IgA1-Pg (≤ 1) and high IgA1-E2/IgA1-Pg (&gt; 1) ratio were revealed in 49.3% and 50.7% of healthy women; in 25.7% and 74.3% of stage I BC patients with tumor Ki-67 &lt; 14 (р &lt; 0.001; OR = 0.4 and OR = 2.8, respectively), and in 17.1% and 82.9% of stage I BC patients with tumor Ki-67 &gt; 30 (р &lt; 0.001; OR = 0.2 and OR = 4.7, respectively). The differences between patients with low and high tumor Ki-67 levels in relation to low and high IgA1-E2/IgA1-Pg ratio were statistically significant (p = 0.03). In stage I BC patients with ER+/PR+ and tumors with Ki-67 &lt; 14, low and high IgA1-E2/IgA1-Pg ratio were found in 25.0% and 75.0% cases (р &lt; 0.001; OR = 0.3 and OR = 2.9, respectively). In stage I BC patients with ER+/PR+ and tumors with Ki-67 &gt; 30, low and high IgA1-E2/IgA1-Pg ratio were found in 12.9% and 87.1% cases (р &lt; 0.001; OR = 0.2 and OR = 6.6, respectively). In patients with ER+/PR+ tumors, the differences between patients with low and high tumor Ki-67 levels in relation to low and high IgA1-E2/IgA1-Pg ratio were also statistically significant (p = 0.009). In patients with ER-/PR- tumors, the differences between patients with low and high Ki-67 levels in relation to low and high IgA1-E2/IgA1-Pg ratio were not revealed. The proportion of breast cancer patients with tumor Ki-67 &gt; 30 increased from I to II–IV BC stages regardless of IgA1-E2/IgA1-Pg ratio.Conclusion. IgA1-E2/IgA1-Pg ratio may serve as a predictor of tumor proliferative activity in stage I BC patients with ER+/PR+ tumors.

Tumor Lipid Signatures Are Descriptive of Acquisition of Therapy Resistance in an Endocrine-Related Breast Cancer Mouse Model.

The lipid metabolism adaptations of estrogen and progesterone receptor-positive breast cancer tumors from a mouse syngeneic model are investigated in relation to differences across the transition from hormone-dependent (HD) to hormone-independent (HI) tumor growth and the acquisition of endocrine therapy (ET) resistance (HIR tumors). Results are articulated with reported polar metabolome results to complete a metabolic picture of the above transitions and suggest markers of tumor progression and aggressiveness. Untargeted nuclear magnetic resonance metabolomics was used to analyze tumor and mammary tissue lipid extracts. Tumor progression (HD-HI-HIR) was accompanied by increased nonesterified cholesterol forms and phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens) and decreased relative contents of triglycerides and fatty acids. Predominating fatty acids became shorter and more saturated on average. These results were consistent with gradually more activated cholesterol synthesis, β-oxidation, and phospholipid biosynthesis to sustain tumor growth, as well as an increase in cholesterol (possibly oxysterol) forms. Particular compound levels and ratios were identified as potential endocrine tumor HD-HI-HIR progression markers, supporting new hypotheses to explain acquired ET resistance.

Abstract 622: Progesterone promotes immunosuppression in the mammary gland through regulatory T cell activity

Abstract Estrogen and progesterone signaling together drive hormone-receptor positive breast cancer growth and progression. However, there have been limited studies on the independent role that progesterone and its receptor, the progesterone receptor, play in breast cancer development. Studies in our lab have shown that progesterone signaling promotes mammary tumor growth and changes the immune landscape of the mammary gland towards immunosuppression. Regulatory T-cells (Tregs) are immune cells known to promote immunosuppression in the tumor microenvironment, in part through decreasing the activity of anti-tumor CD8+ T cells. The data from our lab also show that progesterone increases the number of Tregs in the normal mammary gland. To determine if progesterone signaling increases the number of Tregs in the tumor-bearing mammary gland, we used a syngeneic orthotopic murine tumor model, E0771 cells, engineered to express mouse PR or control empty vector. Mice were treated with progesterone or placebo for 7 days before implantation of the modified E0771 cells. Results from this study show that progesterone promoted tumor growth, as well as changed the immune landscape of the tumor. Flow cytometry analysis at tumor endpoint showed that progesterone receptor-positive tumors treated with progesterone harbored more Tregs than placebo treated mice. Additionally, initial studies into activity markers harbored by Tregs in progesterone-treated mice indicate increased Treg activity following progesterone treatment. As progesterone treatment promoted tumor growth and Treg recruitment in progesterone receptor-positive tumors, these data imply that progesterone treatment may promote the release of secreted factors impacting the immune cells in the mammary microenvironment. To determine if progesterone treatment results in cytokine or chemokine changes that may affect Treg recruitment, cytokine arrays and enzyme-linked immunosorbent assays (ELISAs) were performed using cell culture supernatant from murine mammary tumor cells expressing progesterone receptor (E0771-PR) treated with progesterone (0-72 hours). E0771-PR cells treated with progesterone showed higher levels of cytokines and chemokines that have been linked to Treg recruitment and differentiation, such as CCL5. Our findings demonstrate that progesterone signaling promotes an immune suppressed microenvironment in the mammary gland through an increase in Tregs. This evidence provides rationale to investigate the use of anti-progestins as a mechanism to overcome the immune-cold tumor microenvironment seen in progesterone receptor positive breast tumors. Citation Format: Eilidh I. Chowanec, Lauryn R. Werner, Christy Hagan. Progesterone promotes immunosuppression in the mammary gland through regulatory T cell activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 622.

Does Apoptotic Index Predict the Response to Neoadjuvant Chemotherapy in Patients with Breast Carcinoma?

Neoadjuvant chemotherapy (NACT) plays a major role in the treatment of patients with locally advanced breast carcinoma. Although most patients have benefited from NACT, the rate of residual tumors is still high after treatment (AT). An increase in apoptosis is expected in tru-cut biopsy (TCB) during treatment or AT as the mechanism of NACT is inducing apoptosis. This study aimed to investigate whether evaluating the apoptotic index (AI) from TCB can predict the response before treatment (TC-BT) and whether there is a correlation between AI and clinicopathologic parameters. Seventy cases of breast carcinomas were included. The AI was evaluated BT and AT by quantifying the apoptosis. The receiver operating characteristic analysis was performed with overall survival (OS) data, and low and high AI cut-offs were obtained. The relationship between AI and response and clinicopathological parameters was evaluated. A significant relationship was found between low AI in TC-BT and at least partial response (p=0.025), longer OS (p=0.01) and disease-free survival (p=0.01), and progesterone receptor-positive tumors (p=0.03). Her2-negative tumors were more prone to low AI. A significant decline in AI (p=0.001) and Ki67 proliferation index (p<0.001) was observed in resections AT. These data suggested that the AI is a simple and cost-effective tool that may play an important role in determining response, and a low AI in TC-BT may have some value as a predictive marker in breast carcinomas.

Abstract HER2-14: HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series

Abstract Objectives: The concept of human epidermal growth factor receptor 2 (HER2)-low status has been proposed as a potential treatment target for breast cancers previously considered to be HER2-negative. Defined by an immunohistochemistry (IHC) score of 1+ or 2+ and negative fluorescent in situ hybridization (FISH) for HER2, HER2-low status predicts significant clinical benefit from novel therapeutic compounds in recent clinical trials. The prevalence and clinical implications of HER2-low status in patients with early stage invasive lobular carcinoma (ILC) has not been described. We aimed to describe the clinicopathologic features and prevalence of HER2-low status in ILC, and identify any potential differences in clinical outcome. Methods: We evaluated stage I-III ILC tumors from a prospectively maintained institutional database of patients where both IHC and FISH testing for HER2 status was performed as standard clinical care. Tumors were classified as HER2 negative (IHC=0), HER2-low (IHC=1+ or 2+ and negative FISH), or HER2 positive (IHC=3+ or FISH ratio ⇒2). Data were analyzed in Stata 16.1 using chi-squared tests, t-tests, and Cox proportional hazards models for disease free survival (DFS). Results: 666 ILC tumors with available HER2 status were available for analysis. The mean age at diagnosis was 59.8 years (range 21-91). The majority of patients had stage I disease (63.1%) with an average follow up time of 6.7 years (standard deviation [5.4]). Overall, 184 (27.6%) tumors were HER2 negative, 434 (65.1%) were HER2-low, and 48 (7.2%) were HER2 positive. There were no associations between HER2 status and age, menopausal status, body mass index, tumor stage, grade, presence of lymphovascular invasion, or molecular assay results. Hormone receptor status was significantly associated with HER2 status, with HER2 positive tumors significantly less likely to be estrogen receptor (ER) positive than both HER2 negative and HER2-low tumors (89.6% versus 97.3% and 96.8% respectively, p=0.03). HER2-low tumors were also significantly more likely to have progesterone receptor (PR) positivity (86.6% compared to 79.9% of HER2 negative and 72.9% of HER2 positive tumors, p = 0.01). This difference remained significant when comparing just HER2-low to HER2 negative cases (p=0.034). While there were no differences in use of neoadjuvant or adjuvant chemotherapy by HER2 status, HER2-low patients were significantly more likely to undergo mastectomy versus lumpectomy when compared to HER2 negative and HER2 positive patients (53.7% versus 38.0% and 43.8% respectively, p= 0.001). In a multivariable Cox proportional hazards model adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse DFS than those with HER2 negative tumors (hazard ratio 2.0, 95% confidence interval 1.0 - 4.1, p=0.05). Conclusions: In this analysis of 666 early stage ILC cases, we found that most tumors were HER2-low, and that those with HER2-low disease were significantly more likely to have PR positive tumors and to undergo mastectomy. When adjusting for these variables, we identified a difference in DFS between HER2 negative and HER2-low early stage ILC. These findings support the contention that HER2-low and HER2 negative disease represent two different clinical entities. Further investigation of the potential benefit of HER2 targeted therapy in ILC, which predominately lacks HER2-amplified disease, is needed to ensure optimal outcomes in this understudied tumor type. Citation Format: Harriet T. Rothschild, Elle Clelland, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, Mary Kathryn Abel, W. Fraser Symmans, Christopher J. Schwartz, Rita Mukhtar. HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-14.

Abstract P3-05-35: The impact of parity and age of first full term pregnancy on the prevalence of invasive lobular carcinoma in patients with breast cancer

Abstract Background: The impact of reproductive factors on breast cancer has proven to be complex. The risk for estrogen receptor positive/HER2-negative (ER+/HER2-) breast cancer is estimated to be transiently augmented in the years after giving birth (up to 20 years) while later in life high parity and early first full-term pregnancy (1st FTP) seem to protect against ER+/HER2- breast cancer (BC). Invasive lobular carcinomas (ILC) represents the second most common histological subtype of BC and &amp;gt;90% are ER+/HER2-. In this study, we aimed at investigating whether parity and age at 1st FTP are associated with: 1) the prevalence of ER+/HER2- pure ILC (i.e., not mixed) in an ER+/HER2- BC cohort (overall and according to the age at breast cancer diagnosis), and, 2) standard clinical and pathological features of pure ILC. Patients and methods: We performed a single center retrospective study in UZ Leuven, Belgium of patients diagnosed with non-metastatic ER+/HER2- breast cancer between January 2000 and November 2020. Both patient and tumor characteristics were collected from clinical files. Firth’s logistic regression was performed to investigate the association of BC histology (pure ILC vs all other BC histological subtypes = control group) with parity (yes vs. no and nulliparous, 1 child, 2 children, &amp;gt;2 children) in univariable models and multivariable models adjusted for age group at diagnosis (&amp;lt; 30, 31-40, 41-50, 51-60, 61-70, &amp;gt;70), age at 1st FTP (continuous and per age group: &amp;lt; 21, 21-25, 26-30, &amp;gt;30), Interval between 1st FTP and diagnosis (continuous), year of birth and BMI. Analyses were done in the overall group as well as per age group at diagnosis. Similarly, regression analyses were performed in patients with ER+/HER2- ILC to assess the association of parity (yes vs. no and nulliparous, 1 child, 2 children, &amp;gt;2 children) with the following variables: age at diagnosis, BMI, histological grade, tumor size, nodal involvement and progesterone receptor positivity. Results: 7360 patients were included of which 1121 (15.2%) were diagnosed with pure ER+/HER2- ILC, the remaining 6239 (84.8%) patients were considered as the control group. Overall, in multivariable analyses, parity with &amp;gt;2 children was associated with a higher prevalence of pure ILC as compared to uniparous patients (odds ratio, OR 1.257, 95CI 1.039-1.521, p= 0.019). No significant association was seen for age at 1st FTP and interval 1st FTP – diagnosis. The subgroup analyses per age group are summarized in Table 1. Only for the age group 41-50, an increased age 1st FTP was associated with an increased prevalence of pure ILC. In patients with pure ER+/HER2- ILC, nulliparous women were less likely to have a progesterone receptor (PR)-positive tumor as compared to parous women (OR 0.477, 95CI 0.224-0.907, p= 0.022). No other significant associations were seen for clinicopathological features between nulliparous and parous women, and between uniparous and multiparous women in the overall cohort nor any age group. Conclusions: Within an ER+/HER2- breast cancer cohort, higher parity seems to be associated with a higher prevalence of pure ILC, which is especially seen in the patients diagnosed with breast cancer between the age of 51 and 60. Increased age at the 1st FTP only seems to increase the incidence of ILC in the age group 41-50. With the exception of nulliparous women having less PR positive tumors, parity does not seem to affect the clinicopathological features of ER+/HER2- pure ILC. Table 1: subgroup analyses per age group of association of histology (pure ILC vs control group) with parity, age 1st FTP and interval 1st FTP – diagnosis Citation Format: Karen Van Baelen, Ha-Linh Nguyen, François Richard, Maja Vangoitsenhoven, Giuseppe Floris, Hans Wildiers, Kevin Punie, Ann Smeets, Ines Nevelsteen, Frédéric Amant, Sileny Han, Thaïs Baert, Patrick Neven, Christine Desmedt. The impact of parity and age of first full term pregnancy on the prevalence of invasive lobular carcinoma in patients with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-35.

Abstract P6-08-09: Self-identified race and Area Deprivation Index in patients with invasive lobular carcinoma of the breast: associations with tumor characteristics and event free survival

Abstract Objectives: Investigators have shown a relationship between race/ethnicity and survival in invasive lobular carcinoma (ILC), the second most common type of breast cancer. While non-white patients with ILC were shown to have worse outcomes, there are no data evaluating the impact of socioeconomic factors. Herein we evaluated the relationship between self-reported race and socioeconomic factors with tumor features and outcomes in early-stage patients with ILC. Methods: We used chi-squared tests, t-tests, the Kruskal-Wallis test, multivariate Cox proportional hazards models, and tests for trend in Stata 16.1 to evaluate race, area deprivation index (ADI), and event-free survival (EFS) in a single institution cohort of patients with stage I-III ILC. Race was self-reported and categorized as black, white, or other. ADI was ascertained from a publicly available database using measures of income, education level, employment, and housing quality to provide information about neighborhood adversity. ADI was evaluated in quintiles, with quintile 1 signifying the least resource deprived neighborhoods, and quintile 5 signifying the most resource deprived. Tumor receptor subtype was defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Body mass index (BMI) of 18.5-24.9 kg/m2 was categorized as normal, 25-29.9 kg/m2 as overweight, and ≥ 30 kg/m2 as obese. Results: Of 823 patients in our institutional database, self-reported race/ethnicity data were available for 808, with 28 (3.5%) identifying as black, 638 (79.0%) as white, and 142 (17.6%) as other. ADI data were available for 816 patients, with 174 (21.3%) in quintile 1, 210 (25.7%) in quintile 2, 110 (13.5%) in quintile 3, 163 (20.0%) in quintile 4, and 159 (19.5%) in quintile 5. Tumor receptor subtype differed by ADI, with patients in the highest ADI category (most resource-deprived) being most likely to have ER positive, PR positive, and HER2 negative tumors (81.8% in ADI category 5 versus 69.0% in ADI category 1, p=0.001). Those in higher ADI categories were also more likely to have lymphovascular invasion (9.2% in ADI category 5 versus 4.3% in ADI category 1, p=0.008), and were less likely to present with stage I disease (55.5% in ADI category 5 versus 67.9% in ADI category 1, p=0.002). BMI was not associated with tumor characteristics, but was significantly associated with ADI, with a significant trend towards higher BMI in areas of higher ADI (p&amp;lt; 0.001). Among patients who self-identified as black, age at diagnosis was significantly higher compared to those identifying as white or other (mean age 65.8, 59.9, and 58.0 years respectively, p=0.0074). There were no differences in tumor receptor subtype, grade, presence of LVI, or stage by self-identified race. Black-identifying patients were significantly less likely to have the lowest ADI category (0% versus 22.6% and 20.4% in white and other categories respectively, p=0.016), and were significantly more likely to have elevated BMI (79.2% overweight/obese versus 47% of white and 41.5% of other patients, p=0.003). On univariate analysis, self-identified black race, elevated ADI, and overweight/obesity were each associated with significantly worse EFS. However, in a multivariate model containing all three predictors, only overweight/obesity remained significantly associated with worse EFS (hazard ratio 1.6, 95% confidence interval 1.1-2.3, p=0.022). Conclusions: Although prior investigators identified a relationship between non-white race and worse outcomes in patients with ILC, our data show complex relationships between many factors that impact breast cancer outcomes. The relationship between race and EFS was mitigated by ADI and obesity, suggesting that race is not an independent predictor of outcome in patients with ILC. Citation Format: Mandeep Kaur, Anne Patterson, Julissa Molina-Vega, Harriet T. Rothschild, Elle Clelland, Mary Kathryn Abel, Laura J. Esserman, Olufunmilayo I. Olopade, Rita Mukhtar. Self-identified race and Area Deprivation Index in patients with invasive lobular carcinoma of the breast: associations with tumor characteristics and event free survival [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-09.

Telomerase Inhibition by MST-312 Sensitizes Breast Cancer Cells to the Anti-cancer Properties of Plumbagin.

Breast cancer is the most common cause of malignancy and the second most common cause of death due to cancer in women. This heterogeneous disease is currently broadly classified as estrogen receptor (ER), progesterone receptor (PR) positive luminal tumors, human epidermal growth factor receptor 2 (HER2) amplified tumors and triple-negative breast cancers (TNBC). Phytochemicals are proven to be promising anti-cancer chemotherapeutics agents with minimal cytotoxic effects on normal cells. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is a phytochemical derived from the roots of Plumbago zeylanica and it is known to possess anti-cancer properties similar to other compounds of naphthoquinones. In about 90% of cancer cells, the telomerase enzyme activity is revived to add telomeric repeats to evade apoptosis. In this study, a combinatorial approach of combining the anti-cancer compound plumbagin to induce genotoxicity and a potent telomerase inhibitor, MST-312 (synthetic derivative of tea catechins), was used to determine the combinational treatment-induced lethality in breast cancer cells such as MDA-MB-231 (TNBC) and MCF-7 (lumina) cells. MDA-MB-231 cells were responsive to combination treatment in both short-term (48 h) and long-term treatment (14 days) in a synergistic manner, whereas in MCF-7, the combination treatment was more effective in the long-term regimen. Furthermore, the cytotoxic effects of the plumbagin and MST-312 combination treatment were not recoverable after the short-term treatment. In conclusion, a combination treatment of MST-312 and plumbagin is proven to be more effective than a single plumbagin compound treatment in inducing DNA damage and telomere dysfunction leading to greater genome instability, cell cycle arrest and eventually cell death in cancer cells.

Clinicopathologic Features and the Loss of ARID1A Expression in Ovarian Seromucinous Borderline Tumors and Seromucinous Carcinomas.

The current study highlighted the ARID1A and SALL4 expression and described histopathologic and immunohistochemical features of ovarian seromucinous tumors (SMTs) including borderline tumors (SMBTs) and seromucinous carcinomas (SMC; namely as endometrioid carcinoma with mucinous differentiation according to WHO 2020 classification). The clinicopathological and immunohistochemical features of 38 SMTs were analyzed, including ARID1A, SALL4, estrogen receptor (ER), progesterone receptor (PR), TP53, keratin 7, keratin 20, CEA, CDX2, WT1, PAX2, and PAX8. SMCs and SMBTs comprised 68.4% (n = 26) and 31.6% (n = 12) of all SMTs, respectively, studied. The mean age of diagnosis was 47.4 years and 41.4 years, and the mean size was 9 cm and 7.45 cm for SMC and SMBT, respectively. There was endometriosis or endometriotic cyst in 61.5% of SMCs and 50% of SMBTs. Immunohistochemically, loss of ARID1A staining was observed in 15 (65.2%) of 26 SMCs, and 3 (33.3%) of the 12 SMBTs. Only one SMC showed focal SALL4 positivity. All SMTs were positive for ER, PR, PAX8, and keratin 7. SMTs were negative for WT1, keratin 20, CDX2, and CEA (negative in 66.7% to 92.3% of the cases). While all SMBTs and 24 (92.3%) of 26 SMCs exhibited "wild-type" TP53 staining, 2 (7.7%) SMCs, both were stage III, showed mutant type TP53 overexpression. We indicate there is a similarity between SMC and SMBT according to the immunohistochemical features. SMBTs are keratin 7, ER, PR positive tumors, and some of them have loss of ARID1A expression and are likely to develop in the background of endometriosis similar to SMC.

Correlation of P53 Expression with Clinicopathological Parameters, Hormone Receptors and HER 2 Neu Status in Breast Carcinoma

Background: Progesterone receptor (PR), estrogen receptor (ER) expression, human epidermal growth factor 2 (HER 2 neu) amplification/ overexpression, and p53 nuclear protein accumulation are all significant prognostic biomarkers in breast cancer (BC). This work aims to assess the co-presence of p53 overexpression with ER, PR, and HER 2 neu expression in invasive BC specimens by IHC and compare their expression with various clinicopathological features. Objectives: To evaluate the expression of ER, PR, HER-2neu and p53 in invasive breast carcinoma specimens and to correlate the expression of p53 with ER, PR, HER-2 neu and the clinicopathological parameters. Methods: Cases of Modified Radical Mastectomy received from June 2015 to May 2017 were studied. In addition to hematoxylin and eosin sections, immunohistochemical staining was done for ER, PR, HER 2 neu and p53. The expression of ER, PR, HER 2 neu and p53 was noted and the findings were correlated with other clinicopathological parameters. Results: Among 86 cases studied most of them belonged to the age group 41-60 years (54, 62.8%). A significant positive correlation of p53 over expression with ER and PR positive tumours and Triple Negative tumours was noted. Also p53 overexpression showed a positive significant correlation with tumour grade. Conclusion: P53 overexpression in breast carcinoma indicates an aggressive clinical course and can be used as a marker of poor prognosis.

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.

Prognostic factors for relapse in young breast cancer patients

Objective. Breast cancer is the leading cause of cancer mortality in women. Most deaths from breast cancer are due to recurrences or metastatic disease. The purpose of this study is to determine the impact of age in treatment strategy correlated with clinicopathological features. Methodology: In this retrospective study, 60 female patients with histologically-confirmed primary breast cancer were included. The women were treated in the Oncofort Hospital Bucharest, Romania between 2018 and 2020. The estrogen receptor (ER), progesterone receptor (PR) and HER2 status were determined using immunohistochemistry. Results. The mean age was 34.14 years (range = 24 – 40 years). Invasive ductal carcinoma of no specific type was seen in 84.1% of patients. The rates of grade I, II and III carcinomas were 6.7%, 28,3% and 65%, respectively. Among all patients, 33.3% had estrogen receptor, progesterone receptor positive tumors and 66.66% had estrogen receptor, progesterone receptor negative tumors. The proportion of patients overexpressing oncoprotein HER2 was 13.3%. Conclusion. Prognostic value of proliferation index (Ki-67) and hormonal receptors, may vary depending on age.

Expression of ERBB gene family in females with breast cancer and its correlation with clinicopathological characteristics of the disease

Breast cancer (BC) is the most prevalent and fatal cancer in women. Given that there are very few studies investigating the overexpression of four members of ERBB genes, we decided to investigate the correlation between these four genes with clinicopathological characteristics in breast cancer cases. Tumoural tissue of 50 patients with sporadic invasive ductal BC was recruited. Also, control samples were provided from adjacent non-cancerous tissues (ANCTs) of the same patients. The expression of four ERBB genes was evaluated by real-time PCR and its correlation with clinicopathological characteristics was assessed. Only ERBB2 (HER2) was overexpressed in tumoural tissue compared with ANCTs. Our data showed a significant relationship between ERBB1 overexpression with triple-negative tumors, ER, and PR negativity (P < 0.05). Also, ERBB2 overexpression indicated a significant correlation with several pathological characteristics such as age < 50, tumor size larger than 2cm, early and advanced stages, negative involvedlymph nodes, luminal B, triple-negative, ERBB2-enrich, estrogen receptor (ER) and progesterone receptor (PR) negative tumors, Ki-67 mutation more than 15%, and finally HER2/neu immunohistochemistry (IHC) positive and intermediate (P < 0.05). Moreover, this study demonstrated that ERBB4 overexpression had a significant correlation with tumor size smaller than 2cm, grade I and II tumors (early-stage tumors), luminal A, ER and PR positive tumors, HER-2/neu IHC intermediate, and tumors that had a Ki-67 mutation lower than 15% (P < 0.05). Besides, our analysis showed a significant correlation between the expression of ERBB1 with ERBB2 and ERBB3 with ERBB4 (P < 0.05). Our findings showed a significant relationship between unfavorable clinicopathological characteristics with ERBB1 and ERBB2 overexpression, but overexpression of ERBB4 was correlated with favorable outcomes.

Chemotherapy refusal and subsequent survival in older women with high genomic risk, estrogen receptor–positive breast cancer.

520 Background: Patients with estrogen receptor (ER)- positive breast cancer and high-risk 21-gene recurrence score (RS) assay results benefit from chemotherapy, however some patients choose to decline chemotherapy. We evaluated factors associated with chemotherapy refusal by older women with high RS breast cancer and investigated the association of chemotherapy refusal with mortality. Methods: We used the National Cancer Database (2010-2017) to retrospectively identify women aged ≥65 years with ER-positive, HER2-negative, high RS (≥26) breast cancer. Women with Charlson Comorbidity Index ≥1, stage III or IV disease, or any unknown variables were excluded. Women with high RS who refused chemotherapy were compared to women with high RS who received chemotherapy. Refusal trends were analyzed using the Cochrane Armitage test. Factors associated with chemotherapy refusal were evaluated with a multivariable regression model. Overall survival (OS) by age and by treatment were evaluated with Kaplan-Meier and Cox proportional hazards modeling. Results: 6827 women met study criteria; 5449 (80%) received chemotherapy and 1378 (20%) refused. Relative to those who received chemotherapy, those who refused chemotherapy were older (median age 71 vs 69 years; p &lt; 0.05), more often insured with Medicare (83% vs 80%; p = 0.05), were diagnosed more recently (2014-2017 vs 2010-2013, 67% vs 61%; p &lt; 0.05), had lower grade tumors (grade 1 or 2 vs grade 3, 57% vs 48%; p &lt; 0.05), more frequently had progesterone receptor-positive tumors (68% vs 63%; p &lt; 0.05), and received radiation less frequently (67% vs 71%; p &lt; 0.05). Chemotherapy refusal was significantly associated with increasing age (age 75-79 vs 65-74 OR 1.61, CI 1.4-1.85; age ≥80 vs 65-74 OR 3.24, CI 2.76-3.79) and more recent year of diagnosis (2014-2017 vs 2010-2013; OR 1.3 CI 1.14-1.48). Chemotherapy refusal was significantly associated with decreased 5-year OS for patients aged 65-74 years (92% vs 95%; p &lt; 0.05) and patients aged 75-79 years (85% vs 92%; p &lt; 0.05), but not for those aged ≥80 years (84% vs 91%; p = 0.07). Overall, when controlling for patient factors, hazard of death with chemotherapy refusal was significantly increased (HR 1.12, CI 1.04-1.2), but was not increased for women aged ≥80 years when stratified by age. Conclusions: Among healthy women aged ≥65 with high genomic risk ER-positive breast cancer, chemotherapy refusal increased with increasing age. Chemotherapy refusal was significantly associated with decreased OS in women aged 65-79, but did not impact OS in women aged ≥80. Lower use of chemotherapy in women ≥80 may demonstrate pragmatic decision-making between physicians and patients. Furthermore, the routine use of genomic assays may not be appropriate in this age group. More research is needed to determine why women aged 65-79 refuse chemotherapy, and whether patients remain satisfied with these choices.

Evaluating plasma antibody repertoires in breast cancer patients with progesterone receptor positive and negative tumors

Abstract Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. Early cancer detection and tumors molecular characterization are the key measures for effective therapy. Molecular changes associated with tumor development are detected by the immune system and reflected with specific antibody production. We used microarrays containing 120K of peptides with random amino acid sequences to analyze the repertoire of circulating antibodies in the blood plasma of patients with early stages of breast cancer (BC). Previously we have shown that healthy donors and BC patients have distinct circulating antibody repertoires. Further analysis reviled that BC patients with various progesterone receptor (PR) expression levels also have circulating antibodies reacting with different peptides (mimotopes) on microarrays. In this study we selected 61 peptides from 120K peptides presented on microarrays that show statistically significant difference for the interaction with the circulating antibodies of blood plasma from PR+ and PR- BC patients. Peptides interacting with PR+ and PR- patients plasma have common amino acid motifs suggesting that patients with tumors expressing different PR levels mount specific immune response reflecting molecular changes associated with various tumor subtype. Therefore, the panel of peptides that specifically interact with the immunoglobulins of patients with different PR expression can be used for the development of non-invasive test systems. Thus, peptide microarrays can be used to create a new tool for studying the repertoire of circulating antibodies for different diseases evaluation. Supported by grant FZMW-2020-0007. Supported by grants from the Ministry of Science and Higher Education of the Russian Federation (FZMW-2020-0007)

The diffusion MRI signature index is highly correlated with immunohistochemical status and molecular subtype of invasive breast carcinoma.

To evaluate the relationship of the signature index (S-index), an advanced diffusion MRI marker, and the immunohistochemical (IHC) status, proliferation rate, and molecular subtype of invasive breast cancers. A retrospective study of patients with invasive carcinoma was conducted between 2017 and 2021. All patients underwent dynamic contrast-enhanced MRI and DWI using a 3-T system. For DWI, three b values (0, 200, and 1500 s/mm2) were used to derive the S-index. Three-dimensional ROIs were manually placed over the whole tumor on DWI. Mean and 85th percentile S-index values were compared to the IHC status, proliferation rate, and molecular subtypes of lesions. The study included 153 patients (mean age, 60 ± 13 years) with 160 invasive carcinomas. S-index values were significantly higher in estrogen receptor-positive (mean, p = .005; 85th percentile, p < .001) and progesterone receptor-positive (mean, p = .003; 85th percentile, p < .001) tumors, and significantly lower in human epidermal growth factor receptor 2 (HER2) - positive tumors (mean, p = .023; 85th percentile, p < .001). Mean and 85th percentile S-index values were significantly different among breast cancer subtypes (mean, p = .015; 85th percentile, p = .002), and the AUC of these values for the prediction of IHC status were 0.64 and 0.66 for HER2, and 0.70 and 0.74 for hormone receptors, respectively. The DWI S-index showed significantly higher values in invasive carcinomas with immunohistochemical status associated with good prognosis, suggesting its usefulness as a noninvasive imaging biomarker to estimate IHC status and orient treatment. • The signature index, an advanced diffusion MRI marker, showed good discrimination of immunohistochemical status in invasive breast carcinomas. • The signature index has the potential to differentiate noninvasively invasive breast carcinoma subtypes and appears as an imaging biomarker of prognostic factors and molecular phenotypes.

Relation of Receptor Status and Tumor Grade with Menopausal Status in Patients of Carcinoma Breast

Background: Carcinoma of the breast is the most common female cancer and its incidence is rapidly increasing over the last few decades. In Bangladesh, breast cancer is an issue of gaining concern. Receptor status and histological grade are two important prognostic factors of carcinoma breast. Aim of the study: To assess the relation and distribution of receptor status and tumor grade among pre and postmenopausal patients of carcinoma breast. Methods: This cross-sectional observational study was carried out in the Department of General Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU) Dhaka over a period of one year, a total of 59 admitted female patients with histologically proven carcinoma of the breast were divided into two groups included in this study. The premenopausal age group was considered as a group I (n=31) and the postmenopausal age group was considered as group II (n=28). Data regarding the tumor histopathological type, grading, and receptor status along with other variables were included in a pre-designed data collection sheet. After compiling data, Statistical analyses of the data were done with Statistical Packages for Social Sciences (SPSS- 22). Results: Sociodemographic variables and personal histories leading to a risk of breast cancer have no significant difference between pre and postmenopausal groups. Invasive ductal carcinoma (grade-II) was predominant in both groups. Estrogen and progesterone receptor-negative tumors were more frequent in premenopausal patients and estrogen and progesterone receptor-positive tumors were more frequent in a postmenopausal patient, but no statistically significant difference between the two groups. More than eighty percent of tumors were human epidermal growth factor-2 negative in both groups. The frequency of estrogen and progesterone receptor positivity gradually reduce from grade I to III in both groups and the frequency of estrogen and progesterone receptor negativity gradually increase from grade