Estrogen Receptor Negative Tumors Research Articles

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in < 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of < 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between < 40 and ≥ 50 y groups were performed. Results: Pts < 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were < 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ < 40y pts. The median time to recurrence was < 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( < 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of >2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both < 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-11.

Association of Chlamydia trachomatis Infection With Breast Cancer Risk and the Modification Effect of IL-12

BackgroundChlamydia trachomatis (C. trachomatis) infection has been implicated in various cancers, yet its association with breast cancer remains unexplored. This infection triggers a cascade of immune responses primarily regulated by Interleukins-12 (IL-12). Thus, the objective of this case-control study was to investigate the link between C. trachomatis infection and breast cancer risk, as well as the modification effect of IL-12. MethodsWe assessed IgG levels against C. trachomatis in serum of 1,121 women with breast cancer (861 with estrogen receptor-positive (ER+) and 260 with estrogen receptor-negative (ER-) tumors) and 400 controls in Guangzhou, China. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk in association with C. trachomatis infection. The interaction between C. trachomatis infection and IL-12 on breast cancer risk was estimated by the product terms in the logistic regression models. ResultsSeropositivity of C. trachomatis IgG showed a slight association with an increased risk of breast cancer (OR = 1.20; 95% CI: 0.86∼1.78). This association was more pronounced among women with a higher (OR = 5.82; 95% CI: 1.31∼25.94) than a lower (OR = 0.73; 95% CI: 0.41∼1.30) level of IL-12, with a statistically significant interaction observed (Pinteraction = 0.013). In addition, C. trachomatis IgG seropositivity was related to an increased risk of breast cancer among PR+ patients (OR = 1.53; 95% CI: 1.04∼2.23). ConclusionsC. trachomatis infection may contribute to the development of hormone-responsive breast cancer, particularly for women with high levels of IL-12. Further exploration is needed to uncover the underlying mechanisms.

Second primary cancer risks according to race and ethnicity among U.S. breast cancer survivors.

Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIRAANHPI = 1.49, 95% CI = 1.44-1.54; SIRBlack = 1.41, 95% CI = 1.37-1.45; SIRLatina = 1.45, 95% CI = 1.41-1.49; SIRWhite = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.

Prognostic value of molecular classification in stage IV endometrial cancer

ObjectivesMultiple studies have proven the prognostic value of molecular classification for stage I–III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients...

Abstract 1201: Pervasive HLA disruption fuels cancer evolution

Abstract Disruption of the human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. However, although genomic loss of HLA is frequent in non-small cell lung cancer (NSCLC) and in some types of breast cancer, the extent and importance of transcriptomic disruption to HLA presentation, including transcript repression and alternative splicing (AS), remains unclear. To address this, we developed MHC Hammer, a tool to call HLA allele-specific mutations, loss of heterozygosity (LOH), transcriptional repression, and alternative splicing. We first assessed HLA allelic expression and the prevalence of AS in normal tissue. Applying MHC Hammer to 510 normal lung samples and 407 normal breast samples from the Genotype-Tissue Expression cohort, we identified extensive heterogeneity in HLA allelic expression depending on both the allele and tissue type. In addition, HLA allelic AS, occurring in at least 20% of the allele transcripts, was observed in 19% of normal lung and 13% of normal breast samples. Next, we applied MHC Hammer to 413 TRACERx NSCLCs and 743 TCGA breast tumours. While mutations were uncommon, HLA LOH was a frequent event, occurring in 32% of lung adenocarcinomas (LUAD) and 57% of lung squamous cell carcinomas (LUSC). We observed a similar rate of HLA LOH in estrogen receptor positive (ER+) and negative (ER-) tumors (ER+: 14%, ER-: 15%), while in triple negative breast tumours we observed a higher rate of LOH (31%). Due to the heterogeneity in HLA expression observed in the normal samples, to measure tumor specific HLA repression and alternative splicing, we restricted our analysis to tumours with WES, tumor and tumor-adjacent normal RNAseq data. This resulted in a cohort of 88 NSCLCs from the TRACERx study as well as 44 ER+ breast tumours from the TCGA cohort. 61% of LUAD, 75% of LUSC and 35% of ER+ tumours harbored class I HLA transcriptional repression that could not be explained by underlying genomic loss. 27% of LUAD, 7% of LUSC and 55% of ER+ breast tumor patients exhibited no HLA disruption. Tumor specific AS affecting HLA exons 2, 3 or 4, potentially disrupting HLA antigen presentation, was identified in 8% of LUADs, 11% of LUSC and 7% of ER+ breast tumours. Tumor specific AS of exon 5, yielding soluble HLA molecules without a transmembrane domain was identified in 20% of LUAD, 14% of LUSCs and 18% of ER+ breast tumours. LUAD and LUSC tumor regions without HLA LOH or repression were enriched for somatic HLA AS events and alleles with somatic HLA AS had a higher neoantigen burden than those without. We found no relationship between survival and HLA expression or AS in the normal tissue. However, consistent with the importance of HLA dysfunction in tumor evolution, LUADs with low HLA expression in at least one tumor region were associated with shorter disease-free survival, HLA LOH was more common in LUAD’s that metastasized and HLA repression was enriched in LUSC primary regions seeding metastases. Citation Format: Clare Puttick, Thomas P. Jones, Michelle Leung, Oriol Pich, Felipe Galvez Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Carlos Martinez-Ruiz, Robert Bentham, Krijn K. Dijkstra, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A. Quezada, Nicholas McGranahan, Charles Swanton. Pervasive HLA disruption fuels cancer evolution [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 1201.

Abstract B031: High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes

Abstract Introduction: Recent publications have identified ‘low risk’ (LR-NSMP) and ‘high risk’ no specific molecular profile (HR-NSMP) endometrial cancers (ECs). Although LR-NSMP (low grade (G1/2) estrogen receptor (ER) positive tumors have extremely low rates (&amp;lt;2%) of death from disease and are considered candidates for de-escalation of adjuvant therapy, little is known about the newly defined entity of HR-NSMP (G3 and/or ER-negative), including optimal management, with 27% of HR-NSMP patients dying from their disease We aimed to perform in-depth characterization of a cohort of HR-NSMP ECs to identify additional prognostic or predictive features that may inform management. Methods: Clinicopathologic data collection, immunohistochemistry (IHC), and next generation sequencing was performed on a cohort of 148 HR-NSMP ECs testing for associations with outcomes. Three subgroups of HR-NSMP were assessed: i) low grade without any ER expression (G1/2ER-, n=40), ii) high grade with ER (G3ER+, n=67), and iii) high grade without ER expression (G3ER-, n=41). Results: In a univariate analysis, advanced stage (III/IV), positive lymph node (LN) status, no LN assessment, and PIK3CA mutations were associated with inferior progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS). HR-NSMP patients with positive LNs had a hazard ratio (HR) of death of 7.55 (95% CI: 3.41−16.73) compared to node negative. Additionally, patients with no LN assessment had an increased risk of death with a HR of 2.33 (95% CI: 1.12−4.85) compared to node negative. Within the three HR-NSMP subgroups, the worst OS (HR 7.06, CI 4.12-12.09, p&amp;lt; 0.001), DSS (HR 20.43, CI 10.14-41.19, p&amp;lt; 0.001), and PFS (HR 3.69, CI 1.59-8.63, p&amp;lt;0.001) were observed in patients with both adverse features (G3ER-). PIK3CA mutations were found in 32.7% of all HR-NSMP tumors tested (G1/2ER- 45.5%, G3ER+ 42.3%, G3ER- 6.7%) and associated with inferior OS (HR 4.84, CI 1.21-19.41, p=0.014), DSS (HR 4.84, CI 1.21-19.41, p=0.014), and PFS (HR 3.22, CI=1.08-9.66, p=0.028). There was a trend towards decreased OS and DSS in HR-NSMP patients with overexpression of HER2 IHC. L1CAM IHC overexpression and CTNNB1 mutation status were not associated with outcomes when assessed across all HR-NSMP or within subgroups. Conclusion: Among HR-NSMP ECs, the worst clinical outcomes were observed in patients harboring both high grade and ER negative tumors. In contrast to LR-NSMP ECs where patients who had no lymph node assessment had excellent outcomes mirroring node negative status, HR-NSMP patients who had no nodal assessment had a high rate of recurrence and death from disease suggesting the importance of comprehensive staging in this cohort. PIK3CA appears to be a prognostic stratification feature within HR-NSMP and represents a potential therapeutic pathway. More work is needed to understand the association of HER2 expression and ER status and whether HER2 -targeted therapies represent actionable opportunities for these patients. Citation Format: Andrea Neilson, Amy Jamieson, Derek Chiu, Samuel Leung, Amy Lum, Jennifer Pors, Stefan Kommoss, Aline Talhouk, David G. Huntsman, Naveena Singh, C. Blake Gilks, Jessica N. McAlpine. High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B031.

Sex-specific outcomes in cancer therapy: the central role of hormones.

Sex hormones play a pivotal role in modulating various physiological processes, with emerging evidence underscoring their influence on cancer progression and treatment outcomes. This review delves into the intricate relationship between sex hormones and cancer, elucidating the underlying biological mechanisms and their clinical implications. We explore the multifaceted roles of estrogen, androgens, and progesterone, highlighting their respective influence on specific cancers such as breast, ovarian, endometrial, and prostate. Special attention is given to estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) tumors, androgen receptor signaling, and the dual role of progesterone in both promoting and inhibiting cancer progression. Clinical observations reveal varied treatment responses contingent upon hormonal levels, with certain therapies like tamoxifen, aromatase inhibitors, and anti-androgens demonstrating notable success. However, disparities in treatment outcomes between males and females in hormone-sensitive cancers necessitate further exploration. Therapeutically, the utilization of hormone replacement therapy (HRT) during cancer treatments presents both potential risks and benefits. The promise of personalized therapies, tailored to an individual's hormonal profile, offers a novel approach to optimizing therapeutic outcomes. Concurrently, the burgeoning exploration of new drugs and interventions targeting hormonal pathways heralds a future of more effective and precise treatments for hormone-sensitive cancers. This review underscores the pressing need for a deeper understanding of sex hormones in cancer therapy and the ensuing implications for future therapeutic innovations.

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.

Predictors of successful neoadjuvant treatment in HER2‑positive breast cancer.

The prognosis of local or locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer after a complete response from neoadjuvant systemic treatment (NAT) is excellent. However, some of the patients succumb to their disease, so novel predictive factors to identify these patients at risk are needed. Retrospective data from 119 patients treated at the Helsinki University Hospital Comprehensive Cancer Centre (Helsinki, Finland) were collected. All patients had in situ hybridization-confirmed HER2-positive breast cancer and underwent NAT with a curative intention. The primary tumours were relatively large, most patients had cytologically confirmed lymph node metastases and the treatments used were current regimens. A total of 63 (52.1%) patients had a pathological complete response (pCR) to neoadjuvant therapy. Achieving pCR predicted longer disease-free survival (DFS; P=0.0083) but not overall survival (P=0.061). The patients with a pCR had an estimated DFS rate of 96.8% at 5 years, compared with only 59.7% of the patients with non-pCR. Radiological complete response (CR) was associated with pCR (P=0.00033), although imaging yielded 30.4% false-negative and 36.9% false-positive results. The association between the radiological CR and pCR was more obvious in oestrogen receptor-negative tumours. Moderate (compared with strong) immunohistochemical HER2 expression predicted a lower chance of pCR (P=0.0078) and worse breast cancer-specific survival (P=0.0015). In conclusion, pCR after NAT served as an important prognostic factor in women with high-risk HER2-positive breast cancer. The patients with only moderate immunohistochemical HER2 expression had a lower chance of reaching a pCR, as well as a shorter breast cancer-specific survival.

Interrelation of HLA-I and class II major histocompatibility complex molecules with clinical and morphological signs of breast cancer: A retrospective cohort study

Background. For a long time, interest in the HLA peptide complex is unabated, the clinical significance of which in cancer is still the subject of intense debate. Through the presentation of HLA antigens, tumor cells become available for recognition and destruction by effector cells of the immune system. A detailed analysis of the expression status of HLA molecules by breast cancer cells is of both scientific and important practical value. It can provide additional information about the immune system to determine a further strategy for treating breast cancer.&#x0D; Aim. To evaluate the frequency of expression of HLA-I and class II molecules by breast cancer cells and to determine its relationship with the morphological and clinical characteristics of the tumor.&#x0D; Materials and methods. This study included 82 patients with breast cancer who received treatment at the Blokhin National Medical Research Center of Oncology. Immunophenotyping of the primary tumor was performed by the immunohistochemical method (immunofluorescent staining) on cryostat sections. The reaction was evaluated using a ZEISS luminescent microscope (AXIOSKOP, Germany). The frequency of expression of HLA-I and class II molecules was studied depending on the clinical and morphological characteristics of breast cancer.&#x0D; Results. It was found that the frequency of expression of HLA I and II class molecules by breast cancer cells differed. HLA class I antigens are preserved in almost half of the cases 54.5%, while HLA class II antigens are preserved in 22.0%. Associations of molecules of the major histocompatibility complex with clinical and morphological signs of breast cancer were revealed. The frequency of HLA-DR negative cases increases in the stage advanсed (p=0.029). The frequency of monomorphic expression of HLA class II with T1 tumor was 50% versus 0% at T4 tumor (p=0.032). Estrogen receptor-negative tumors in most cases did not express HLA-II class (85.2% vs 64%; p=0.034). No connection with other clinical and morphological features of the tumor has been established.&#x0D; Conclusion. In most cases of breast cancer, the expression of HLA class II molecules is lost, while the expression of HLA class I is preserved in half of the cases. Monomorphic expression of HLA class II is characteristic of the early stage of breast cancer development and predominantly of receptor-positive tumors.

Association of the Duffy-null allele and endometrial cancer characteristics: An effort to explore racial disparity in Black women with endometrial cancer.

5603 Background: Efforts are needed to identify factors that account for the disparately high mortality in Black women with endometrial cancer. The Duffy antigen receptor for chemokines (DARC) is expressed on erythrocytes and endothelial cells and modulates levels of inflammatory chemokines in circulation and in tissues. The African ancestry-specific Duffy-null allele, in which erythrocyte expression and function of DARC is lost, is associated with worse breast cancer phenotypes and survival. Here, we characterize Duffy-null status and associated prognostic and clinical outcomes in patients with endometrial cancer. Methods: Patients with endometrial cancer were prospectively consented, and germline DNA was extracted from saliva or blood samples. Duffy-null genotype was determined using an allelic discrimination assay. Associations between Duffy-null genotype status and clinicopathologic characteristics were performed using Fisher’s Exact analysis. Results: 33 patients were enrolled (Table); 17 (51.5%) were Duffy-null, 5 (15.2%) were Duffy-null allele carriers, and 11 (33.3%) were non-carriers. Compared with non-carriers, Duffy-null patients were more likely to be Black (100% v 9.1%, p&lt;0.0001) and have non-endometrioid histology (64.7% v 10%, p=0.0173). There was a trend towards higher rates of grade 3 histology (70.6% v 36.6%), intact tumor mismatch repair (MMR) (86.7% v 54.6%), estrogen receptor (ER) negative tumor status (25% v 10%), advanced stage (37.5% v 18.2%), and positive lymph nodes (25% v 0%) (Table). Over a minimum of 12 months of follow up, only Duffy-null individuals died from disease (4 v 0, p=0.0006). Conclusions: Duffy-null status was associated Black race, aggressive histologic subtypes, intact MMR mechanisms, and worse survival. Further investigation is needed to explore the underlying mechanism of the Duffy-null phenotype on endometrial cancer outcomes to better elucidate risk factors and underlying causes that may contribute to endometrial cancer disparities.[Table: see text]

Coping After Breast Cancer: Protocol for a Randomized Controlled Trial of Stress Management eHealth Interventions.

One-third or more of breast cancer survivors report stress and other psychological and physical complaints that can negatively impact their quality of life. Psychosocial stress management interventions, shown to mitigate the negative impact of these complaints, can now be delivered as accessible and convenient (for the patient and provider) eHealth interventions. In this randomized controlled trial (RCT), Coping After Breast Cancer (CABC), 2 modified versions of the stress management eHealth intervention program StressProffen were created: one with predominantly cognitive behavioral stress management content (StressProffen-cognitive behavioral therapy intervention [StressProffen-CBI]) and another with predominantly mindfulness-based stress management content (StressProffen-mindfulness-based intervention [StressProffen-MBI]). This study aims to investigate the effects in breast cancer survivors of using StressProffen-CBI and StressProffen-MBI compared with a control group (treatment as usual). Women diagnosed with breast cancer (stage I-III, unequivocally human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors) or ductal carcinoma in situ (DCIS) aged 21-69 years who completed the Cancer Registry of Norway-initiated health survey on quality of life are invited to the CABC trial about 7 months after diagnosis. Women who give consent to participate are randomized (1:1:1) to either the StressProffen-CBI, StressProffen-MBI, or control group. Both StressProffen interventions consist of 10 modules of stress management content delivered through text, sound, video, and images. The primary outcome is between-group changes in perceived stress at 6 months, assessed with Cohen 10-item Perceived Stress Scale. The secondary outcomes comprise changes in quality of life, anxiety, depression, fatigue, sleep, neuropathy, coping, mindfulness, and work-related outcomes approximately 1, 2, and 3 years after diagnosis. Long-term effects of the interventions on work participation, comorbidities, relapse or new cancers, and mortality will be assessed using data from national health registries. Recruitment is scheduled from January 2021 to May 2023. The goal is to recruit 430 participants (100 in each group). As of April 14 2023, 428 participants have been enrolled. The CABC trial is possibly the largest ongoing psychosocial eHealth RCT in patients with breast cancer. If 1 or both interventions prove to be effective in reducing stress and improving psychosocial and physical complains, the StressProffen eHealth interventions could be beneficial, inexpensive, and easily implementable tools for breast cancer survivors when coping with late effects after cancer and cancer treatments. Clinicaltrials.gov NCT04480203; https://clinicaltrials.gov/ct2/show/NCT04480203. DERR1-10.2196/47195.

DNA methylation differences in noncoding regions in ER negative breast tumors between Black and White women.

Incidence of estrogen receptor (ER)-negative breast cancer, an aggressive tumor subtype associated with worse prognosis, is higher among African American/Black women than other US racial and ethnic groups. The reasons for this disparity remain poorly understood but may be partially explained by differences in the epigenetic landscape. We previously conducted genome-wide DNA methylation profiling of ER- breast tumors from Black and White women and identified a large number of differentially methylated loci (DML) by race. Our initial analysis focused on DML mapping to protein-coding genes. In this study, motivated by increasing appreciation for the biological importance of the non-protein coding genome, we focused on 96 DMLs mapping to intergenic and noncoding RNA regions, using paired Illumina Infinium Human Methylation 450K array and RNA-seq data to assess the relationship between CpG methylation and RNA expression of genes located up to 1Mb away from the CpG site. Twenty-three (23) DMLs were significantly correlated with the expression of 36 genes (FDR<0.05), with some DMLs associated with the expression of single gene and others associated with more than one gene. One DML (cg20401567), hypermethylated in ER- tumors from Black versus White women, mapped to a putative enhancer/super-enhancer element located 1.3 Kb downstream of HOXB2. Increased methylation at this CpG correlated with decreased expression of HOXB2 (Rho=-0.74, FDR<0.001) and other HOXB/HOXB-AS genes. Analysis of an independent set of 207 ER- breast cancers from TCGA similarly confirmed hypermethylation at cg20401567 and reduced HOXB2 expression in tumors from Black versus White women (Rho=-0.75, FDR<0.001). Our findings indicate that epigenetic differences in ER- tumors between Black and White women are linked to altered gene expression and may hold functional significance in breast cancer pathogenesis.

Abstract 5757: Breast cancer diagnosis and treatment associated with acceleration of biological aging over time in a racially diverse cohort of women

Abstract Leukocyte DNA methylation (DNAm) at individual sites across the genome can be used to construct measures of biological age. Positive age acceleration—when biological age is older than chronological age—is associated with higher risk of age-associated diseases. Recent adjuvant therapy is reported to increase age acceleration, but the longer-term effects of a breast cancer diagnosis and treatment on age acceleration remain unknown. Here, we use blood samples collected at two timepoints to examine changes in age acceleration over time comparing women who did and did not develop breast cancer. Paired whole blood samples were drawn an average of 8 years apart (range: 5-11 years) in a sample of non-Hispanic White and Black (Hispanic and non-Hispanic) women. DNAm was profiled using Infinium MethylationEPIC BeadChips. Approximately half the women were diagnosed and treated for breast cancer between blood draws (cases; n= 190, baseline mean age= 57) whereas the other half remained breast cancer-free (controls; n= 227, baseline mean age= 56). Longitudinal changes in three age acceleration metrics were compared to determine whether an intervening breast cancer diagnosis and treatment was associated with trajectories in biological aging. On average, the cases were diagnosed with breast cancer 3.5 years after the initial blood draw and 4 years before the second blood draw. Among the cases, 36% were treated with chemotherapy, 65% with radiation therapy, and 70% with hormonal therapies; 45% of the cases received two types of therapy, and 13% received all three. Compared to women who remained cancer-free, women diagnosed and treated for breast cancer had increases in age acceleration over time as measured by PhenoAgeAccel (adjusted standardized mean difference (β)= 0.13, 95% CI: 0.00, 0.26), GrimAgeAccel (β= 0.13, 95% CI: 0.03, 0.24), and DunedinPACE (β= 0.35, 95% CI: 0.23, 0.48). The associations did not vary by timing of diagnosis between the blood draws or race; however, women diagnosed with estrogen receptor (ER) negative tumors appeared to experience faster increases in age acceleration than women diagnosed with ER positive tumors (GrimAgeAccel; ER negative β= 0.27, 95% CI: 0.07, 0.47; ER positive β= 0.10, 95% CI: -0.01, 0.21; P-interaction= 0.14). To investigate the impact of different types of breast cancer therapies, associations were examined using a case-only design. In models that simultaneously included chemotherapy, radiation therapy and hormone therapy, radiation therapy had the strongest associations with accelerated biological aging as measured by PhenoAgeAccel (β= 0.38, 95% CI: 0.18, 0.58), GrimAgeAccel (β= 0.27, 95% CI: 0.09, 0.45), and DunedinPACE (β= 0.25, 95% CI: 0.03, 0.47). We find that years after the initial diagnosis, breast cancer survivors have significantly accelerated biological aging; treatment modalities may differentially influence these rates. Citation Format: Jacob K. Kresovich, Katie M. O'Brien, Zongli Xu, Clarice R. Weinberg, Dale P. Sandler, Jack A. Taylor. Breast cancer diagnosis and treatment associated with acceleration of biological aging over time in a racially diverse cohort of women. [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 5757.

Abstract 5516: Identifying DNA methylation biomarkers in Brazilian women of African descent

Abstract Breast cancer is the most common cancer, and the leading cause of cancer-related deaths in Brazilian women. Studies have shown that in Brazil while breast cancer mortality has increased in the last decade for all women, mortality in women of African descent has doubled. A recent study showed that Afro-Brazilian women suffer from higher excess breast cancer mortality even after adjusting for extent of disease, year of diagnosis, age and socioeconomic status, which suggests biological factors also contribute to the differences in the clinicopathological make-up of the disease in women in this group. DNA methylation biomarkers, representing a combination of genetic and non-genetic factors, have the potential to be especially valuable when considering the combined contribution of the environment and genetics in breast cancer etiology. Several groups have found differences in DNA methylation levels associated with race and ethnicity in breast cancer. In addition, research has shown that women of different races/ethnicities with similar breast cancer tumor subtypes have distinct DNA methylation patterns. To explore further the association between race, ancestry and DNA methylation, we conducted a study in paired tumor and non-tumor tissue samples of forty-eight Brazilian women who self-identified as Black or Brown and were treated at National Cancer Institute Breast Cancer Hospital in Rio de Janeiro, Brazil. We carried out a DNA methylation profiling analysis using Illumina EPIC (850k) arrays in bisulfite converted DNA originally extracted from frozen tissue samples. A total of 739,883 differentially methylated probes (DMP) were identified, of which a large proportion 6,241 (78.4%) were hypomethylated. Lower DNA methylation was more common on intragenic regions and gene bodies, while hypermethylation was more commonly found on the promoter regions. DNA methylation was often higher in non-tumor than tumor samples. Among our top hits we found genes previously associated with estrogen receptor negative tumor types, CDH4, CERK, PROX1 and ADHFE1, and with high risk of breast cancer mortality (ST6GAL1, LYN, TFF1 and BMP3). A DPM enrichment pathway analysis predicted effects in known signaling pathways and transcriptional misregulation. We are currently analyzing the associations between the top differentially methylated regions with ancestry informative markers, and the clinicopathological characteristics of disease, to gain a better understanding of the role of DNA methylation marks in this population. This study adds to our current knowledge on epigenetics marks that will ultimately help us address mortality due to this disease in this population. Citation Format: Lissette Delgado-Cruzata, Diego J. Gomes de Paula, Jennifer Vieira Gomes, Tatiana A. Simão, Leonor Gusmão, Luis Felipe Ribeiro Pinto, Sheila C. Soares-Lima. Identifying DNA methylation biomarkers in Brazilian women of African descent. [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 5516.

Parental occupational exposure to chemicals and risk of breast cancer in female offspring

ObjectivesParental exposure to chemicals at work has been hypothesized to be a potential predisposing factor for breast cancer in next generations. The objective of the present nationwide nested case-control study was to contribute with evidence to this area. MethodsWomen with primary breast cancer were identified using the Danish Cancer Registry and they were required to have information on either maternal or paternal employment history, which resulted in the inclusion of 5587 cases. For each case, 20 female cancer free controls were matched on year of birth using the Danish Civil Registration System. Employment history was linked to job exposure matrices to assess specific occupational chemical exposures. ResultsFor maternal exposures, we observed an association between ever exposure to diesel exhaust (OR = 1.13, 95% CI: 1.01–1.27) and exposure to bitumen fumes in the perinatal period (OR = 1.51, 95% CI: 1.00–2.26) and breast cancer in female offspring. Highest cumulative exposure to benzo(a)pyrene, diesel exhaust, gasoline and bitumen fumes was further indicated to increase the risk. Results further indicated a stronger association between diesel exhaust (OR = 1.23, 95% CI: 1.01–1.50) and benzo(a)pyrene exposure (OR = 1.23, 95% CI: 0.96–1.57) and estrogen receptor negative tumors than tumors with ER expression, while bitumen fumes seemed to elevate the risk of both hormonal subtypes. For paternal exposures, the main results did not indicate any associations with breast cancer in female offspring. ConclusionsOur study suggests an elevated breast cancer risk in daughters of women occupational exposed to some occupational pollutants, including diesel exhaust, benzo(a)pyrene and bitumen fumes. These findings need to be confirmed in future large-scale studies before any firm conclusions can be reached.

Abstract PL2: Plenary Lecture 2: Premenopausal ER+ Breast Cancer: Past, Present, and Future

Abstract Adjuvant endocrine therapy for premenopausal ER+breast cancer had a relatively challenging initial pathway. The earliest trials testing adjuvant ovarian ablation in premenopausal breast cancer were hampered by the lack of ability to test for the relevant target, namely the estrogen receptor (ER). Therefore, trials testing adjuvant ovarian ablation and subsequently ovarian suppression with gonadotropin releasing hormone agonists (GnRHa) were diluted by the inclusion of women with estrogen receptor negative tumors. The subsequent demonstration of the effectiveness of adjuvant chemotherapy, initially with the CMF regimen, diverted some attention away from adjuvant endocrine therapy in premenopausal women, notwithstanding the fact that CMF, initially given for 12 months, resulted in permanent ovarian function suppression in many premenopausal women. Use of adjuvant CMF made it even more challenging to discern the added value of ovarian ablation or suppression. Oral adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen became recommended for postmenopausal women, subsequently refined to only those with ER+ breast cancer, but the value of tamoxifen in premenopausal women was initially considered uncertain. Eventually, 5 years of adjuvant tamoxifen became a standard recommendation for premenopausal ER+ early breast cancer, although it took some time for evidence to emerge on the value of adding tamoxifen in women who received chemotherapy. The value of extending adjuvant endocrine therapy beyond 5 years was subsequently studied. More recent randomized premenopausal adjuvant endocrine therapy trials have focused of delineating the value of ovarian function suppression (OFS) added to tamoxifen or to an aromatase inhibitor. There are now a range of options for adjuvant endocrine therapy for premenopausal ER+ breast cancer, and identifying the clinical-pathologic features most appropriate for intensification of adjuvant endocrine therapy can assist with optimizing recommendations for an individual patient. Citation Format: Carlos Arteaga, Prudence Francis. Plenary Lecture 2: Premenopausal ER+ Breast Cancer: Past, Present, and Future [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 PL2.

Abstract P3-03-08: Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study

Abstract Background: The importance of mental health to improve the quality of cancer survivorship and outcomes is gaining increased attention. Major depressive disorder (MDD) has been associated with higher breast cancer (BC) incidence, BC-specific and all-cause mortality. The effect of MDD on BC recurrence remains under-studied. The Veterans Health Administration (VHA) provides a unique opportunity to examine this relationship as it mandates annual MDD screening in the primary care setting and reports national screening rates of 96%. Objective: To examine the relationship between pre-existing MDD and BC recurrence among a diverse cohort of women in the United States. Methods: We established a retrospective cohort of women (age ≥ 18 years) diagnosed with early-stage incident BC from 2010 through 2019 using the VHA’s electronic medical record database. We used a two-year window to identify women with clinically diagnosed MDD prior to their BC diagnosis. Our outcome of interest was BC recurrence (local recurrence/second primary and distant recurrence). We used multivariable proportional hazards regression to examine the association between MDD and BC recurrence, accounting for competing risk of death. Our analyses were adjusted for age, race, ethnicity, marital status, priority group rating (proxy for socioeconomic status), rurality of primary residence, geographical region, cancer stage, year of BC diagnosis, and comorbidity burden. Priority group rating is a metric that incorporates patients’ income, receipt of VHA assistance benefits, capacity for gainful employment, and severity of service-connected conditions. We conducted subgroup analyses by tumor subtype. RESULTS: Our cohort consists of 6,045 women with BC, of whom 1,750 (29.0%) had a pre-existing MDD diagnosis. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall and 56 years (SD=10 years) among women with MDD. Sixty-one percent of women were white, 29% were black, 27% were married, and 28% were rural dwelling. Forty-four percent of invasive carcinomas were localized and 21% were regional. Thirty-five percent of patients had ductal carcinoma in situ. Women with MDD had a higher average Charlson Comorbidity Index score (mean=0.75, SD=1.13 vs. mean=0.58, SD=1.03) and proportion with a priority group rating between 1-4 (40% vs. 32%). The distribution of other described patient characteristics among women with MDD were similar to the overall cohort. On multivariable analysis, women with MDD had a 31% (95% CI: 1.11, 1.56) higher risk of BC recurrence compared to women without MDD. MDD was associated with a 29% (95% CI: 1.01, 1.66) and 33% (95% CI: 1.05, 1.67) higher risk of local recurrence/second primary and distant recurrence, respectively. The relationship between MDD and BC recurrence remained significant after adjusting for tumor subtype (HR=1.40, 95% CI: 1.07, 1.83). In subgroup analyses stratified by tumor subtype, MDD was associated with a higher risk of BC recurrence among women with estrogen receptor positive versus negative tumors (HR=1.65, 95% CI: 1.27, 2.14 vs. HR=0.71, 95% CI: 0.34, 1.46) and HER2/neu negative versus positive tumors (HR=1.53, 95% CI: 1.16, 2.00 vs. HR=1.24, 95% CI: 0.51, 2.96). The interaction between estrogen receptor status and MDD was statistically significant (p-interaction=0.02). CONCLUSION: Women with incident BC should be screened for MDD early in the cancer care continuum given the prevalence of MDD and association with increased risk of local recurrence/second primary and distant BC recurrence. Further research is needed to understand the interplay between these two diseases and their treatments. Citation Format: Maya Aboumrad, Brian Shiner, Avonne Connor, Bradley V. Watts, Kala Visvanathan. Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study [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 P3-03-08.

Differential Protein Citrullination in Human ER- and ER+ Tumor and Adjacent Healthy Breast Tissue.

Post-translational modification of arginine to citrulline is catalyzed by members of the peptidylarginine deiminase (PAD) family. Dysregulation of this catalysis is a significant driver of the pathogenesis of numerous inflammatory diseases, including cancer. However, dysregulation of PAD activity has not been examined in breast cancer with respect to hormone receptor status. In this study, we measured PAD enzyme levels using Western blotting and investigated protein citrullination using a mass spectrometry-based proteomics approach in primary estrogen receptor negative (ER-) or positive (ER+) breast tumor and matched adjacent normal tissue. Our findings reveal 72 and 41 citrullinated proteins in ER- tumor and adjacent healthy tissue, respectively, where 20 of these proteins are common between the two groups. We detected 64 and 49 citrullinated proteins in ER+ tumor and adjacent healthy tissue, respectively, where 32 proteins are common. Interestingly, upon comparison of ER- and ER+ tumor tissue, only 32 citrullinated proteins are shared between the two and the rest are unique to the tumor's receptor status. Using the STRING database for protein-protein interaction network analysis, these proteins are involved in protein-folding events (i.e., heat shock proteins) in ER- samples and blood-clotting events (i.e., fibulin) in ER+ samples. Constituents of the extracellular matrix structure (i.e., collagen and fibrinogen) were found in both. Herein, we establish evidence that supports the role of this unique post-translational modification in breast cancer biology. Finally, to aid drug discovery against citrullination, we developed a liquid chromatography-ultraviolet method to measure PAD enzymatic activity and optimized glucagon-like peptide II to quantitatively measure the ability of PADs to citrullinate its substrate.

Preferences Regarding Breast Surgery Omission Among Patients With Breast Cancer Who Receive Neoadjuvant Chemotherapy.

Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery. We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed. Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017). The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk.