Antihormonal Therapy Research Articles

Abstract P3-05-55: The Effects of Comorbidities on the Effectiveness of Neoadjuvant Chemotherapy in Breast Cancer

Abstract Background: Neoadjuvant chemotherapy has been used in a variety of cancer treatments to transform inoperable tumors to operable tumors. Within breast cancer treatment, it has successfully been used to increase the rates of breast conservation therapy. Neoadjuvant chemotherapy is being used to downgrade locally advanced breast cancer, as well as treat inflammatory breast cancer, and node negative breast cancers with genetic expression profiling results that predict the need for adjuvant chemotherapy. There have been several studies that have evaluated the effects of age and comorbidities of patients with breast cancer on treatment decisions, particularly chemotherapy. However, very few studies have reviewed additional factors outside of tumor characteristics for predicting complete response to neoadjuvant chemotherapy. The purpose of this study is to determine if there are any patient factors, particularly comorbidities, that play a role in modifying chemotherapy regimens and if that affects the patient’s response to chemotherapy. Methods: A retrospective chart review was performed on patients between 18-89 years of age at the time of their breast cancer diagnosis, who underwent neoadjuvant between 1/1/2014 and 1/1/2019. Patients included were treated by Dr. Kara Friend or Dr. Jennifer Reed at Sentara Leigh Memorial Hospital. Data collected included demographics, tumor characteristics, treatment regimens (chemotherapy, radiation therapy, antihormone therapy, and surgery), noting when chemotherapy regimens had to be modified, pathologic response to neoadjuvant chemotherapy, and long term outcomes. Comorbidities were identifed and used to calculate the Charleson Comorbidity Index (CCI), which was used to categorize patients. Results: A total of 111 patients were reviewed. All patients were female and ages ranged from 24 to 84, with most patients being in their fourth or fifth decade. 30% of the patients had triple negative tumors, and 48% had HER2+ tumors. Most patients had invasive ductal carcinoma, with only 6 patients (5.4%) having invasive lobular carcinoma. 26 patients had positive genetic panels, 10 of which were BRCA positive. 28 patients had negative panels, and 57 were not tested. The most common chemotherapy regimens were TCHP, AC/T, and TCH. Two patient’s cycles were reduced from the beginning due to low ejection fractions, 3 were modified due to pulmonary reactions, 1 for renal failure, 1 for Hepatitis C activation, and 10 for neutropenia or infections. One patient self-discontinued chemotherapy in favor of alternative medicine. 65.7% of the patients underwent antihormone therapy. 27% of the patients underwent radiation. Most patients had CCI scores of 0. Of those with a CCI score of 0, 4 needed modified regimens (8.3%). Of those with a CCI score of 1, three needed modified regimens (10.3%). Of those with a CCI score of 2, three patients needed modified regimens (23.3%). Of those with a CCI score of 3 or greater, 8 needed modified regimens (38.1%) When evaluating the effect of a CCI of 0-2 compared to 3 or greater on likelihood of reduced chemotherapy, there was not a statistically significant result (p = 0.99). However, the appeared to be a trend of increasing need for modified regimen with increasing CCI score. When evaluating if a reduced chemotherapy regimen led to progression during neoadjuvant chemotherapy or no response, the result was not statistically significant (p=0.24). Conclusion: Our study suggests that an increasing CCI score corresponds to an increased likelihood of needing a modified regimen, however this result was not statistically significant. Increased comorbidities and the need for modifying chemotherapy regimens do not appear to have an effect on pathologic response to neoadjuvant chemotherapy. This study is limited by the sample size, and a greater sample size will be necessary to make further conclusions. Citation Format: Kara Friend, Rebecca Breese, Tracey Pu, Jasmine Wood, Fatima Arif. The Effects of Comorbidities on the Effectiveness of Neoadjuvant Chemotherapy in 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 P3-05-55.

Abstract P1-10-08: Incidence of rib fracture following treatment with proton therapy for breast cancer

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had > 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for 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 P1-10-08.

Abstract P1-02-06: Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients

Abstract Background: Poor survival outcome in young women with hormone-sensitive breast cancer was reported. And previous studies have demonstrated that the addition of ovarian function suppression (OFS) significantly improved disease-free survival (DFS) in patients with premenopausal hormone receptor–positive breast cancer. In this study, we examined whether ovarian function suppression treatment in premenopausal women is effective in survival comparable to postmenopausal status. Methods: We evaluated 1,298 breast cancer patients included in the post-trial follow-up of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial who received either tamoxifen (TAM) only (n=647) or TAM + OFS (n=635), randomly assigned in a 1:1 ratio and postmenopausal patients in AMC (Asan Medical Center; Seoul, Korea) treated with aromatase inhibitor (AI) (n=603). All patients analyzed in this study underwent surgery between March 2009 and November 2011. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS). We use propensity-score matching by lymph node status, tumor size, tumor grade, histologic type of cancer, human epidermal growth factor receptor-2 (HER2) status, chemotherapy regimen, surgical modality, and radiotherapy in the overall cohort and in separate subgroups according to anti-hormonal therapy regimens. Results: In the overall matched cohort, there was a significant difference between the postmenopausal AI group and premenopausal Tam only group in DFS (hazard ratio for the postmenopausal AI group, 0.654; 95% CI, 0.432 to 0.991) and OS was not significantly different between the premenopausal Tam only group and postmenopausal AI group (p=0.061). On the other hand, there was no significant difference between the postmenopausal AI group and premenopausal Tam+OFS group in disease free survival (hazard ratio for the postmenopausal AI group, 1.156; 95% confidence interval [CI], 0.735 to 1.820) or the overall survival (hazard ratio for the postmenopausal AI group, 1.04; 95% CI, 0.553 to 1.956). Conclusion: This study’s findings suggest that the poor prognosis of young women with hormone-sensitive breast cancer is improved by adding OFS to Tam and the effect is not inferior to that of using AI in post-menopausal women. Outcomes in a Cohort of Patients Matched for Propensity Scores postmeno AI, postmenopausal patients who treated with aromatase inhibior in Asan Medical Center; premeno Tam+OFS, premenopausal ASTRRA participants who treated with tamoxifen and ovarian function suppression; premeno Tam, premenopausal ASTRRA participants who treated with tamoxifen only Citation Format: Young-jin Lee, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Seonok Kim, Hee Jeong Kim. Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients [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 P1-02-06.

Androgen deprivation therapy ± new antihormonal therapy for the treatment of metastatic hormone-sensitive prostate cancer

From 1941 to 2014, metastatic hormone-sensitive prostate cancer (mHSPC) was solely treated by surgery or medical castration (androgen deprivation therapy [ADT]). In 2014, the addition of docetaxel chemotherapy (CTX) was shown to significantly improve overall survival. However, CTX is not ideal for all patients. Some are too old, too sick, or oppose to treatment with CTX. Therefore, alternatives with low toxicity and equal efficacy were explored. Abiraterone (Abi), apalutamide (Apa), and enzalutamide (Enza) are new antihormonal therapies (NHT) which meet these requirements. To review the role of NHTs + ADT in mHSPC. Prerequisites and challenges are summarized and key data on combination therapy with NHTs + ADT in mHSPC are reviewed. Treatment of mHSPC with Abi, Apa, or Enza represents abig step forward. Especially for patients who do not qualify for CTX or oppose CTX, NHTs are avalid alternative. The use of Abi is more challenging than the use of Apa and Enza due to more complex conditions that need to be fulfilled for its use. Thus, the time for the patient in the mHSPC stage will be longer with more intensive androgen deprivation, which may lead to increased risk of cardiovascular disease and osteoporosis. When choosing atreatment with NHTs in this setting, possible follow-up treatment needs to be considered. Treatment of mHSPC using NHTs + ADT is an important new standard. Almost every patient can be treated with one of the NHTs with relatively low risk of toxicity. Therefore, these treatments are widely used. In the future, the addition of new therapeutics could further strengthen the relevance of NHTs in the mHSPC setting.

A Systematic Review on the Potential Acceleration of Neurocognitive Aging in Older Cancer Survivors.

As survival rates increase, more emphasis has gone to possible cognitive sequelae in older cancer patients, which could be explained by accelerated brain aging. In this review, we provide a complete overview of studies investigating neuroimaging, neurocognitive, and neurodegenerative disorders in older cancer survivors (>65 years), based on three databases (Pubmed, Web of Science and Medline). Ninety-six studies were included. Evidence was found for functional and structural brain changes (frontal regions, basal ganglia, gray and white matter), compared to healthy controls. Cognitive decline was mainly found in memory functioning. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes with an increased risk of Alzheimer's disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in patients with non-central nervous system cancer but can play a role in patients with central nervous system cancer, while neurosurgery seemed to improve their cognition in the short-term. Individual risk factors included cancer subtypes (e.g., brain cancer, hormone-related cancers), treatment (e.g., anti-hormonal therapy, chemotherapy, cranial radiation), genetic predisposition (e.g., APOE, COMT, BDNF), age, comorbidities (e.g., frailty, cognitive reserve), and psychological (e.g., depression, (post-traumatic) distress, sleep, fatigue) and social factors (e.g., loneliness, limited caregiver support, low SES). More research on accelerated aging is required to guide intervention studies.

Contralateral lymph node metastasis in recurrent ipsilateral breast cancer with Lynch syndrome: a locoregional event

IntroductionContralateral axillary lymph node metastasis (CALNM) in breast cancer (BC) is considered a distant metastasis, marking stage 4cancer. Therefore, it is generally treated as an incurable disease. However, in clinical practice, staging and treatment remain controversial due to a paucity of data, and the St. Gallen 2021 consensus panel recommended a curative approach in patients with oligometastatic disease. Aberrant lymph node (LN) drainage following previous surgery or radiotherapy is common. Therefore, CALNM may be considered a regional event rather than systemic disease, and a re-sentinel procedure aided by lymphoscintigraphy permits adequate regional staging.Case reportHere, we report a 37-year-old patient with Lynch syndrome who presented with CALNM in an ipsilateral relapse of a moderately differentiated invasive ductal BC (ER 90%, PR 30%, HER2 negative, Ki-67 25%, microsatellite stable), 3 years after the initial diagnosis. Lymphoscintigraphy detected a positive sentinel LN in the contralateral axilla despite no sign of LN involvement or distant metastases on FDG PET/CT or MRI. The patient underwent bilateral mastectomy with sentinel node dissection, surgical reconstruction with histological confirmation of the CALNM, left axillary dissection, adjuvant chemotherapy, and anti-hormone therapy. In addition to her regular BC follow-up visits, the patient will undergo annual colonoscopy, gastroscopy, abdominal, and vaginal ultrasound screening. In January 2023, the patient was free of progression for 23 months after initiation of treatment for recurrent BC and CALNM.ConclusionThis case highlights the value of delayed lymphoscintigraphy and the contribution of sentinel procedure for local control in the setting of recurrent BC. Aberrant lymph node drainage following previous surgery may be the underlying cause of CALNM. We propose that CALNM without evidence of systemic metastasis should be considered a regional event in recurrent BC, and thus, a curative approach can be pursued. The next AJCC BC staging should clarify the role of CALNM in recurrent BC to allow for the development of specific treatment guidelines.

Cell State Transitions and Phenotypic Heterogeneity in Luminal Breast Cancer Implicating MicroRNAs as Potential Regulators.

Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype.

Pharmacological Treatment of Perianal Gland Tumors in Male Dogs.

The presence of androgen (AR) and estrogen (ER) receptors has been demonstrated both in normal perianal (hepatoid) glands and in perianal tumors. The aim of this study was to demonstrate the relationship between the expression of AR and ER in perianal gland tumors and the effectiveness of antihormonal treatment. The study was performed on 41 male dogs with neoplastic lesions of the anal region. Histopathological evaluation of the lesions revealed 24 adenomas, 12 epitheliomas, and five carcinomas. Treatment was administered orally with tamoxifen at a dose of 1 mg/kg BW and cyproterone acetate at a dose of 5 mg/kg. Tumor diameters were measured regularly with calipers and recorded in millimeters starting with the measurement before treatment, and then after 1, 2, 3, 6, 12, 18, and 24 months of therapy. The results show that hepatoid adenomas that are characterized by high expression of AR and ER receptors respond positively to antihormonal therapy, resulting in complete tumor regression. For locally malignant hepatoid epitheliomas and carcinomas with low expression of AR and ER receptors, antihormonal therapy makes it possible to reduce the size of the tumor, but does not make it possible to cure it completely.

Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha.

Breast cancer (BC) is the most common neoplastic and lethal malignancy in women. Although antiendocrine therapy is the main treatment for estrogen receptor alpha (ERα)-positive BC, the development of resistance is a major clinical complication. In this study, we aimed to explore the role of ubiquitin-specific peptidase 8 (USP8) in ERα signaling and identify potential targets for endocrine resistance. Public databases were used to analyze USP8 expression, prognosis, clinical characteristics, and immune cell infiltration. Immunohistochemistry and western blot assays were used to detect protein levels and ERα signaling. Quantitative reverse transcription-PCR was used to measure ERα target gene expression. The cell counting kit-8, wound-healing, clone formation, and Transwell assays were used to investigate the effects of USP8 depletion or inhibition on cell proliferation, migration, and invasion. An immunofluorescence assay was used for localizing USP8 and ERα, and a protein stability assay was performed for detecting the degradation of ERα protein. The cell cycle and apoptosis were assessed using flow cytometry. USP8 was highly expressed in the luminal subtype of BC and was associated with poor prognosis. The infiltration levels of many immune cells were positively correlated with USP8 expression. Depletion of USP8 dramatically decreased the ERα signaling activity and weakened the proliferation, migration, and invasion capabilities of BC cells. USP8 knockdown markedly induced apoptosis and cell cycle arrest (G0/G1). Colocalization analysis and protein stability assays indicated a probable mechanism by which USP8 regulates ERα. Our study demonstrates that USP8 might be crucial in BC development and may be considered a potential target for treating ER-positive BC malignancies in vitro.

Initial observations on sexual dysfunction as a symptom of chemotherapy-induced peripheral neuropathy.

Peripheral neuropathy (PNP) in feet and/or hands and sexual dysfunction are common side effects of cancer therapies. In patients with other diseases, there is evidence of an association between peripheral nervous system disorders and sexual dysfunction due to the impact of impaired neuronal control on genital organ sensitivity. In cancer patient interviews, it has now been observed that PNP and sexual dysfunction may be related. The aim of the study was to investigate the potential association between PNP, sexual dysfunction, and physical activity behavior. Ninety-three patients with PNP of the feet and/or hands were interviewed in August/September 2020 in a cross-sectional study regarding medical history, sexual dysfunction and functionality of the genital organs. Thirty-one persons who participated in the survey provided seventeen evaluable questionnaires (four men, thirteen women). Nine women (69%) and three men (75%) reported sensory disorders of the genital organs. Three men (75%) had erectile dysfunction. All men who had sensory symptoms of the genital organs received chemotherapy, and one man also received immunotherapy. Eight women were sexually active. Five (63%) of them reported genital organ symptoms and mainly lubrication disorders. Four (80%) of the five sexually inactive women reported genital organ symptoms. Eight of the nine women with sensory symptoms of the genital organs received chemotherapy, and one woman received immunotherapy. Our limited data suggest genital organ sensory symptoms in chemotherapy and immunotherapy patients. Genital organ symptoms do not appear to be directly related to sexual dysfunction, and the association between PNP and genital organ symptoms appears to be more pronounced in sexually inactive women. Chemotherapy could cause sensory symptoms of the genital organs and sexual dysfunction by damaging genital organ nerve fibers. Chemotherapy and anti-hormone therapy (AHT) could trigger a disturbance of the hormone balance, which in turn could be causative for sexual dysfunction. It remains open whether the cause of these disorders is the symptomatology of the genital organs or the altered hormone balance. The significance of the results is limited due to the small number of cases. To our knowledge, this study is the first of its kind in cancer patients and allows a better understanding of the association between PNP, sensory symptoms of the genital organs, and sexual dysfunction. In order to be able to narrow down the cause of these initial observations in cancer patients more precisely, larger studies are needed that can relate the influence of cancer therapy-induced PNP, physical activity level and hormone balance to sensory symptoms of the genital organs and sexual dysfunction. The methodology of further studies should take into account the frequent problem of low response rates in surveys on sexuality.

Pseudoangiomatous Stromal Hyperplasia of the Breast: A Case Report of a 32-year-old Woman

Pseudoangiomatous Stromal Hyperplasia (PASH) is a benign breast tumor with a histological pattern that mimics the appearance of angiomatous proliferation. The lesion appears as a complex tissue with slit-like spaces lined by spindle cells resembling endothelial cells with a background of stromal hyperplasia. PASH manifests as a palpable mass, multifocal nodules, or a large diffuse mass that makes the breast asymmetrical. We report a case of breast lump in a 32-year-old woman caused by PASH. Biopsy of the mass showed histopathologic features of PASH. This patient then received tumor excision to remove the mass. Treatment of PASH tumors depends on the size and growth rate of the tumor. Anti-hormonal therapy such as tamoxifen may be an option for non-invasive therapy, but after the diagnosis has been confirmed through a core biopsy and the tumor size is no more than 2 cm. Surgical excision of the tumor by minimizing damage to the surrounding breast tissue is the most recommended treatment.

Predictors of adherence and the role of primary non-adherence in antihormonal treatment of breast cancer

BackgroundAntihormonal treatment for hormone receptor (HR) positive breast cancer has highly beneficial effects on both recurrence rates and survival. We investigate adherence and persistence in this group of patients.MethodsThe study population comprised 1192 patients with HR-positive breast cancer who were prescribed adjuvant antihormonal treatment from 2004 to 2013. Adherence was defined as a medical possession ratio (MPR) of ≥80.ResultsOf the 1192 included patients, 903 (75.8%) were adherent and 289 (24.2%) were non-adherent. Primary non-adherence was seen in 101 (8.5%) patients. The extremes of age (< 40 and ≥ 80 years) were associated with poor adherence. Patients with metastasis to axillary lymph nodes and those who received radiotherapy and/or chemotherapy were more likely to be adherent. Better adherence was also shown for those who switched medication at 2 years after diagnosis. Primary non-adherence seems to be associated with cancers with a good prognosis.ConclusionAdherence to antihormonal therapy for breast cancer is suboptimal. Primary non-adherence occurs among patients with a relatively good prognosis. Non-adherent patients tend to terminate their antihormonal therapy in the initial part of the treatment period. Targeted interventions to improve adherence should be focused on the first part of the treatment period.

PSUN347 A Novel Mechanism-based Inhibitor of Ribonucleotide Reductase is Highly Effective in Preclinical Models of Endocrine Therapy-Resistant Breast Cancer

Abstract Approximately 70% of breast cancers express Estrogen Receptor (ER), and patients with ER+ disease benefit from first-line targeted anti-hormone therapies (e. g. tamoxifen). However, at least 30% of patients develop therapeutic resistance. Second-line therapy includes CDK4/6 inhibitors, yet patients nearly uniformly develop resistance to these drugs as well, highlighting the need to identify additional targets in resistant tumors. In this regard, tamoxifen-resistant breast cancer cells and tumors display increased expression of several key cell cycle and chromosomal maintenance-related genes. This includes elevated expression of genes in the Chromosomal Instability (CIN70) signature, comprising of 70 genes that promote CIN and facilitate tumor progression. RRM2 is one such gene that encodes the small subunit of Ribonucleotide Reductase (RNR). In public RNA-seq data, RRM2 was one of the most differentially expressed CIN70 genes in tamoxifen-resistant cells and tumors, and increased expression is associated with poor patient outcomes. We hypothesized that elevated RRM2 drives CIN and subsequent tamoxifen resistance, and that targeting RRM2 or RNR activity will exacerbate CIN to intolerable levels, leading to drug-resensitization and cell death. We confirmed that RRM2 expression is elevated in multiple tamoxifen-resistant ER+ breast cancer cell lines compared to their parental counterparts. Moreover, we found that tamoxifen-resistant cells also exhibit increased CIN phenotypes as indicated by nuclear defects (micro-, multi-, and dysmorphic nuclei). As a model of intrinsic resistance to endocrine therapy, we examined RRM2 expression in triple-negative breast cancer (TNBC) cells that lack ER and found that these cells also have elevated RRM2 compared to ER+ cells. These data affirm the utility of targeting RNR for treating aggressive disease. While there are five currently approved RNR inhibitors, they cause significant patient toxicities due to their chelator mechanism of action. To address this limitation, we developed a novel mechanism-based inhibitor of the catalytic activity of RNR (RRM127) that is less toxic in mouse models. We demonstrate that RRM127 induces excessive CIN in breast cancer cell lines with high RRM2 expression. Most importantly, we have found that RRM127 suppresses growth of both cell line and patient-derived TNBC xenografts in mice. Together, these results indicate that elevated RRM2 and its associated RNR activity promote CIN and that catalytic inhibition with RRM127 has strong efficacy in preclinical models of breast cancer. Current studies are focused on identifying the mechanisms by which RRM127 blocks breast cancer cell growth. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The impact of standardized structured reporting of pathology reports for breast cancer care

PurposeWith the increasing complexity of modern oncological patient management and the growing amount of information needed from the pathologist, traditional narrative pathology reports (NR) do not suffice. Standardized synoptic reporting (SR) increases both completeness and readability. In the Netherlands SR for breast cancer was introduced in 2009. We explore the impact of synoptic reporting on breast cancer care. MethodsUsing data from the Netherlands Cancer Registry and Dutch Nationwide Pathology Databank, a retrospective population-based cohort study was performed. Data of breast cancer resections from 2007 to 2014 were collected to compare NR and SR for all outcome measures. Kaplan-Meier analyses and log-rank testing were used to estimate overall survival. ResultsOver time there was an increase from 12% to 78.9% in the use of SR. SR resulted in higher completeness of pathology reports, particularly for hormone and HER2/neu receptor status. Although there was no difference in the administration of antihormonal therapy, anti-HER2 treatment was more frequently administered to eligible patients in the SR group. An effect on overall survival could not yet be confirmed on multivariate analysis. ConclusionsWe demonstrate that SR has led to more complete pathology reports, which meets the needs for precision of information in breast cancer care. This is expected to improve communication and discussions between specialists regarding parameters important for adjuvant breast cancer treatment decisions. SR thereby improves breast cancer care and leads to improved allocation of treatment based on pathologic parameters and more personalized treatment regimens.

Anti-Hormonal Therapy in Breast Cancer and Its Effect on the Blood-Brain Barrier.

Simple SummaryAnti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases.The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer.

Higher Expressions of SHH and AR Are Associated with a Positive Receptor Status and Have Impact on Survival in a Cohort of Croatian Breast Cancer Patients.

Breast cancers (BC) are usually classified into four molecular subtypes according to the expression of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors and proliferation marker Ki-67. Despite available anti-hormonal therapies and due to the inherent propensity of some subtypes to develop metastasis, there is a permanent need to discover new prognostic and predictive biomarkers, as well as therapeutic targets for BC. In this study, we used immunohistochemical staining to determine the expression of androgen receptor (AR) and sonic hedgehog protein (SHH), the main ligand of the Hedgehog-GLI (HH-GLI) signaling pathway, in 185 archival primary BC tissue samples and correlated it with clinicopathological characteristics, molecular subtypes, receptors statuses, and survival in a cohort of Croatian BC patients. Results showed that higher SHH and AR expressions were associated with positive receptor status, but increased SHH expression had a negative impact on survival in receptor-negative BCs. On the contrary, higher AR expression was mostly protective. However, multivariate analysis showed that only higher AR expression could be considered as an independent prognostic biomarker for poorer overall survival in triple-negative breast cancer patients (TNBC) (HR 10.9, 95% CI 1.43–83.67; p = 0.021), what could be Croatian population-related. SHH could be a potential target for treating TNBCs and HER2-enriched BCs, in cases where HH-GLI signaling is canonical (SHH-dependent).

Role of β1-integrin in promoting cell motility and tamoxifen resistance of human breast cancer MCF-7 cells.

The mechanism of acquired resistance of tamoxifen in endocrine therapy of breast cancer is not fully understood. In this study, we investigated the genomic changes in acquired tamoxifen-resistant cell lines. Tamoxifen-resistantsubclones (MCF-7R) derived from parent MCF-7 cells, which is an ER(+) breast cancer cell line, cultured with 4-hydrotamoxifen more than 6 months were used to obtain genomic alterations. Cell growth, microarray, and quantitative real-time PCR (q-RTPCR) assays were conducted. Additionally, the ITGB1 function was investigated in MCF-7R cells and MCF-7R ITGB1-silenced subclones using MTT and Transwell assays. Online pathway analysis was performed to assess the genetic characteristics of tamoxifen resistance. The gene expression profile of the tamoxifen-resistant cell line was considerably changed compared to the tamoxifen-sensitive cell line. Of 4102 genes with altered expressions, 1986 genes were upregulated, whereas 2116 were downregulated. The ITGB1 expression in MCF-7R cells was higher than that in MCF-7 cells. Interestingly, ITGB1 silencing partially rescued the sensitivity of MCF-7R cells to tamoxifen and reduced their motility. The activation of the β1-integrin signaling pathway was probably responsible for this phenomenon. Our data confirm the presence of alterations in the genes of tamoxifen-resistance breast cancer cells. ITGB1 probably partially contributes to tamoxifen resistance and cell motility via the β1-integrin signaling pathway. Thus, ITGB1 may be a potential target for the improvement of anti-hormone therapy reaction in ER(+) breast cancer patients.

Breast Cancer Subtypes and Prognosis: Answers to Subgroup Classification Questions, Identifying the Worst Subgroup in Our Single-Center Series

PurposeMany studies report the triple negative breast cancer (TNBC) as the worst subgroup, as such patients do not benefit from anti-hormonal therapy and human epidermal growth factor receptor 2 (HER2) antagonists. While HER2 overexpression was a poor prognostic factor in breast cancer before trastuzumab (Herceptin) was available, TNBC is often reported as the worst BC subgroup since targeted therapy is currently not possible. Since the patience-specific experiences and the current literature did not always align, we aimed to determine the BC subgroup with the shortest survival in our center.MethodsThe records of patients with BC who were admitted to Trakya University Faculty of Medicine Department of Medical and Radiation Oncology between July 1999 and December 2019 were reviewed. Patients were divided into four main groups (Luminal A, Luminal B, TNBC, and HER2-enriched) according to the St Gallen International Consensus Panel and four subgroups in accordance with estrogen receptor, progestin receptor and HER2 positivity. Patient characteristics, treatment characteristics and clinical outcomes of the four main subgroups were evaluated. Survival curves were generated using the Kaplan–Meier method, and the significance of survival differences among the selected variables was compared by using the Log rank test. Factors affecting disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression analysis.ResultsStatistical analysis was performed on 2017 patients, after excluding patients with phyllodes tumor, carcinoma-in-situ and missing information from a total of 2474 patients with BC. There were 952 (47.1%) patients in the Luminal A group, 236 (34.1%) in the Luminal B group, 236 (11.7%) in the TNBC group and 142 (7.1%) patients in the HER2 enriched group. HER2-enriched patients had the shortest survival (p < 0.001), with 113.70 ± 7.17 months of DFS and 125.45 ± 3.03 months of OS. For patients who received Herceptin, DFS was 101.50 ± 6.4 months and OS was 118.14 ± 6.16. Patients who did not receive Herceptin had 92.79 ± 18 months of DFS and 94.44 ± 15.23 months of OS.ConclusionThe HER2-enriched subgroup had the worst prognosis despite receiving targeted therapy. While the duration of DFS and OS had no significant difference between TNBC and Luminal A-B subgroups, HER2 enriched subgroup had significantly shorter survival when compared to any other subgroup. HER2-enriched subgroup had a 10-fold greater risk of death compared to the Luminal A subgroup.

A proof of concept for targeting the PrPC - Amyloid β peptide interaction in basal prostate cancer and mesenchymal colon cancer

The cellular prion protein PrPC partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrPC and CAV1 across cancer. Using cell-based assays, we show that PrPC regulates the expression of and interacts with CAV1. PrPC additionally controls the expression of the amyloid precursor protein APP and of the Aβ generating enzyme BACE1, and regulates the levels of Aβ, whose accumulation is a central event in Alzheimer’s disease. We further identify DKK1 and DKK3, involved in both Alzheimer’s disease and cancer progression, as targets of the PrPC-dependent axis. Finally, we establish that antibody-mediated blocking of the Aβ-PrPC interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aβ-PrPC-dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aβ-PrPC axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.

Association of Serum Levels of Plasticizers Compounds, Phthalates and Bisphenols, in Patients and Survivors of Breast Cancer: A Real Connection?

Phthalates and bisphenols are ubiquitous environmental pollutants with the ability to perturb different systems. Specifically, they can alter the endocrine system, and this is why they are also known as endocrine-disrupting compounds (EDCs). Interestingly, they are related to the development and progression of breast cancer (BC), but the threshold concentrations at which they trigger that are not well established. Objectives: The aim of this study was to compare the concentration measures of parent EDCs in three groups of women (without BC, with BC, and BC survivors) from two urban populations in Mexico, to establish a possible association between EDCs and this disease. We consider the measure of the parent compounds would reflect the individual’s exposure. Methods: The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP) and di-ethyl-phthalate (DEP), bisphenol A (BPA) and bisphenol S (BPS) were determined by gas chromatograph-mass spectrometry in 102 subjects, including 37 women without any pathological disease, 46 patients with BC and 19 women survivals of BC of Mexico and Toluca City. Results: All phthalates were detected in 100% of women, two of them were significantly higher in patients with different BC subtypes in Mexico City. Differential increases were observed mainly in the serum concentration of phthalates in women with BC compared to women without disease between Mexico and Toluca City. In addition, when performing an analysis of the concentrations of phthalates by molecular type of BC, DEP and BBP were found mainly in aggressive and poorly differentiated types of BC. It should be noted that female BC survivors treated with anti-hormonal therapy showed lower levels of BBP than patients with BC. BPA and BPS were found in most samples from Mexico City. However, BPS was undetectable in women from Toluca City. Discussion: The results of our study support the hypothesis of a positive association between exposure to phthalates and BC incidence.