Endocrine Therapy For Breast Cancer Research Articles

Primary results from PATRICIA cohort C (SOLTI-1303), a randomized phase II study evaluating palbociclib with trastuzumab and endocrine therapy in pretreated HER2-positive and PAM50 luminal advanced breast cancer.

1008 Background: The PATRICIA trial (cohorts A-B) demonstrated that palbociclib plus trastuzumab (T) is safe and active in patients (pts) with T-pretreated HER2-positive Hormone Receptor-positive (HR+/HER2+) PAM50 Luminal advanced breast cancer (ABC). Here, we present the primary efficacy analysis of the randomized cohort C from the PATRICIA trial that compares the efficacy of palbociclib + T + endocrine therapy (ET) with treatment of physicians’ choice (TPC). Methods: PATRICIA (cohort C) is a randomized, open-label, phase II study conducted at 34 sites in Spain recruiting from August 2019 to August 2023. Pts with HER2+/HR+ and centrally tested PAM50 Luminal A or B intrinsic subtype ABC who had received at least one prior line of anti-HER2 based regimens were eligible. Pts were randomized 1:1 to Cohort C1 (Palbociclib 125 mg/day orally 3 weeks/1 week off + T + ET) or Cohort C2 (TPC, including T + any ET or chemotherapy (CT) + T, or T-DM1). The stratification factors were number of previous regimens for ABC and presence of visceral disease. The primary endpoint was progression-free survival (PFS). The trial was designed to recruit a total of 102 pts, having an 80% power with one-sided alpha=0.1 to detect a HR of 0.62 in favor of the palbociclib cohort. The study was closed after 73 pts were randomized due to slow recruitment. Results: At data cut-off, 264 pts were pre-screened, and 73 pts were randomized. Baseline pts characteristics are summarized in Table 1. In cohort C1, 50% of the pts received fulvestrant and 50% aromatase inhibitor as ET. In cohort C2, 37.1% of pts were treated with TDM-1, 45.7% with CT+ T, 11.4 % with ET + T and two pts withdrew their consent before starting the treatment. Palbociclib + T + ET was associated with longer PFS compared to TPC (median 9.1 vs 7.5 months, stratified HR=0.52 [95%CI 0.29-0.94]; two-sided p=0.031); 12-months PFS rates were 43.7% and 21.4%, respectively. The overall response rate was 18.9% (95% CI 8.6-35.7) in cohort C1 and 8.3% (95% CI 1.4-28.5) in cohort C2. Grade ≥3 adverse events occurred in 63.2% of pts in C1 and 45.5% in C2 cohort. The most frequent grade ≥3 adverse event in the experimental arm was neutropenia (55.3%). Conclusions: The combination of palbociclib, T and ET showed a statistically significant improvement in PFS in patients with previously treated PAM50 luminal A or B HER2+ advanced breast cancer, as compared to TPC. Clinical trial information: NCT02448420 . [Table: see text]

Evaluating the efficacy of neoadjuvant endocrine therapy in HER2 low vs. HER2 negative breast cancer: An NCBD analysis.

599 Background: Neoadjuvant endocrine therapy (NET) is an important treatment option for hormone receptor (HR)-positive breast cancer (BC). Innovative ADCs targeting HER2 low tumors has sparked debate regarding the distinct nature of HER2 low tumors and whether it merits a unique treatment approach. With favorable outcomes in metastatic disease, there is interest in adopting similar strategies for early-stage treatment approaches. Methods: We examined the National Cancer Database for stage I-III ER-positive BC in women who underwent neoadjuvant endocrine therapy (NET) from 2010 to 2017, for at least 90 days to a maximum of 270 days. Patients with prior neoadjuvant chemotherapy, other malignancies, HER2-positive disease by either IHC or FISH, metastatic disease, or unknown stage were excluded. HER2 status was grouped as negative or low per 2023 ASCO-CAP guidelines. Patients’ response to therapy included pathologic complete response (CR), partial pathologic response (PR), stable pathologic response, or progression in primary tumor at time of resection. We employed multivariable binomial logistic regression to examine how clinicopathologic factors influence the probability of any response (combining CR and PR) to neoadjuvant hormonal therapy. Results: 3,808 patients met the inclusion criteria. 1,055 (27.8%) patients had HER2 negative disease, and 2,753 (72.2%) patients were HER2-low. 48 (1.2%) patients had primary tumor CR, and 1,484 (39%) had PR. Among HER2-low patients, 37 (1.3%) had pathologic CR, and 1,134 (41.1%) had PR. Among HER2-negative patients, 11 (1.0%) had pathologic CR, and 350 (33.1%) had PR. Multivariable logistic models revealed that age, duration of NET, and HER2 status were significant predictors of any response to NET. HER2-low tumors were more likely to have any response compared to HER2-negative (aOR=1.16, 95% CI 1.01 - 1.34, p=0.04). Patients who received >150 days of hormonal therapy were more likely to respond (aOR=1.33, 95% CI 1.16 - 1.52, p=<0.001); patients >50 years old were more likely to have any response (aOR=1.41, 95% CI 1.07 - 1.90, p=0.02). Clinical node positivity and tumor grade did not have significant effect on response to NET at time of resection. Conclusions: Our study offers a real-world estimate of outcomes associated with NET in localized BC. HER2 low tumors had greater significant clinical responses to NET when compared to HER2 negative, suggesting that HER2 low tumors may benefit from tailored treatment in the neoadjuvant setting. [Table: see text]

Escalation of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer: to whom, when and why?

This review presents the evolution of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer, describes late relapse phenomenon, provides clinical rationale for escalation of treatment, analyzes the key stages of the metastatic cascade, and provides a scientific rationale for the introduction of CDK4/6 inhibitors into adjuvant treatment regimens. The main results of two large randomized studies of therapy including abemaciclib (MonarchE) and ribociclib (NATALEE) in patients with early stages of hormone-dependent HER2-negative breast cancer are presented; the oncological results of escalation of treatment and the safety of therapy are assessed.

Cognitive impairment following breast cancer treatments: an umbrella review.

Cancer-related cognitive impairment (CRCI) refers to a cognitive decline associated with cancer or its treatments. While research into CRCI is expanding, evidence remains scattered due to differences in study designs, methodologies, and definitions. The present umbrella review aims to provide a comprehensive overview of the current evidence regarding the impact of different breast cancer therapies on cognitive functioning, with a particular focus on the interplay among objective cognitive deficits (ie, measured with standardized tests), subjective cognitive concerns, (ie, self-reported), and other mediating psycho-physical factors. The search was made in Pubmed, Embase, and Scopus for articles published until July 2023, following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis protocol. Chemotherapy and endocrine therapy appear consistently associated with CRCI in patients with breast cancer, primarily affecting memory, attention/concentration, executive functioning, and processing speed. Subjective cognitive concerns were often found weakly or not associated with neuropsychological test results, while overall CRCI seemed consistently associated with psychological distress, fatigue, sleep quality, and inflammatory and biological factors. Current evidence suggests that CRCI is common after chemotherapy and endocrine therapy for breast cancer. However, heterogeneity in study designs and the scarcity of studies on more recent treatments such as targeted therapies and immunotherapies, highlight the need for more systematic and harmonized studies, possibly taking into account the complex and multifactorial etiology of CRCI. This may provide valuable insights into CRCI's underlying mechanisms and potential new ways to treat it.

Inflammatory Rheumatic Disorders as a Complication of Endocrine Therapy for Breast Cancer

Inflammatory Rheumatic Disorders as a Complication of Endocrine Therapy for Breast Cancer

Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor

Estrogen receptor (ER) β (ERβ) is the second ER subtype that mediates the effects of estrogen in target tissues along with ERα that represents a validated biomarker and target for endocrine therapy in breast cancer. ERα was the only known ER subtype until 1996 when the discovery of ERβ opened a new chapter in endocrinology and prompted a thorough reevaluation of the estrogen signaling paradigm. Unlike the oncogenic ERα, ERβ has been proposed to function as a tumor suppressor in breast cancer, and extensive research is underway to uncover the full spectrum of ERβ activities and elucidate its mechanism of action. Recent studies have relied on new transgenic models to capture effects in normal and malignant breast that were not previously detected. They have also benefited from the development of highly specific synthetic ligands that are used to demonstrate distinct mechanisms of gene regulation in cancer. As a result, significant new information about the biology and clinical importance of ERβ is now available, which is the focus of discussion in the present article.

Abstract PO5-12-05: A Retrospective Study of the Rate of Cognitive Impairment and Influencing Factors during Postoperative Endocrine Therapy for Breast Cancer

Abstract Background Although cancer-related cognitive impairment (CRCI) has been gradually recognized, general cognitive function tests such as the MMSE are not sensitive enough to diagnose CRCI. There is also a lack of evidence on the incidence and its response. However, even mild cognitive impairment can have a significant impact on quality of life. In this study, we retrospectively analyzed the prevalence of cognitive impairment in patients undergoing endocrine therapy at our hospital and the factors influencing the symptoms. Subjects 349 patients who continued single-agent postoperative endocrine therapy for at least 6 months between January 1 and October 31, 2022, and who responded to the cognitive dysfunction questionnaire at least once. Data from the cognitive dysfunction items of the endocrine therapy questionnaire administered during the period were used to retrospectively examine the CRCI awareness rate and factors involved. Results and Discussion The patients who were aware of cognitive dysfunction was 170, or 49% of all patients, and univariate analysis showed that age was significantly higher in the group with CRCI, but there were no significant differences in type of endocrine therapy or history of chemotherapy between the groups with and without CRCI. Physical symptoms such as menopausal symptoms (hot flashes and sweats), arthralgia, myalgia, fatigue, depressed mood, and malaise were significantly more frequent in patients with CRCI, which could be considered side effects of endocrine therapy. Risk factors such as low cognitive reserve, low level of education, advanced age, race, depression, fatigue, and anxiety have been reported in the past, and in this study, fatigue, depressed mood, and malaise were found significantly more frequently in patients with cognitive dysfunction. However, the diagnosis of depression and dementia may also be important.Non-pharmacological interventions, especially cognitive rehabilitation and exercise, are expected to be effective in improving symptoms, but there is no certain opinion yet. The limitation of this study is that it was a single-center, retrospective analysis. In addition, it was difficult to evaluate the results over time, including before the start of oral medication, so we are considering conducting a prospective data collection study so that comparisons can be made in the future. Conclusion: This study was a simple screening, based only on subjective symptoms. In recent years, postoperative endocrine therapy has been prolonged to 10 years, and there is a possibility to improve the quality of life of patients by recognizing the possibility of cognitive dysfunction in both providers and patients, and by taking measures that include multiple factors. Citation Format: Akari Murakami, Mayuko Aono, Kaho Utsunomiya, Kumiko Okujima, Kana Takemoto, Megumi Takaoka, Erina Kusakabe, Kana Taguchi, Kanako Nishiyama, Yoshiaki Kamei, Yasutsugu Takada, Hitoshi Tanimukai. A Retrospective Study of the Rate of Cognitive Impairment and Influencing Factors during Postoperative Endocrine Therapy for Breast Cancer [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 PO5-12-05.

Abstract PO4-20-03: HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13)

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [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 PO4-20-03.

Real-world clinical evaluation of natural and induced vasomotor symptoms in the USA and Europe

Objective This study aimed to examine physicians’ and patients’ perceptions regarding symptom burden and impact in women experiencing natural vasomotor symptoms (nVMS) or vasomotor symptoms induced by endocrine therapy for breast cancer (iVMS). Methods The cross-sectional survey based on real-world clinical consultations was conducted in the USA and five European countries. Obstetrician–gynecologists, primary-care physicians and oncologists provided demographic and symptom data for patients experiencing VMS; patients optionally self-reported their experiences via questionnaires, including their symptom profile and work/activity burden through the Menopause Quality of Life (MENQOL) and Work Productivity and Activity Impairment (WPAI) tools. Results Physicians completed survey forms on 2451 consulting patients; patients completed 1029 questionnaires. nVMS and iVMS severity was significantly associated with the severity of mood symptoms and sleep disturbances (p < 0.0001). However, around half of the patients with mild nVMS/iVMS also experienced moderate–severe mood changes (55.4%/43.7%) or sleep disturbances (42.4%/40.4%). Presence of mood/sleep disturbances alongside nVMS increased MENQOL vasomotor scores (p = 0.004/p < 0.001). Presence of sleep disturbances increased WPAI activity impairment (p < 0.001) but mood changes did not. Similar findings were reported for iVMS patients. Conclusion Significant burden from the triad of natural or induced menopausal symptoms, sleep disturbances and mood changes affected women’s daily activities, work and quality of life more than vasomotor symptoms alone.

Abstract PO4-27-08: A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients

Abstract Background: This Phase II study aimed to determine the efficacy and safety of administering palliative radiotherapy (RT) to bone metastases (mets) in patients (pts) receiving concurrent palbociclib and hormone therapy (HT) for hormone receptor positive, Her2/neu negative breast cancer. The primary endpoint was response rate 3 months after RT. Methods: Pts with painful bone mets or asymptomatic bone mets with risk for impending clinical event were treated with RT to 30 Gy in 10 fractions or 20 Gy in 5 fractions with concurrent palbociclib and HT. Change in maximum pain score on the Brief Pain Inventory was used to assess pain response 3 months post RT relative to baseline. Among pts with asymptomatic bone lesions, response was defined as prevention of a clinical event (e.g., bone fracture) without evidence of local tumor growth on surveillance imaging. Patient reported outcomes (PROs) of fatigue, depression, anxiety, and quality of life were collected. Blood-based biomarkers were examined to determine their relationship with response and PROs. Using a non-inferiority study design, a sample size of at least 33 pts was needed to achieve 80% power to detect a non-inferiority proportion of 60% using a one-sided binomial test and assuming a Type I error of 0.05. Results: Among 38 patients enrolled, 79% had painful bone mets. 35 pts completed baseline and 3-month post RT assessments. 61% and 37% of pts received aromatase inhibitors and fulvestrant, respectively, with palbociclib. Median age was 60 years (31-83) and 25% of pts were non-Hispanic Black. The majority (72%) of pts received 5 fraction RT and 69% received RT to one bone region. 29 patients (83%) were responders [95% CI: 66%-93%, p=.003]. Median progression free survival (PFS) was 30.4 months (1.3 - 44.0). Three-year PFS and overall survival were 45.6% and 67.2%, respectively. Grade 3 neutropenia developed in 4 (11%), 4 (11%), and 7 (20%) pts at end of RT, 1 month, and 3 months post RT, respectively. No pts developed Grade 4 neutropenia. One patient developed Grade 3 gastrointestinal toxicity during RT, another developed Grade 3 dyspnea 1 month post XRT, and another developed a bone fracture 6 months after RT. &amp;gt;While patient reported measures of fatigue, depression, and overall quality of life did not significantly change during or after RT relative to baseline, pain scores (i.e., BPI pain severity and interference, BM22 pain characteristics and pain site subscales, EORTC C15 pain) significantly decreased 3 months post XRT relative to baseline. Heightened inflammatory marker levels (e.g., TNFRII, IL1ra, CRP, TNF alpha) were significantly associated with worse symptoms of fatigue (MFI) and depression (HADS), increased pain interference (BPI), and lower overall quality of life (SF-36), controlling for age and time using mixed effect models. Patients with improved pain symptoms and lower pain scores had significantly lower inflammatory marker levels relative to baseline (e.g., interleukin-6). Conclusions: Our study demonstrated high rates of response to concurrent RT with palbociclib and HT with acceptable levels of toxicity. These results suggest that RT to bone mets effectively alleviates pain in patients taking palbociclib and pain response to treatment is associated with decreased inflammatory markers. RT may be given to pts receiving palbociclib and HT for breast cancer. Clinical Trial Identification: NCT03691493 Citation Format: Mylin Torres, Jolinta Lin, Sarah Friend, Canhua Xiao, Yichun Cao, Shannon Kahn, Karen Godette, Sheela Hanasoge, David Yu, Tony Eng, Matthew Cheney, Nancy Wiggers, Andrew Pippas, Keerthi Gogineni, Jane Meisel, David Schuster, Aditya Bardia, Andrew Miller, Jennifer Felger, Jeffrey Switchenko, Amelia Zelnak, Kevin Kalinsky, Manali Bhave. A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients [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 PO4-27-08.

Abstract RF02-02: BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism

Abstract PI3Kα is the most mutated kinase and the second most mutated oncogene in human cancer. Activation of PI3Ka can be achieved by receptor tyrosine kinases such as insulin receptor and insulin-like growth factor receptor 1 and/or by directly interacting with RAS family members. Previous elegant preclinical studies have established that RAS-driven PI3Ka activation is important in tumor cells but may not be involved in cell types controlling glucose metabolism. Alpelisib, a small molecule inhibitor of the kinase activity of PI3Ka, has been approved for the treatment of ER+ PIK3CA mutant breast cancer in combination with fulvestrant after endocrine therapy in advanced or metastatic breast cancer based on an improvement in PFS versus fulvestrant alone. Inhibition of PI3Ka activity by alpelisib in normal tissues resulted in a severe (G3/4) hyperglycemia rate of 37% with frequent dose interruptions and discontinuations. Additionally, preclinical studies have demonstrated that the dysregulation of glucose homeostasis resulting from PI3Ka kinase inhibition leads to hyperinsulinemia that increases pathway flux, rendering kinase inhibitors less effective. Here, we report on a novel covalent small molecule designed to inhibit RAS-mediated activation of the AKT pathway via PI3Ka without the resultant hyperglycemia associated with direct inhibition of PI3Ka kinase activity. BBO-10203 disrupts the physical interaction between RAS and PI3Ka in tumor cells resulting in potent signaling pathway inhibition. This agent selectively binds to PI3Ka and disrupts its interaction with K-,H-, and N-RAS with low single digit nanomolar potency (~5 nM). Breaking the interaction between these two oncogenes inhibits basal pAKT cellular levels (BT-474/KYSE-410 IC50: ~5 nM) in HER2 amplified (HER2amp) and wild-type or mutant PI3Ka cell lines. Even though BBO-10203 does not inhibit the kinase activity of PI3Ka, its effects on cancer cell signaling inhibition and transcriptional regulation highly resemble those of alpelisib. BBO-10203 displays excellent drug-like properties and oral bioavailability. Single dose treatment of KYSE-410 (HER2amp/KRASG12C) tumor bearing mice with increasing doses (1-100 mg/kg, PO) of BBO-10203 results in dose and time dependent inhibition of pAKT in vivo. Maximal inhibition (~80%) is achieved at 30 mg/kg and lasts for 24 hours. Repeated dose treatment of tumor bearing mice with BBO-10203 is well tolerated and results in significant efficacy in PIK3CA mutant as well as HER2amp human xenograft models. In the KYSE-410 xenograft model, BBO-10203 daily oral dosing of 30 mg/kg results in significant tumor regressions. Importantly, treatment with BBO-10203 does not affect insulin signaling in differentiated adipocytes in vitro, nor does it impact glucose metabolism in vivo at 3-times the maximal efficacious dose level in xenograft studies. In conclusion, we have identified a novel approach to inhibit the PI3Ka signaling pathway by blocking its interaction with, and activation by RAS. This approach can achieve strong pAKT inhibition in tumor cells without changes in glucose metabolism. Clinical investigation of BBO-10203 for the treatment of both ER+/PIK3CA mutant and HER2amp breast cancer is warranted. Citation Format: Pedro Beltran, Simanshu Dhirendra, Rui Xu, Ming Chen, Daniel Czyzyk, Sofia Donovan, Siyu Feng, Cindy Feng, Lijuan Fu, Felice Lightstone, Ken Lin, Anna Maciag, Dwight Nissley, Erin Riegler, Kerstin Sinkevicius, Andrew Stephen, James Stice, David Turner, Bin Wang, Keshi Wang, Yue Yang, Cathy Zhang, Frank McCormick, Eli Wallace. BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism [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 RF02-02.

Interrupting Breast Cancer Endocrine Therapy for Pregnancy

Interrupting Breast Cancer Endocrine Therapy for Pregnancy

Adherence to adjuvant endocrine therapy for breast cancer: a qualitative exploration of attribution of symptoms among post-menopausal women.

Oral adjuvant endocrine therapy (AET) is an effective treatment for hormone receptor positive breast cancer to decrease recurrence and mortality, but adherence is poor. This study explored post-menopausal women's experiences with AET, with a particular focus on adherence to AET as well as distress and symptoms experienced prior to and during AET treatment. Participants were recruited from a hospital registry, stratified by adherence to/discontinuation of AET. Telephone interviews followed a semi-structured interview guide and were recorded and transcribed verbatim. Transcripts were systematically coded using team-based coding, with analysis of themes using a grounded theory approach. Thirty-three participants were interviewed; ages ranged from 57 to 86years. Participants included 10 discontinued patients and 23 patients who completed their AET course or were adherent to AET at the time of interviewing. Both adherent and discontinued patients reported symptoms throughout their AET treatment course, and both attributed symptoms to factors other than AET (e.g., older age and pre-existing comorbidities). However, discontinued patients were more likely to attribute symptoms to AET and to describe difficulty managing their symptoms, with some directly citing symptoms as the reason for discontinuing AET therapy. Conversely, adherent patients were more likely to describe the necessity of taking AET, despite symptoms. AET adherence was associated with beliefs about AET, symptom attribution, and symptom management. Routine symptom monitoring during AET and addressing both symptoms and patients' understanding of their symptoms may promote adherence to AET.

Abstract 6576: Discovery of potent and selective novel small molecule drugs to target estrogen receptor mutants in endocrine-resistant breast cancer

Abstract Introduction: The acquisition of estrogen receptor alpha (ERα) gene (ESR1) mutations is a key driver for the development of resistance to current endocrine therapy in breast cancer. Clinical studies have shown that ESR1 mutations are frequently observed in metastatic ER-positive breast cancer patients and are associated with poor survival. It is well appreciated that activating ESR1 somatic mutations, especially Y537S and D538G, can drive estrogen-independent activities. In addition, these ESR1 mutations diminish the potency of the current standard-of-care agents (tamoxifen and fulvestrant) that bind ERα directly. Therefore, it is an unmet need to develop next-generation antiestrogens that inhibit ERα mutant signaling in breast cancer to improve patient survival. Here, we search for small molecule inhibitors against ERα mutants Y537S and D538G using DNA-encoded chemical library (DEL). Methods: ERα ligand binding domain (LBD) proteins corresponding to wild type (WT), Y537S and D538G mutants were expressed in E. coli and purified by Ni-NTA, anion exchange, and size exclusion chromatography. The ability of these purified proteins to bind ligands was tested in biochemical assays to validate their use in DEL selections. We conducted a DEL affinity selection using our in-house collection of 6 billion small molecule compounds against WT, Y537S and D538G mutants ER LBD proteins in the presence and absence of estradiol. Selection hits that enriched with these targets were resynthesized off-DNA and tested in biochemical and functional studies using CRISPR-Cas9 knock-in Y537S or D538G mutant breast cancer cells. Results: We have successfully purified microgram amounts of ERα LBD for WT, Y537S, and D538G proteins. In our biochemical assay, the SRC3 peptide binds to the WT ERα LBD in the presence of estradiol, whereas Y537S and D538G LBDs bind the SRC3 peptide in the absence of estradiol, consistent with these mutants constitutively binding to SRC3. Our multibillion small molecule collections of DELs can screen and identify several hits in WT and mutant ERα LBDs. To confirm the selection output, we synthesized off-DNA compounds and validated these in biochemical and cell-based studies. Compounds CDD-1274 and CDD-1802 dramatically decrease the WT and mutant ERα protein levels in multiple ER+ breast cancer cells. These compounds greatly reduce protein levels for GREB1, TFF1, c-MYC, E2F1, and survivin in wildtype and mutant breast cancer cells, and they increase levels of cleaved PARP, a marker for apoptosis in wildtype and mutant ER+ breast cancer cells but not in ER-negative breast cancer cells. Conclusion: Our study rapidly identified potent and novel small molecule drugs to target estrogen receptor mutants using our DNA-encoded chemical library platform. Acknowledgments: Funding sources (NIH/NCI R03 CA259664 and CPRIT RP220524 to MP). Citation Format: Anil Kumar Devakrishnan, Chandrashekhar Madasu, Suzanne A.W Fuqua, Martin M. Matzuk, Murugesan Palaniappan. Discovery of potent and selective novel small molecule drugs to target estrogen receptor mutants in endocrine-resistant breast cancer [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 6576.

Abstract 864: Pan-cancer analysis of lactic acid metabolism landscape across the Cancer Genome Atlas

Abstract Introduction: Metabolic reprogramming plays an important role in tumor occurrence and progression. Our studies confirmed the survival state of patients with different metabolic systems was heterogeneous and glycolytic metabolism may cause tumor progression. Based on these findings, lactic acid metabolism in glycolysis aroused our interest. This study evaluated the potential association between lactate metabolism gene and tumor clinical process in hepatocellular carcinoma, and proved that it can be used as an effective tool for survival prediction and treatment guidance of 32 kinds of tumor patients by establishing lactate score prognosis model. Methods: We used the expression profile, proteomics and epigenetics of HCC lactate gene set in the Cancer Genome Atlas Database to systematically describe the changes of lactate related genes. The differentially expressed genes were then verified in 32 clinical tumor data sets. A prognostic model of tumor lactic acid infiltration was constructed to evaluate its correlation with the prognosis of patients. Finally, we analyzed the effects of lame score, immunotherapy and drug response on the clinical process of tumor. Results: Firstly, we analyzed the differential expression of lactate metabolism genes in HCC and found that the prognosis of patients with high lactate infiltration was significantly lower than that of mild infiltration. AF angiogenesis factor and EMT factor in high infiltration may be the main reason for their differential expression. We constructed a tumor lactic acid prognosis model through six significantly different lactic acid genes, and found that lame score can be used as a predictor of immunotherapy. In addition, we proved the role of lame score in Pan cancer. PGA was positively correlated with lame score in most tumors. The prognosis of 16 tumors with high lame score group was significantly lower than that of low lame score group. There were significant differences in lame score between metastatic and non metastatic cancer groups of Cesc, kirc and kirp. The high and low risk groups of some tumors showed different dryness indices and dampness. At the same time, methylation gene modification has a significant impact on the Lame score of pan cancer, and the Lame score is used to link the drug tolerance and specific pathway enrichment of pan cancer tumor cell lines, confirming the targeted effect of Lame score on tumor treatment. Finally, we used the clinical characteristics and immunohistochemical analysis of a cohort study of real patients with breast cancer endocrine therapy (Tamoxifen) and hepatocellular carcinoma targeted therapy (Lenvartinib) to verify the clinical treatment prediction ability of lame score. Conclusions: Our study provides a comprehensive analysis of lactate metabolic across cancers and highlights the potential treatment of lactate targeted therapies for cancers. Citation Format: Xiaolin Wei, Lei Cai, Qian He. Pan-cancer analysis of lactic acid metabolism landscape across the Cancer Genome Atlas [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 864.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism

Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.Graphical

205 (PB-112) Poster - Inflammatory response to neoadjuvant endocrine therapy in hormone receptor-positive breast cancer

205 (PB-112) Poster - Inflammatory response to neoadjuvant endocrine therapy in hormone receptor-positive breast cancer

Impact of the Breast Cancer Index for Extended Endocrine Decision-Making: First Results of the Prospective BCI Registry Study.

The Breast Cancer Index (BCI) test assay provides an individualized risk of late distant recurrence (5-10 years) and predicts the likelihood of benefitting from extended endocrine therapy (EET) in hormone receptor-positive early-stage breast cancer. This analysis aimed to assess the impact of BCI on EET decision-making in current clinical practice. The BCI Registry study evaluates long-term outcomes, decision impact, and medication adherence in patients receiving BCI testing as part of routine clinical care. Physicians and patients completed pre-BCI and post-BCI test questionnaires to assess a range of questions, including physician decision-making and confidence regarding EET; patient preferences and concerns about the cost, side effects, drug safety, and benefit of EET; and patient satisfaction regarding treatment recommendations. Pre-BCI and post-BCI test responses were compared using McNemar's test and Wilcoxon signed rank test. Pre-BCI and post-BCI questionnaires were completed for 843 physicians and 823 patients. The mean age at enrollment was 65 years, and 88.4% of patients were postmenopausal. Of the tumors, 74.7% were T1, 53.4% were grade 2, 76.0% were N0, and 13.8% were HER2-positive. Following BCI testing, physicians changed EET recommendations in 40.1% of patients (P<.0001), and 45.1% of patients changed their preferences for EET (P<.0001). In addition, 38.8% of physicians felt more confident in their recommendation (P<.0001), and 41.4% of patients felt more comfortable with their EET decision (P<.0001). Compared with baseline, significantly more patients were less concerned about the cost (20.9%; P<.0001), drug safety (25.4%; P=.0014), and benefit of EET (29.3%; P=.0002). This analysis in a large patient cohort of the BCI Registry confirms and extends previous findings on the significant decision-making impact of BCI on EET. Incorporating BCI into clinical practice resulted in changes in physician recommendations, increased physician confidence, improved patient satisfaction, and reduced patient concerns regarding the cost, drug safety, and benefit of EET.

Ribociclib + adjuvant hormone therapy in early breast cancer: prevention of recurrence. New opportunities. A review

Breast cancer (BC) occupies a leading position among all malignant neoplasms in women worldwide and is the 4th deadliest. Most cases are diagnosed in stages I–III. Among the molecular biological variants, luminal HER2 negative (HER2-) prevails, accounting for 70–75%. Currently, therapies combining surgery with chemotherapy and, more rarely, radiation therapy, followed by adjuvant hormone therapy for up to 10 years, are a standard of care in BC. The goal of these regimens is the prevention of early recurrence in patients in the high-risk group with a primary hormone-resistant tumor. However, at the end of treatment, it occurs in 27–57% of patients with stage II–III breast cancer. For its prevention in early HR-positive (HR+) HER2- BC, an innovative class of drugs, cyclin-dependent kinase 4/6 inhibitors, is used combined with hormone therapy (aromatase inhibitors, anti-estrogens, gonadotropin-releasing hormone agonists), which is the subject of a randomized phase III NATALEE study evaluating the efficacy and safety of ribociclib in combination with endocrine therapy in early non-metastatic BC. The study enrolled patients with stage II–III breast cancer, including those with N0. Patients of the study group received ribociclib at a dose of 400 mg/day for 21 days in combination with aromatase inhibitors, and in the control group, only aromatase inhibitors. The median follow-up was 34 months. Three-year survival without invasive disease was 90.7% in the ribociclib group and 87.6% in controls. The risk of distant metastasis and invasive diseases was reduced by 25.1% in the ribociclib group. Therefore, ribociclib tended to improve overall survival. The initial dose of 400 mg/day reduced the incidence of adverse events; the most common were neutropenia (62.5%), arthralgia (37.3%) and hepatic toxicity (26.4%). The most common reasons for discontinuing ribociclib were hepatic toxicity (8.9%) and arthralgia (1.3%). The results demonstrate a statistical and clinical superiority of ribociclib in combination with hormone therapy in the treatment of early HR+ HER2- breast cancer with a high risk of recurrence.

Developing questions to assess and measure patients’ perceived survival benefit from adjuvant endocrine therapy in breast cancer: a mixed methods pilot study

This mixed method study developed multiple question types to understand and measure women’s perceived benefit from adjuvant endocrine therapy. We hypothesis that patients do not understand this benefit and sought to develop the questions needed to test this hypothesis and obtain initial patient estimates. From 8/2022 to 3/2023, qualitative interviews focused on assessing and modifying 9 initial varied question types asking about the overall survival (OS) benefit from adjuvant endocrine therapy. Subsequent focus groups modified and selected the optimal questions. Patients’ self-assessment of their OS benefit was compared to their individualized PREDICT model results. Fifty-three patients completed the survey; 42% Hispanic, 30% rural, and 47% with income < $39,999 per year. Patients reported adequate health care literacy (61.5%) and average confidence about treatment and medication decisions 49.4 (95% CI 24.4–59.5). From the original 9 questions, 3 modified questions were ultimately found to capture patients’ perception of this OS benefit, focusing on graphical and prose styles. Patients estimated an OS benefit of 42% compared to 4.4% calculated from the PREDICT model (p < 0.001). In this group with considerable representation from ethnic minority, rural and low-income patients, qualitative data showed that more than one modality of question type was needed to clearly capture patients’ understanding of treatment benefit. Women with breast cancer significantly overestimated their 10-year OS benefit from adjuvant endocrine therapy compared to the PREDICT model.