Adjuvant Aromatase Inhibitors Research Articles

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.

BackgroundWomen treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, there are concerns of risks of recurrence of BC and death following treatment.MethodsOur study included longitudinal data from a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor–positive nonmetastatic BC, who received no treatment or 5 years of adjuvant endocrine therapy. We ascertained prescription data on hormone therapy, VET or MHT, from a national prescription registry. We evaluated mortality and risk of recurrence associated with use of VET and MHT vs non-use using multivariable models adjusted for potential confounders.ResultsAmong 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively.ConclusionsIn postmenopausal women treated for early-stage estrogen receptor–positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

Cancer Treatment-Induced Bone Loss: Role of Denosumab in Non-Metastatic Breast Cancer.

Chemotherapeutic agents, endocrine therapy and radiotherapy used in the management of breast cancer are known to cause decreased bone mineral density, and thus, increased incidence of fractures. A majority (~60%) of the breast cancer patients in India are either estrogen (ER) or progesterone hormone receptor (PR) positive. Adjuvant treatment with aromatase inhibitors (AIs) is the treatment mainstay for hormone-sensitive disease in postmenopausal (PM) women, with reduced bone mineral density (BMD), which results in increased fracture rates. Zoledronic acid, alendronate, risedronate and denosumab have been the agents of choice for managing bone loss. Denosumab 60 mg is approved for gaining bone mass in women with breast cancer who are at high risk for fracture following adjuvant AI treatment. The phase III HALT-BC data indicate an improvement in BMD with denosumab and a 50% reduction in clinical fractures, with significant improvements seen at the lumbar spine, distal third of the radius, and total hip. Denosumab has several advantages over other bone modifying agents such as subcutaneous self-administration by the patient themselves, no requirement of hospitalization, no dose modifications in renal impairment, and low incidence of acute phase anaphylactic reactions. We review the available evidence of denosumab for managing bone loss in non-metastatic breast cancer patients.

Changes in Vertebral Marrow Fat Fraction Using 3D Fat Analysis & Calculation Technique Imaging Sequence in Aromatase Inhibitor-Treated Breast Cancer Women.

Aromatase inhibitor (AI) is a cornerstone drug for postmenopausal women with estrogen receptor-positive early-stage breast cancer. Fat-bone interactions within the bone marrow milieu are growing areas of scientific interest. Although AI treatment could lead to deterioration of the skeleton, the association between AI medication and subsequent marrow adiposity remains elusive. A total of 40 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients who underwent treatment with adjuvant AIs and 40 matched controls were included. Marrow proton density fat fraction (PDFF) at the L1−L4 vertebral bodies using 3D Fat Analysis & Calculation Technique imaging (FACT) sequence at 3.0T, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and serum bone turnover biomarkers were determined at baseline and at 6 and 12 months. We found that, in comparison to baseline, an increase of type I collagen cross-linked telopeptide was detected at 12 months (P <0.05). From baseline to 12 months, the PDFF measured using FACT was greatly increased. At 12 months, the median percent change of PDFF (4.9% vs. 0.9%, P <0.05) was significantly different between the AI treatments and controls. The same trend was observed for the marrow PDFF at 6 months relative to the respective values at baseline. Although BMD values were significantly reduced after 12 months in AI-treated women, changes in BMD vs. baseline condition were not significantly different between the AI-treated and control groups [Δ BMD −1.6% to −1.8% vs. −0.3% to −0.6%, respectively, P > 0.05]. In the AI-treated group, Δ PDFF was associated with Δ BMD at the lumbar spine (r = −0.585, P < 0.001), but not in the controls. Taken together, over a 12-month period, spinal marrow fat content assessed with FACT sequence significantly increased in postmenopausal women with hormone-receptor-positive breast cancer receiving AI treatment.

Socioeconomic disparities in supportive therapy use and tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer.

523 Background: Socioeconomic disparities impact breast cancer survival with significantly higher mortality among women of lower socioeconomic status. Little is known about how disparities affect patients with early-stage hormone receptor positive (HR+) breast cancer (BC) and patients’ tolerance and adherence to standard of care adjuvant aromatase inhibitor (AI) therapy. AI-related adverse effects are common and can cause therapy intolerance and early discontinuation. Supportive therapies have been shown to improve symptom tolerability when utilized by patients. This study assessed socioeconomic disparities in utilization of supportive therapies and adherence to initial AI therapy. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+, BC who were initiated on adjuvant AI between 2011-2020. We collected information on side effects, duration of first AI and use of supportive therapies. We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. Primary endpoints were the rate of discontinuation of AI at 1-year and utilization of supportive therapies in relation to income, insurance coverage and primary language. The Fisher's exact test, Pearson's Chi-squared test, and Wald test methods were used to compare rates of discontinuation of front-line AI therapy and use of supportive therapies for each group. Results: We identified 1006 patients of whom 95% (n = 954) had AI related side effects yet only 31% (n = 311) received supportive therapies in the first year of AI treatment. The majority (59%) of patients were in the middle-income range ($52,200-$156,000), followed by upper (24%) and lower (17%) income. Upper-income was associated with higher use of supportive therapies (OR 1.46, p = 0.031) but was not associated with lower 1-year discontinuation rate. Medicare was the most common insurance coverage (45%), followed by Commercial (32%) and Medicaid (23%). English was the primary language for 86% of patients. Neither insurance coverage nor primary language was associated with either endpoint. In evaluating race, Black patients had the least use of supportive therapies (p &lt; 0.001), yet this group had the lowest 1-year discontinuation rate (p = 0.005). Conclusions: Our results demonstrate that income and race were associated with use of crucial supportive therapies that are proven to help patients mitigate AI toxicities. The etiology of these disparities is likely multifactorial and requires further study to ensure equitable care and access for all patients.

Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6).

TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.

Aromatase Inhibitors and Risk of Metabolic and Cardiovascular Adverse Effects in Breast Cancer Patients-A Systematic Review and Meta-Analysis.

Aromatase inhibitors (AIs) have been considered first-line therapy for patients with hormone-dependent breast cancer due to their high efficacy and good tolerability. However, AIs are not free of adverse events, and studies show that therapy with AIs is associated with an increased risk of cardiovascular events and the development of insulin resistance and diabetes. We searched the Cochrane Central Register of Controlled Trials, PubMed and EMBASE up to 27 October 2020 for the prevalence of cardiovascular and/or metabolic adverse effects during treatment with AIs in postmenopausal women with breast cancer. A meta-analysis was performed using a random effects model. Odds ratios and 95% confidence intervals were calculated and illustrated using forest plot charts. We performed separate analyses depending on trial design. Twenty two studies met the inclusion criteria. AIs were associated with a higher risk of cardiovascular events, especially when we compared study arms in which AIs were used (alone or in sequence with TAM) with the arms in which TAM was used alone (OR = 1.16; 95%CI 1.04–1.30) or when comparing patients taking AIs alone to patients taking TAM alone or in sequence with AIs (OR = 1.24; 95%CI 1.11–1.38). A pooled analysis of five trials comparing adjuvant AIs to TAM showed the odds for arterial hypertension being 1.31 times higher for patients taking AIs; however, this did not reach statistical significance (OR = 1.31; 95%CI 0.47–3.65). We have not shown an increased risk of dyslipidemia or weight gain with the use of AIs. Our results suggest that postmenopausal women with breast cancer treated with AIs have an increased risk of cardiovascular events in comparison with TAM, potentially due more to a cardioprotective effect of the latter than the cardiotoxicity of AIs. We were unable to prove a similar association for hypertension, dyslipidemia, hyperglycemia or weight gain. Further high-quality RCTs and post-marketing safety observational studies are needed to definitively evaluate the impact of AIs on metabolic disorders in breast cancer patients.

84P Serum 25-hydroxyvitamin D and cancer-related fatigue: Associations and effects on health-related quality of life in breast cancer survivors during adjuvant endocrine therapy

The high prevalence of vitamin D deficiency in postmenopausal women starting adjuvant Aromatase Inhibitors (AI) supports the hypothesis that hypovitaminosis D would be one of the biological explanations for the adverse effects of AI. These condition, even as cancer-related fatigue (CRF), may be related to poor Health-Related Quality of Life (HRQoL) in breast cancer (BC) survivors during adjuvant endocrine therapy.

90TiP Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6)

About 30% of patients (pts) with HR+ EBC on treatment with aromatase inhibitors (AIs), discontinue AIs due to toxicity (Henry et al. JCO 2012). For this population, there are currently limited therapy options, including switch to another AI or tamoxifen. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer.

The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer.

Breast cancer is the most frequently diagnosed cancer in women worldwide. Aromatase inhibitors (AIs) are effective treatment options for both early-stage and advanced hormone receptor-positive breast cancer. Because of AIs are used long term in adjuvant therapy, side effects are also very important. It is considered that AIs may affect cognitive functions by decreasing the level of estrogen in the brain. The purpose of our study is that evaluate the relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy. Two-hundred patients diagnosed with breast cancer who were treated with AIs as adjuvant treatment were included. The patients were surveyed for demographic characteristics. Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were performed to evaluate patients' cognitive functions. The total scores of the tests and the orientation, short-time memory, visuospatial functions, attention, language, executive functions which are the MoCA subscales were evaluated separately. Patients were grouped as 0-6, 6-12, 12-24, 24-36, 36, and more months according to the duration of AIs using time. The total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. There was no relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (P > 0.05). Prolonged adjuvant treatment with AIs does not affect cognitive functions in hormone receptor-positive breast cancer patients.

Abstract P5-18-11: Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer

Abstract Background: Aromatase inhibitors (AI) are standard of care in the treatment of early-stage hormone positive (HR+) breast cancer (BC). Commonly, these medications cause significant side effects which limit tolerability and often require a change in therapy. Supportive therapies are an essential part of treatment plans to improve adherence and quality of life. Studies in the last decade have demonstrated the critical role of supportive management in mitigating side effects from AI, such as the reduction in AI related joint pain with acupuncture or use of low dose oxybutynin for hot flashes. The aim of this study was to evaluate the real world use of supportive therapies for AI toxicities over the last decade and to determine if they were associated with patient adherence to initial AI treatment. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+ BC who were initiated on adjuvant AI therapy between 2011-2020. From the electronic medical record, we collected information on patient demographics, AI side effects (hot flashes, vaginal dryness, joint pains, osteopenia/osteoporosis), use of supportive therapies, and duration of first AI therapy. Primary endpoint was the rate of discontinuation of AI at 1 year among those who used supportive therapies compared with those who did not. The Wilcoxon rank sum test, Fisher's exact test, Kruskal-Wallis rank sum test, and Pearson's Chi-squared test methods were used to compare rates of discontinuation of front-line AI therapy for each group. Results: We identified 990 patients (pts) with early-stage, HR+ BC who were started on adjuvant AI between 2011-2020. Of these patients, 97% (n= 963) had AI related side effects yet only 51% (n=504) received supportive therapies. The overall discontinuation rate within 1 year was 14.8% (147 of 990 pts). Patients who received at least 1 supportive therapy were more likely to remain on AI and had a lower 1 year discontinuation rate of 10% (51 of 504 pts) compared to 20% (96 of 486 pts) for those who did not receive any supportive therapy (p&amp;lt;0.001). The most commonly used supportive therapies were bone strengthening agents, with 35.6% (n=352) of patients receiving either denosumab or zoledronic acid, followed by acupuncture used in 11.2% (n=111) of patients. The use of acupuncture increased in 2018, compared to years prior (35 pts from 2011-2017, and 76 pts from 2018-2020). Similarly, oxybutynin use increased in 2019, compared to years prior (9 pts from 2011-2018, and 28 pts from 2019-2020). Upon further analysis, younger age was significantly associated with a higher 1 year discontinuation rate (median age 62 years in &amp;lt;1 year AI treatment group, and 64 years in &amp;gt;1 year AI treatment group, p=0.003). Race also appeared to have an impact on AI tolerance. Although only 31% (39 of 126 pts; p &amp;lt; 0.001) of Black patients received supportive therapy, this group had the lowest 1 year discontinuation rate at 8.7% (11 of 126 pts). Conversely, 56% (277 of 491 pts) of White patients received at least one supportive therapy, yet had the highest 1 year discontinuation rate at 17% (83 of 491 pts). Conclusions: Supportive therapies are essential to help patients mitigate side effects of AI. Patients who received at least one supportive therapy had increased rates of AI adherence beyond 1 year compared to those who did not receive any supportive treatment. The most commonly used therapies were bone strengthening agents and acupuncture. Use of acupuncture and low dose oxybutynin have increased in the past 3 years and 2 years, respectively, following publication of their efficacy. It is critical to further evaluate the impact that race and age have in relation to duration of treatment and use of supportive management. Further studies on how to improve patient tolerability and adherence to AI therapy are needed. Citation Format: Melanie W Kier, Zhiqiang Li, Brittney S Zimmerman, Rima Patel, Yunchen Yang, Mark Y Fink, Jason D Wells, Xiang Zhou, Scott Newman, Rong Chen, Eric Schadt, William Oh, Amy Tiersten. Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-11.

Abstract GS2-05: Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials

Abstract Background The updated combined SOFT+TEXT analysis, after 9 years median follow-up (MFU), revealed that adjuvant E+OFS vs T+OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI) but not overall survival (OS) in premenopausal women with HR+ early BC (Francis et al NEJM 2018). Given the high rate of OS in both arms and the long-term risk of relapse in HR+ BC, continued follow-up is key to assessing treatment benefit. We report a planned update analysis including OS with database lock of May 2021, after 13 years MFU.. Methods TEXT and SOFT enrolled premenopausal women with HR+ early BC from November 2003 to April 2011 (2660 in TEXT, 3047 in SOFT intention-to-treat (ITT) populations). TEXT randomized women within 12 weeks of surgery to 5 years E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5 years E+OFS vs T+OFS vs T alone, within 12 weeks of surgery if no CT planned, or within 8 months of completing (neo)adjuvant CT. Both trials were stratified by CT use. For the combined analysis of E+OFS vs T+OFS, the primary endpoint was DFS defined as invasive local, regional, distant recurrence, contralateral BC, second malignancy, death. Secondary endpoints included invasive breast cancer-free interval (BCFI), DRFI and OS.. Results: At database lock there were 953 DFS events and 473 deaths among 4690 pts assigned to T+OFS or E+OFS. In the ITT population, DFS, BCFI and DRFI outcomes for pts assigned E+OFS (n=2346) continued to be significantly improved over T+OFS (n=2344). 12-yr DFS was 80.5% vs. 75.9% (4.6% absolute improvement; HR 0.79 95% CI 0.70-0.90), 12-yr BCFI was improved by 4.1% and 12-yr DRFI by 1.8%. At 12 years OS was excellent in both groups, 90.1% in pts assigned E+OFS vs 89.1% in pts assigned T+OFS (HR 0.93; 95% CI, 0.78-1.11). There was heterogeneity of relative treatment effect according to HER2 status. When enrollment commenced, anti-HER2 adjuvant therapy was not standard; 53% of 583 pts with HER2+ tumors received HER2-targeted therapy. Below are Kaplan-Meier 12-yr estimates for patients with HER2 negative tumors by trial and chemotherapy stratum and for those with high-grade tumours, as an example of high-risk feature (Table). There is an emerging OS benefit for E+OFS vs T+OFS in pts with HER2 negative tumors who received chemotherapy in both trials.In pts with HER2-negative tumors, clinically-relevant outcome benefits were also seen in other high-risk subgroups: 12-yr DFS and OS were improved by 7.4% and 2.7%, respectively, in pts with pN1a disease, and by 10.6% and 4.5%, respectively, in those with tumors &amp;gt;2cm. Conclusions After 13 years MFU, adjuvant E+OFS, as compared with T+OFS, shows a sustained reduction in the risk of recurrence, more consistent in HER2 negative patients and in those with high-risk disease features, e.g., indication for adjuvant chemotherapy and G3 tumors. Oncologists may use this information to discuss potential benefits of E+OFS with individual patients. Follow-up continues for 5 additional years. Chemotherapy HER2-negativeSOFTT+OFS (n=424)E+OFS (n=411)Absolute difference12-yr DFS67.4%74.1%6.7%12-yr OS81.1%84.4%3.3%TEXTT+OFS (n=656)E+OFS (n=661)Absolute difference12-yr DFS71.0%78.4%7.4%12-yr OS83.5%86.8%3.3%No chemotherapy HER2-negativeSOFTT+OFS (n=445)E+OFS (n=447)Absolute difference12-yr DFS82.9%88.2%5.3%12-yr OS96.1%96.9%0.9%TEXTT+OFS (n=499)E+OFS (n=492)Absolute difference12-yr DFS80.2%86.7%6.5%12-yr OS95.9%96.2%0.2%G3 HER2-negativeT+OFS (n=423)E+OFS (n=405)Absolute difference12-yr DFS62.7%73.0%10.3%12-yr OS78.1%83.6%5.5% Citation Format: Meredith M Regan, Barbara A Walley, Gini F Fleming, Prudence A Francis, Marco A Colleoni, István Láng, Henry L Gómez, Carlo A Tondini, Harold J Burstein, Matthew P Goetz, Eva M Ciruelos, Vered Stearns, Hervé R Bonnefoi, Silvana Martino, Charles E Geyer, Jr, Claudio Chini, Alessandro M Minisini, Simon Spazzapan, Thomas Ruhstaller, Eric P Winer, Barbara Ruepp, Sherene Loi, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-05.

Abstract OT2-11-06: SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease

Abstract Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors. Concurrent use of luteinizing hormone-releasing hormone agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy and the disease is incurable in these cases. New therapies are needed to combat endocrine therapy resistance, maintain patient health-related quality-of-life, and delay the need for chemotherapy. AZD9833 (camizestrant) is a highly potent, next-generation selective ER degrader and pure ER antagonist that has demonstrated anticancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, AACR 2020). A Phase I dose-escalation and expansion study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor activity when administered alone or in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, Phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+/HER2− ABC who have not received systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1342 patients with de novo or recurrent ER+/HER2− ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive oral treatment with either (a) AZD9833 75 mg once daily, palbociclib 125 mg once daily for 21 days followed by 7 days off treatment and a placebo for anastrozole 1 mg once daily or (b) anastrozole 1 mg once daily, palbociclib (same as active arm) and a placebo for AZD9833 75 mg once daily. Men and premenopausal women will also receive a luteinizing hormone-releasing hormone agonist. The primary endpoint is progression-free survival (PFS; up to 5 years). Secondary endpoints include overall survival (up to 8 years), second PFS, time to chemotherapy, objective response rate, and changes in health-related quality-of-life measures. Enrollment began in January 2021. As of 02 July 2021, the number of open sites is 57 across 15 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, for providing medical writing support funded by AstraZeneca Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Citation Format: Fabrice André, Seock-Ah Im, Patrick Neven, Richard D Baird, Johannes Ettl, Matthew P Goetz, Erika Hamilton, Hiroji Iwata, Zefei Jiang, Anil Abraham Joy, Vincent Haddad, Andrew Walding, Manuel Selvi Miralles, Cynthia Huang Bartlett, Antonio Llombart-Cussac. SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-06.

Abstract P3-09-03: Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study

Abstract Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level &amp;lt;0.012 were considered significant and included in multivariate models.Multivariate models’ covariates included: treatment arm (5 vs 3-2 years letrozole), (neo)adjuvant chemotherapy, previous hormone replacement therapy, age, BMI, previous biphosphonates, hypercholesterolemia and hypertension at baseline. SNPs were tested for Hardy–Weinberg equilibrium (HWE) and linkage disequilibrium (LD). Interaction between SNPs of interest and treatment arm was also investigated. Results: Of 2,056 patients enrolled in the GIM4 trial, 647 entered this translational study. All SNPs were in HWE. The CT and TT variants of rs10046 were less associated to skeletal events compared to variant CC, suggesting a dominant effect of the minor T allele (odds ratio [OR]: 0.47,. 95% confidence interval [CI]: 0.28-0.79, p=0.005). The association was independent from the other covariates (adjusted OR [aOR]: 0.43, p=0.002). Patients with rs10046-TT had no significant differences in the odd of skeletal events according to treatment arm. Conversely, in patients with rs10046-CC, skeletal events were more likely with 5-year letrozole (interaction p=0.043). Compared to rs10046-CC, rs10046-TT/CT was also less associated with CV events at both univariate (OR: 0.46 95% CI: 0.27-077, p=0.003) and multivariate analysis (aOR: 0.41, p&amp;lt;0.001).The rs727479—GG variant was associated with more CV events compared to the GT and TT variants (OR: 2.30, 95%CI: 1.27-4.15, p=0.009), suggesting a recessive effect of the minor G allele. The association remained significant at multivariate analysis (aOR: 2.30, p=0.010). No significant interaction was observed among treatment arms, rs10046 or rs272479 variants (interaction p=0.070 and 0.061). Rs10046-CC and rs727479-GG variants were in high LD (D’=0.92, haplotype-CG frequency: 39%). Hence, the association between genotype rs10046-CC/rs727479-GG and CV events was investigated. The association was significant at the multivariate analysis (aOR: 2.79, p=0.002). With such genotype, the odd of CV events was significantly increased with the 5-year letrozole (interaction p=0.046). Conclusions: SNPs of CYP19A1 could be useful biomarkers of long-term toxicity in HR+ BC patients who are candidates for adjuvant AI. Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Abstract P1-17-06: Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer

Abstract Background: Aromatase inhibitors (AIs) are part of standard endocrine therapy for hormone receptor (HR)-positive breast cancer (BC) and are used in both adjuvant and metastatic settings. Since AIs work by inhibiting the conversion of androgens to estrogen in peripheral adipose tissue, the higher levels of estrogen in obese patients may lead to incomplete inhibition by AIs and influence their efficacy. A retrospective analysis of the ABCSG-12 trial found that overweight premenopausal patients with early-stage BC treated with anastrozole had a 60% increased risk of disease recurrence and more than doubling in risk of death compared with normal weight patients on anastrozole. Similarly, an exploratory analysis from the ATAC trial found that in post-menopausal women with early-stage BC, overall recurrence rates were lower in patients randomized to anastrozole versus tamoxifen but in women with body mass index (BMI) &amp;gt; 30, there was no significant difference in disease recurrence between anastrozole and tamoxifen. While these findings raise concern for the efficacy of adjuvant AI therapy in obese patients with early-stage BC, this has not yet been demonstrated in the metastatic setting. The aim of this study was to determine the impact of BMI on efficacy of AIs in patients with metastatic HR-positive BC. Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001-2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. PFS was compared across BMI groups using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression model was used for univariate and multivariate analyses. Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. The median age was 59 with 45% of patients White, 29% African American, 16% Hispanic/Latino, 5.5% Asian and remainder other/unknown. 32% (71) had HER-2 positive disease. 82% (179) were on an AI in the first-line setting. Overall, 53% were on letrozole, 42% on anastrozole and 5.5% on exemestane. Of the 219 patients, 56% (123) had a low BMI (defined as &amp;lt; 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2; based on the Breast Cancer Weight Loss [BWEL] trial). The median PFS was 21.9 months (95% CI, 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI, 14.3 to 27.5) in the high BMI group with no statistically significant difference (p =0.73). There were 8 (6.5%) deaths in the low BMI group and 7 (7.3%) deaths in the high BMI group. Multivariate cox regression model did not demonstrate any significant impact of BMI on PFS when adjusting for age, race/ethnicity, HER2 status, type of AI, line of therapy, drug partner and type of metastatic disease (HR =0.91, 95% CI =0.64 to 1.30, p =0.6 for high BMI group). Subgroup analysis of patients on an AI in the first line setting also did not show a significant difference in PFS with median PFS 19.3 and 18 months in the low and high BMI groups, respectively. Conclusions: In patients on an AI for metastatic HR-positive breast cancer, there was no statistically significant difference in PFS in patients with low versus high BMI. While BMI influences efficacy of AIs in the adjuvant setting, our results demonstrate that in the metastatic setting, BMI does not significantly impact the efficacy of AIs among our patient population. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest. Additional larger studies are needed to confirm this finding. Citation Format: Rima Patel, Zhiqiang Li, Brittney S. Zimmerman, Marc Y. Fink, Jason D. Wells, Xiang Zhou, Kristin L. Ayers, Arielle Redfern, Scott Newman, Rong Chen, William K. Oh, Amy Tiersten. Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-06.

Abstract PD14-08: Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status

Abstract Background: In post-menopausal women with hormone receptor (HR) positive early breast cancer, aromatase inhibitors (AIs) are more effective than tamoxifen as endocrine therapy. However, some trial reports indicate greater benefit from AIs in lobular than ductal cancers. Invasive lobular cancer can be identified using conventional microscopy and/or immunohistochemistry for e-Cadherin status. We performed an individual patient data meta-analysis to explore possible differential treatment benefits for AI vs tamoxifen in women with lobular vs ductal hormone receptor positive breast cancer. Methods: Individual patient data were collected from three randomised controlled trials (BIG 01-98, TEAM and ATAC) of AI vs tamoxifen for postmenopausal women with estrogen receptor positive breast cancer, as well as results of central pathology review and e-Cadherin expression. Central pathology and e-Cadherin data were available on 9328 and 7654 women. Local pathology data was available for TEAM, BIG 01-98. Data were analysed using the same methodology as the previous EBCTCG meta-analysis of AI vs tamoxifen: results of different methods of diagnosing ductal vs lobular cancer were cross tabulated, and outcomes analysed using log-rank methods, yielding event rate ratios (RR) and confidence intervals. Interactions were evaluated using standard tests for heterogeneity; the primary outcomes were time to any invasive breast cancer recurrence, and time to distant recurrence. Results: Rates of lobular cancer were higher when assessed by central pathology (BIG 01-98 16%; ATAC 16%; TEAM 12%) than e-Cadherin (15% vs 14% vs 9%). Methods agreed in over 80% of cases classified as ductal using either pathology or e-Cadherin, while the agreement rate for lobular cancers was only about 50%. A similar pattern was seen comparing local pathology with either central pathology or e-Cadherin. Consequently, analyses were stratified by pathology and e-Cadherin both separately and together. Consistent with the previous meta-analysis there was a significant reduction in recurrence for AI compared to tamoxifen (RR 0.73 (0.61-0.87) p=0.0004). Exploration of interaction found no evidence of heterogeneity of treatment effect on recurrence by pathology (ductal HR 0.76 (0.64-0.89); lobular HR 0.76 (0.50-1.15) interaction p&amp;gt0.99; nor by e-Cadherin status (interaction p=0.9). No significant interactions were seen on other endpoints. Conclusion: Analyses of three large trials of adjuvant AI vs tamoxifen found discordance in identifying patients with lobular carcinoma by local or central pathology or e-Cadherin status, indicating variability in the consistency of diagnosis. The trials included showed a benefit for AI over tamoxifen in line with the previous meta-analysis, but with no evidence of differential efficacy in lobular compared to ductal carcinomas, however measured. These data cannot rule out smaller quantitative interactions or differences in site of recurrence: however, in contrast to earlier reports, this meta-analysis of the totality of the data does not identify ductal/lobular cancer as a predictive marker for differential endocrine treatment benefit. Citation Format: Robert K Hills, Steffi Oesterreich, Otto Metzger, David Dabbs, Hongchao Pan, Jeremy Braybrooke, Richard Gray, Richard Peto, Rosie Bradley, Ewan Straiton, Richard Berry, Daniel Rea, David Cameron, Jack Cuzick, Meredith Regan, Mitch Dowsett, Ivana Sestak, Jonas Bergh, Sandra M Swain, John Bartlett, Early Breast Cancer Trialists' Collaborative Group. Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-08.

Abstract PD15-04: Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ breast cancer

Abstract Background: Extended endocrine therapy (EET) has shown modest gains in absolute benefit to reduce the long-term risk of recurrence in hormone receptor-positive (HR+) breast cancer but is accompanied by serious adverse events (AEs), such as bone and cardiovascular toxicities, endometrial cancer and other side effects that impair quality of life (QOL). Novel approaches that quantify the benefit-risk balance integrating both survival benefit and harm to determine a net health outcome would advance EET decision making. BCI is a gene expression-based assay that predicts benefit from endocrine therapy. Here, the ability of BCI by HOXB13/IL17BR (H/I) to predict the net benefit from 2.5 vs 5y of extended letrozole in patients treated in the IDEAL trial was examined by integrating both efficacy and toxicity outcomes into a single analysis. Methods: All IDEAL patients with available tumor specimens were eligible for this analysis. The Net Treatment Benefit (NTB) and the Win Ratio (WR) were examined using generalized pairwise comparisons to analyze both efficacy and safety wherein all possible patient pairs, one from each treatment arm, were compared based on several prioritized outcome measures scored as favorable, unfavorable, neutral or uninformative. The first prioritized outcome was recurrence-free survival (RFI) with a clinical threshold of ≥3 months; the second prioritized outcome was toxicity based on the highest grade of treatment related AEs. NTB was estimated as the difference in the proportions of favorable vs unfavorable pairs, representing the net probability of an improved health outcome with EET. WR was calculated as the ratio of favorable vs unfavorable pairs, representing the relative risk of an improvement in health outcomes with EET. AEs were evaluated in annual follow-up visits during the active treatment period. Bone-related AEs of ≥ grade 3 included arthralgia, osteoporosis, decreased joint range of motion, back pain and fracture. The most prevalent QOL-related AEs of ≥ grade 3 included hot flashes, fatigue, depression, insomnia and vaginal dryness. Results: 908 HR+ patients (73% pN+, median age 59y, 45% pT1, 48% pT2) were included, with 88% and 68% receiving prior treatment with an aromatase inhibitor (AI) or chemotherapy, respectively. When toxicity was assessed with treatment related AEs ≥ grade 2, no significant improvement in the benefit-risk was observed for EET in either BCI (H/I)-High or BCI (H/I)-Low group. However, when severe toxicity was assessed with AEs ≥ grade 3, significant benefit-risk improvements were observed for EET in BCI (H/I)-High patients (NTB=7.2%, WR=1.76, p=0.044), but not in BCI (H/I)-Low patients (NTB=-0.7%, WR=0.96, p=0.869). BCI (H/I)-High patients demonstrated significant NTB=7.7%/7.4%, WR=2.24/1.92 when analyzing bone-related and QOL-related toxicities, respectively (p=0.024, 0.024), while no significant results were observed in the BCI (H/I)-Low patients (p=0.902, 0.780, respectively). Prioritizing toxicity over efficacy produced similar results. Conclusion: Novel findings demonstrate that BCI not only significantly predicts preferential survival benefit from longer durations of endocrine therapy, but also significantly predicts the overall benefit/risk and likelihood of an improved health outcome from EET in HR+ patients treated with primary adjuvant AI, when severe AEs are considered. It should be noted that the results of our analysis could be biased due to a shorter AE recording period in the 2.5y arm, hence the true benefit/risk of EET could be larger than reported here. Quantification of a net treatment benefit when considering the impact of both efficacy and toxicity may represent a new paradigm for evaluation of the overall EET benefit and aid in patient selection for EET. Citation Format: Marc Buyse, Jenna Wong, Samuel Salvaggio, Jean-Christophe Chiem, Yi Zhang, Kai Treuner, Elma Meershoek-Klein Kranenbarg, Mickaël De Backer, Gerrit-Jan Liefers, Catherine A Schnabel. Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-04.

Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer.

Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer.

Bone recurrence in early breast cancer patients: The paradox of aromatase inhibitors induced bone resorption.

Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20-45% of them will experience a disease recurrence, particularly bone metastases in 60-80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases. In this single-institution cohort study, we performed a retrospective analysis of "luminal-like" EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR). 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45-65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25-54), while among patients who did not was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p =0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p =0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR. In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.

Ovarian Function Suppression With Luteinizing Hormone-Releasing Hormone Agonists for the Treatment of Hormone Receptor-Positive Early Breast Cancer in Premenopausal Women.

Chemotherapy and endocrine therapies are mainstays of treatment for early and advanced hormone receptor-positive (HR+) breast cancer. In premenopausal women with HR+ tumors, the benefits of adding ovarian function suppression (OFS) to endocrine therapy have been debated. Consequently, for many years, tamoxifen monotherapy has been the standard of care for endocrine treatment in the adjuvant setting. Recent studies have, however, provided new evidence that, in some premenopausal patients, OFS in combination with tamoxifen or aromatase inhibitors (AIs) can significantly increase survival versus tamoxifen alone. Luteinizing hormone-releasing hormone agonists (LHRHa), including goserelin, triptorelin, and leuprorelin, achieve OFS through sustained suppression of the release of follicle-stimulating hormone and luteinizing hormone from the pituitary. In turn, this suppresses production and secretion of estradiol, an ovarian hormone that supports cancer cell growth, survival, and proliferation. In this review, we discuss the clinical evidence supporting the addition of LHRHa to adjuvant endocrine therapies, including tamoxifen and AIs, for premenopausal women with breast cancer. We also discuss the role of LHRHa use in combination with adjuvant chemotherapy to preserve ovarian function and fertility in young patients with breast cancer. Finally, we discuss important practical aspects of the use of LHRHa in breast cancer treatment, including side-effects, patient adherence to treatment, and the use of slow-release, long-acting drug formulations.

Extended adjuvant aromatase inhibitor therapy: less is more

Adjuvant endocrine therapy has transformed outcomes for patients with early-stage, hormone receptor-positive, HER2-negative breast cancer; however, the optimal duration remains undefined. In a recent issue of The New England Journal of Medicine, Gnant etal. report the results of the ABCSG-16/SALSA trial that investigated the optimal duration of extended adjuvant aromatase inhibition and found that 5 years was not more beneficial than a 2-year extension.1.