Elinzanetant Is Effective for Vasomotor Symptoms Caused by Endocrine Therapy for Breast Cancer.

Background: The combination of CDK 4/6 inhibition and endocrine therapy has emerged as the new first line standard of care treatment for patients with hormone receptor (HR) +ve metastatic breast cancer (MBC)1. Ribociclib plus letrozole has been shown to improve PFS (25.3 vs 16.0 months; log-rank P=9.63x10-8) compared to letrozole alone2. More recently, this benefit has also been demonstrated in pre- and peri-menopausal women in combination with ovarian suppression and tamoxifen or an aromatase inhibitor (AI), with an improved overall survival (40.9 months vs OS not reached; HR = 0.712; p=0.00973) in the MONALEESA-7 study3. Approximately 800 patients in Australia participated in the ribociclib medicine access program (MAP) between May 2017 and June 2018, prior to government funding. Beyond eligibility criteria for the program and clinician name, no patient data was initially captured, consistent with usual practice for MAPs, due to the multiple challenges related to ethics, data ownership, security and patient privacy. We have previously demonstrated the feasibility of successful data collection alongside MAPs4 which can yield benefits for clinicians, industry and the broader medical community. Based on this we plan to retrospectively collect data for patients treated as part of the Australian ribociclib MAP. Trial Design: This is a secondary data use, non-interventional study of patients in Australia who received treatment with the combination of an AI and ribociclib, obtained via a MAP, for HR+ HER2- MBC. The target sample size is 250 patients from ~15 sites. De-identified patient data will be retrieved from the patient’s medical records and entered on to an electronic case report form. Data collection is anticipated to commence in July 2019 with the final treatment and survival outcomes collected in late 2020, thus allowing for a minimum of 24 month follow up for all patients from the start date of treatment with ribociclib and AI (May 2017 - June 2018). Study Aims: The primary aim of the study is to describe real world clinical and tumour characteristics of patients with HR+ HER2-ve MBC in Australia who are recommended and received ribociclib in combination with an aromatase inhibitor in the first line setting. Details of adjuvant therapy received and the tolerability of the treatment combination including dose interruptions, dose reductions and significant adverse events of interest related to ribociclib will be assessed. Secondary aims include time to treatment progression and progression free survival for the ribociclib and AI combination, and to explore the disease course post progression, including clinician choice of subsequent lines of therapy in routine clinical practice.

e19627 Background: Hormonal therapy with aromatase inhibitors (AI) or tamoxifen (TAM) is standard of care for hormone receptor positive breast cancer and DCIS. Fractures are a complication of treatment with AI due to accelerated bone loss. Risk factors for fracture in patients on hormonal therapy (HT) for breast cancer and DCIS are poorly defined. Methods: All 71 patients with breast cancer or DCIS seen in the bone and mineral clinic of our institution from 2000 to 2010 were analyzed. Data on demographics, pathology, type and duration of HT, bone mineral density studies (BMD), number and site of fractures were collected. Statistical analysis: t test, chi square test and Fisher’s exact test for categorical data. Results: The age of the patients ranged 40 to 97 years. 65 patients had ER positive breast cancer, 6 patients had DCIS. 9 patients had fractures.41 patients were on an AI alone, 8 were on TAM alone and 14 were on both sequentially. Fractures involved: vertebral compression, femur, hip, distal radioulnar, rib, hand and feet bones. Patients who had osteoporosis at the femur, osteoporosis or osteopenia in the lumbar spine or forearm in the initial BMD study were found to have an increased risk of fracture (P<0.05). Patients who were on TAM and AI sequentially had an increased risk of fracture (P<0.05) compared AI alone. The use of bisphosphonates and the duration of use were significantly associated with fracture (P<0.05) as these patients already had osteoporosis. The age, race, duration of AI use and the use of calcium and vitamin D were not found to be significantly different in patients who had fractures compared to those who did not. In the 24 patients who had two BMD studies, there was no significant change in the BMD overall. Conclusions: Patients with osteoporosis or osteopenia at baseline have an increased risk of fracture with the use of hormonal therapies for breast cancer and DCIS. This risk was not eliminated by the use of bisphosphonates. Sequential use of tamoxifen and aromatase inhibitors increase the risk of fractures. Bone mineral density studies done prior to the initiation of hormonal therapy for breast cancer maybe useful estimating the risk of fracture while on treatment.

Recently, there is increased attention to neo-adjuvant endocrine therapy in breast cancer. Especially for selected tumour types and fragile elderly patients this might be a promising alternative to chemotherapy. Monitoring treatment effect during neo-adjuvant endocrine therapy is crucial to allow a timely switch to chemotherapy in case of a non-successful treatment. Most trials evaluating neo-adjuvant endocrine therapy use palpation as primary outcome and multiple radiological modalities as secondary outcomes. The aim of this study was to determine which evaluation corresponds best to pathological resection size after 6 months of neo-adjuvant endocrine therapy. This analysis was conducted in the TEAM-IIA trial in which 102 patients with early breast cancer (>2 cm and >50% ER expression) were treated with neo-adjuvant exemestane. In total, 83 patients were treated for 6 months and 19 for 3 months. Therapy response evaluation was performed using repeated palpation (mostly by the same clinician), mammography, ultrasound and MRI. Only measurements within 2 months before surgery were considered. After surgery, the size of the remaining tumour was reported and used as reference. In total, 93 resection size measurements were available. From the 93 patients for whom resection size was available, 69 patients were evaluated by palpation, 53 by ultrasound, 42 by mammography and 29 by MRI. Overall, palpation showed to be the most reliable predictor for resection size (correlation of 49%), followed by mammography (31%), ultrasound (14%) and MRI (1%). Mammography showed the smallest mean absolute error (MAE, 8.7 mm), followed by ultrasound (9.2 mm), palpation (11.4 mm) and MRI (12.3 mm). The low correlation of MRI with resection size was mostly due to a relative high number of radiological complete remissions (14%, n=4), of which only one was a true pathological complete response (pCR), while the other tumours were up to 80 mm at resection. Although of less influence on the correlation to resection size, false complete remissions were observed in all other modalities. Time to surgery was an important factor for all modalities. After correcting for non-predictive radiological complete responses and limiting the measurements to one month before surgery, all correlations increased significantly (mammography=72%, palpation=70%, ultrasound=58%, MRI=50%) with a concomitant decrease in mean absolute error. The low correlation of MRI with resection size was mostly due to non-visible measurements, interpreted as radiological complete remissions of which only one in four was a true pathological complete response (pCR) while the other tumours were 25, 65, and 80 mm at resection. This is the first study to report on the reliability of radiological evaluation during neo-adjuvant endocrine therapy. In this study, mammography was the most reliable radiological method, with stronger correlation and small mean absolute error. Non- visible observations in neo-adjuvant endocrine therapy did not always reflect pCR. Hence, in the neo-adjuvant endocrine therapy setting, radiological complete responses should be interpreted carefully, especially in MRI, and use of other modalities or improved image processing methods may be considered. Citation Format: Blok EJ, Charehbili A, Kroep JR, Seynaeve CM, van de Velde CJH, Kuppen PJK. Radiological evaluation of neo-adjuvant endocrine therapy in hormone-receptor positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-01-05.

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.

The association between Akt activation and resistance to hormone therapy in metastatic breast cancer

BackgroundWomen receiving endocrine therapy for hormone receptor (HR)–positive breast cancer or its prevention among those at high risk for breast cancer commonly have vasomotor symptoms. Data are lacking on the effects of elinzanetant, a neurokinin-targeted therapy shown to be effective in treating vasomotor symptoms, in this population.MethodsWe performed a phase 3 trial involving women 18 to 70 years of age with moderate-to-severe vasomotor symptoms associated with endocrine therapy for HR-positive breast cancer or its prevention. Women were randomly assigned in a 2:1 ratio to receive once-daily elinzanetant at a dose of 120 mg for 52 weeks or once-daily placebo for 12 weeks followed by once-daily elinzanetant at a dose of 120 mg for 40 weeks. The primary end points were the change in the mean daily frequency of moderate-to-severe vasomotor symptoms from baseline to week 4 and to week 12.ResultsA total of 316 participants were assigned to the elinzanetant group and 158 to the placebo–elinzanetant group. At baseline, the mean daily frequency of moderate-to-severe vasomotor symptoms was 11.4 episodes (95% confidence interval [CI], 10.7 to 12.2) in the elinzanetant group and 11.5 episodes (95% CI, 10.5 to 12.5) in the placebo–elinzanetant group. At week 4, the mean change from baseline in the mean daily frequency of moderate-to-severe vasomotor symptoms was −6.5 episodes (95% CI, −7.2 to −5.8) among those who were receiving elinzanetant and −3.0 episodes (95% CI, −3.9 to −2.2) among those who were receiving placebo (least-squares mean difference, −3.5 episodes; 95% CI, −4.4 to −2.6; P<0.001). At week 12, the mean change was −7.8 episodes (95% CI, −8.5 to −7.1) among those receiving elinzanetant and −4.2 episodes (95% CI, −5.2 to −3.2) among those receiving placebo (least-squares mean difference, −3.4 episodes; 95% CI, −4.2 to −2.5; P<0.001). During weeks 1 through 12, a total of 220 participants (69.8%) receiving elinzanetant and 98 (62.0%) receiving placebo reported at least one adverse event that occurred while receiving elinzanetant or placebo, with the most common being headache, fatigue, and somnolence. Serious adverse events occurred during weeks 1 through 12 in 8 participants (2.5%) receiving elinzanetant and 1 participant (0.6%) receiving placebo.ConclusionsElinzanetant led to a significantly lower frequency of vasomotor symptoms associated with endocrine therapy than placebo. (Funded by Bayer; OASIS-4 ClinicalTrials.gov number, NCT05587296.)

Historically the endocrine therapy of breast cancer originated from a novel concept proposed by George Thomas Beaston, a surgeon in Glasgow. In 1896, he published a paper about the successful treatment of a premenopausal woman with recurrent breast cancer by bilateral oophorectomy. Actually, the principal hormone of the ovary, estrogen, was identified in 1923. Thereafter, many efforts were made to prevent estrogen production by means of radiation to ovaries, bilateral adrenalectomy, or hypophysectomy. Endocrine therapy experienced a step change in the 1960's when the estrogen receptor (ER) was discovered. This led to the elucidation of the mechanisms of estrogen action and established ER as a new target of endocrine therapy. Tamoxifen, the first selective ER modulator (SERM), has been the gold standard in the endocrine therapy of breast cancer since the drug had first been approved in the 1970s for the treatment of advanced breast cancer in the UK and the USA. Over the last 8 years, tamoxifen has been considered to be the main means of reducing mortality from breast cancer in western countries.(1) The impact of endocrine therapy for breast cancer was confirmed by the 1995 Oxford overview.(2) Recently, new endocrine agents with various action mechanisms, such as the third-generation of aromatase inhibitors, and ER downregulators, revealed equivalent or better results in the treatment of breast cancer as tamoxifen. The 7th International Conference on Adjuvant Therapy of Primary Breast Cancer held at St. Gallen, Switzerland, also recognized the increased role of endocrine therapy in properly selected patients groups, especially in younger patients with ER-positive tumors.(3) At present, numerous trials are ongoing to determine optimal endocrine therapy for breast cancer. In addition, recent advances in research upon estrogen and ER function at the molecular level have provided new strategies and a better understanding of endocrine therapy for breast cancer. Accordingly, in this review, we have attempted to summarize the basic concepts of Current Understanding of Endocrine Therapy for Breast Cancer

20551 Background: The urogenital side effects of endocrine therapy for breast cancer are well recognized but neither their prevalence nor severity is well described in the non-trial setting. These symptoms can negatively impact quality of life (QoL) and may seriously impact the efficacy of therapy if they compromise adherence to the recommended endocrine treatment. Methods: In this questionnaire study, we utilized a 5-point Likert type scale to assess the prevalence and severity of vulvovaginal and urinary tract symptoms and we also assessed the impact of these symptoms on sexual functioning (Sexual Activity questionnaire) and QoL (FACT-ES questionnaire) in a group of post-menopausal women receiving endocrine therapy for adjuvant or metastatic breast cancer. We also asked if women considered non- adherence to treatment due to adverse effects. Results: 252 post-menopausal women were surveyed, with median age 60 (range 32–91). All women were currently receiving endocrine treatment for breast cancer; 84% in the adjuvant and 16% in the metastatic setting. Tamoxifen was used by 30% of women and Aromatase inhibitors by 67%. Of the women surveyed, 63% reported some degree of urogenital symptoms related to their treatment. 48% reported symptoms of vaginal dryness, 32% dyspareunia, 26% vaginal discharge, 27% vaginal itching/irritation, 5% vaginal bleeding and 12% reported urinary symptoms. 48% of patients who reported vaginal dryness had severe/very severe symptoms. Only 9 patients admitted that they had considered discontinuing treatment because of urogenital side effects. Conclusions: Urogenital side effects are common and were found in 63% of patients. The most common urogenital side effect reported was vaginal dryness, which was reported as severe or very severe in 48%. Despite this degree of severity, only 9 patients reported considering discontinuing therapy because of these side effects. No significant financial relationships to disclose.

Radiotherapy concurrent versus sequential with endocrine therapy in breast cancer: A meta-analysis

Multiple symptoms associated with endocrine therapy have a detrimental impact on medication adherence and quality of life. The purpose of this scoping review is to map the symptoms during endocrine therapy for breast cancer to provide implications for current practice and suggestions for future research. The PubMed, CINAHL, and China Science Periodical Databases were searched to identify related studies published in English and Chinese languages. References of included articles were reviewed for additional eligible studies. Of the 2551 articles identified, 57 articles met inclusion criteria and were included in this scoping review. Evidence for the 16 most studied symptoms and 15 most prevalent symptoms were synthesized. Five key symptoms associated with endocrine therapy were identified, including joint/muscle pain, hot flashes, low sexual interest/desire, joint/muscle stiffness, and fatigue/lack of energy. Rarely studied but highly prevalent symptoms and other gaps in the symptom science during endocrine therapy for breast cancer were identified. Nurses caring for women receiving endocrine therapy for breast cancer should assess the 5 key symptoms identified. There remain substantial gaps in the science related to the symptom experience during endocrine therapy for breast cancer. Future studies should focus on the domains of symptom intensity and distress, specific understudied symptoms, symptom clusters, and development of symptom assessment instruments specific to symptoms associated with endocrine therapy. This scoping review identified 5 well-studied and highly prevalent symptoms that should be assessed in women with breast cancer receiving endocrine therapy.

PurposeDespite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice.MethodsWe identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003–2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation.ResultsInitial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95% CI = 1.3–3.3), not undergoing chemotherapy (HR = 1.4, 95% CI = 1.1–1.8) and not undergoing mastectomy (HR = 1.5, 95% CI = 1.2–1.8).ConclusionsLess than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice.

9022 Background: We have previously reported that, in the BIG 1-98 trial, objective cognitive function improved in postmenopausal women one year after cessation of adjuvant endocrine therapy for breast cancer. Here we evaluate changes in subjective cognitive function (SCF). Methods: One hundred postmenopausal women, randomized to receive five years of adjuvant tamoxifen, letrozole, or sequences of both, completed self-reported measures on SCF, psychological distress, fatigue and quality of life during the fifth year of trial treatment (year 5) and one year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. SCF and its correlates were explored. Results: Mean age of participants was 63.9 years [SD=7.1 years]. SCF and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement in hot flushes (p=0.0005). No difference in changes was found between women who were taking tamoxifen or letrozole at year 5. SCF was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman’s R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low. Conclusions: Although objective cognitive function improved after cessation of adjuvant endocrine therapy in the BIG 1-98 trial, improvement in SCF was not evident. The underlying reason for the clear disconnect between objective and subjective cognitive function seen in this and most other studies, is a crucial issue. It should be a research priority in order to effectively tackle the concerns of women about their cognition during and after breast cancer treatment.

The optimal duration and treatment strategies involving adjuvant endocrine therapy in early breast cancer remained largely undetermined. As data emerge on the various modalities of treatment in both pre- and postmenopausal groups, debates, and discussions continue. Most studies to date focused on the 5-year duration of treatment consisting of mainly tamoxifen. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) study demonstrated that anastrozole is superior to tamoxifen and has become the mainstream treatment in postmenopausal women with early breast cancer, although the duration was arbitrarily set for 5years, analogous to tamoxifen treatment. Several clinical trials, however, have emerged to support extended endocrine therapy as it becomes clear that the recurrence risk of breast cancer does not decrease beyond the initial 5years of treatment. The advent of molecular signatures also plays an important role in the breast cancer profiling, and where available should be incorporated in the overall decision-making. Furthermore, side effects and noncompliance pose another issue in achieving an optimal treatment benefit. The decision-making as regards to extended endocrine treatment should therefore focus not only on the cancer biology alone but also include treatment side effects, assessment of risk of recurrence and patients' preference. In this review, we present an overview of the published studies to date as well as ongoing studies on the topic to better refine the options for adjuvant hormonal therapy.

SAT0456 REAL-LIFE RISK OF FRACTURE AND TREATMENT PREVALENCE IN DRUG-INDUCED OSTEOPOROSIS IN ITALY USING A NEW ALGORITHM

12069 Background: Approximately 20% of women receiving endocrine therapy (ET) for early-stage breast cancer (BrCa) discontinue their regimen due to side effects, including vasomotor symptoms and arthralgias, subjecting them to higher rates of disease recurrence. Exercise is one approach to mitigate ET-related toxicity and potentially improve medication adherence by mitigating ET-related symptoms. However, only 11% of women with BrCa adhere to recommended exercise guidelines. Purpose: To examine the effect of a virtual supervised exercise program for women receiving ET for early-stage BrCa on physical function (PF) (primary outcome) and adherence to ET (secondary outcome). Methods: Participants were recruited through referral by oncology care providers from multiple BC Cancer sites and self-referral. Eligible participants were: females with stage I-III BrCa being treated with curative intent, 19-75 years, taking ET for at least 3 months up to 3 years. Using a partial cross-over design (NCT04824339), participants were randomized to the immediate exercise group (INT) or the delayed exercise group (CON), which crossed over at 8 weeks. The 8-week intervention was comprised of a 50-minute resistance exercise circuit, delivered virtually by an exercise physiologist twice per week via Zoom, and self-directed aerobic exercise (progressing to 90 minutes or more per week of at least moderate intensity). PF was assessed using the 30-second chair stand test. ET adherence was measured by the Voils self-reported medication non-adherence questionnaire. Values reported as means and standard deviations. The difference at 8 weeks by intervention arm was examined using two sample t-test (continuous) or kappa measure of agreement (categorical). Results: A total of 132 women were randomized. On average, women were 54 years, White (European) (47%), married (64%), had at least a bachelor’s degree or higher (51%), and had a body mass index of 27.7 kg/m2. The most common type of ET women received was Letrozole (43%), followed by Tamoxifen (36%). At 8 weeks, there was a significant improvement in PF for INT versus CON (mean change +2.5±2.9 vs. +0.7±2.2 stands, p&lt; 0.001). There was no difference between groups in change in medication adherence status (k = 0.35). Conclusions: An 8-week virtual supervised exercise program for women receiving ET for early-stage BrCa significantly improved PF but did not change medication adherence at 8 weeks. The potential impact of the intervention on long-term medication adherence will be explored up to one year and with covariates. Based on improvement in PF, future trials to establish effectiveness and inform implementation are warranted. Clinical trial information: NCT04824339 .