“Bridge” Neoadjuvant Endocrine Therapy for Early Stage Breast Cancer Patients During COVID-19 at an Academic Hospital in NYC: Lessons Learned and Future Directions

Taking a Second Look at Neoadjuvant Endocrine Therapy for the Treatment of Early Stage Estrogen Receptor Positive Breast Cancer During the COVID-19 Outbreak.

Background: Neoadjuvant endocrine therapy has traditionally been considered a treatment option for locally advanced and/or surgically high-risk women with hormone positive disease. Early stage hormone-positive breast cancer, on the other hand, is usually managed with upfront surgery, with post-operative hormone therapy as a risk-reducing adjunct. During the COVID-19 pandemic, however, widespread closures of operating rooms throughout the country resulted in many breast cancer patients being offered presurgical endocrine therapy as a bridge to surgery. We explored the demographic and clinicopathologic characteristics of these patients and quantified their rate of uptake. Methods: The Institutional Breast Cancer Database was queried for all patients who were diagnosed with ER+ stage 0, I, or II breast cancer and were offered presurgical endocrine therapy (tamoxifen or aromatase inhibitor) by a medical oncologist from 3/12/2020 to 4/30/2020. Variables of interest included demographics, tumor characteristics, and rate of medication uptake and compliance. Results: Of 192 newly diagnosed breast cancer patients seen at NYU Perlmutter Cancer Center during this time period, 136 patients had early stage ER+ breast cancer. Forty-five patients had not yet undergone surgery, and were recommended to receive presurgical hormonal therapy as a bridge given the COVID-19 pandemic (Table 1). The average age was 60.5 years old (SD=13.8 years, range 31-89), and all were female. Thirty-four of 44 patients were post-menopausal (75.6%), while 10 were premenopausal (22.2%), and one was perimenopausal (2.2%). Twenty-six patients were white (57.8%), 12 were black (26.7%) 3 were Asian (6.7%), and 4 were other (8.9%). Thirty-four patients (75.6%) had invasive disease, while 8 had ductal carcinoma in situ (DCIS, 17.8%), and 3 had DCIS with microinvasion (6.7%). Nine patients (20%) did not take the medication for various reasons: 1 contracted COVID-19, 1 refused any treatment, 1 decided to transfer care out of state, 1 preferred to take a homeopathic remedy instead of endocrine therapy, 1 preferred to wait for surgery without medication, and 4 were scheduled for surgery sooner than anticipated and did not start the medication. The remaining 36 patients (80%) took medication for an average of 43.6 days (SD=27.3 days, range 9-101 days) prior to surgery. Twenty-eight patients (77.8%) took an aromatase inhibitor, and 8 (22.2%) took tamoxifen. Forty-two patients have now undergone surgery (93.3%); the remainder include the patient who is refusing all treatment, the patient who transferred out of state, and one patient who has not yet scheduled surgery, but is reportedly still taking an aromatase inhibitor. Conclusion: Improving adherence to long-term adjuvant endocrine therapy is an urgent need as patient acceptance is low. Reported completion rates range around 50%, and have not been improved by educational or technology-based interventions. The unique situation posed by the current COVID-19 pandemic has temporarily changed the management of early-stage breast cancer, and resulted in a high initial acceptance of endocrine therapy (80%), although duration is shorter in this presurgical setting. Further investigations will evaluate length of use, the psychosocial and behavioral factors that influence willingness to take endocrine therapy, and apply these lessons to management of early-stage hormone-positive breast cancer. Patient Demographics and Tumor CharacteristicsVariablesTotal (N=45)%Median Age (years)60.5 (31-89)RaceWhite2657.8Black1226.7Asian36.7Other48.9Menopause StatusPre-menopausal1022.2Peri-menopausal12.2Post-menopausal3475.6Mean BMI (kg/m2)28.3 (17.8-46.5)PalpabilityNon-palpable3066.7Palpable1533.3Mammographic Breast DensityEntirely Fatty24.4Scattered Fibroglandular1737.8Heterogeneously Dense2453.3Extremely Dense24.4HistologyDCIS817.8DCIS with microinvasion36.7Invasive carcinoma3475.6Clinical Stage0817.8I2760II1022.2Endocrine Therapy(N=36)Tamoxifen822.2Aromatase Inhibitor2877.8Mean Duration of Endocrine Therapy (days)43.6 (9-101) Citation Format: Cindy Cen, Freya Schnabel, Sylvia Adams, Magdalena Plasilova, Janet Yeh, Marleen Meyers, James Speyer, Elliot Belenkov, Maryann Kwa, Yelena Novik, Elena Katz, Amber Guth. “Bridge” neoadjuvant endocrine therapy for early stage breast cancer patients during COVID-19 at an academic hospital in NYC: Lessons learned [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-26.

Purpose/Objective(s):. Several trials have compared endocrine therapy (ET) alone vs. ET and radiotherapy (RT) in low risk early stage estrogen receptor (ER)-positive breast cancer and have shown that the addition of RT to ET modestly reduces the rate of loco-regional recurrence (LRR) without altering survival. ET may also yield modest reductions in contralateral breast events. ET alone has thus become a standard strategy in select patients. Data evaluating the efficacy of RT alone are scarce. However, the toxicity of ET is not trivial and its effectiveness is dependent upon treatment adherence. As RT courses become ever shorter and safer, a re-evaluation of the strategy of RT alone is warranted. This analysis reports on the treatment outcomes of ER-positive early stage breast cancer treated with adjuvant RT or ET alone at a multi-hospital health system. We hypothesized that adjuvant RT alone would yield loco-regional control comparable to that of ET alone and that ET adherence would influence outcomes. Materials/Methods:. The shared electronic health record of multiple facilities within a university health system was queried to identify women with pathologic T1-2 N0 breast cancer treated with breast-conserving surgery between 2007 and 2016. Data collection included demographic features, tumor characteristics, treatment type, and evidence of LRR. Analysis was restricted to those patients with ER positive disease who underwent either RT alone or ET alone. Five-year LRR were compared across groups using the Kaplan-Meier method. Results:. 240 patients met inclusion criteria. Of these, 86 were treated with RT alone and 154 with ET alone. Patient, tumor and ET variables are listed in the table below. ET adherence and duration information were available for 135 out of 154 patients who received ET alone. Patients who completed 5 years of ET or whose ET was discontinued due to the disease recurrence or death were categorized as ET-adherence (ET-A). Patients who discontinued ET before reaching 5 years due to other reasons were categorized as ET-non adherence (ET-NA). Median ET duration in ET-A was 60 months (range, 15-101 months) and in ET-NA was 13 months (range, 1-54 months). The 5-year rates of LRR for RT alone vs. ET alone were 4.1 % (95% CI 0-8.8) vs. 5.0 % (95% CI 1.1-8.9). The 5-year rates of LRR for ET-A vs. ET-NA were 2.0 % (95% CI 0-4.7) vs. 16.4 % (95% CI 1.1-31.7). While the difference in the LRR rates between RT alone vs. ET-A was not statistically significant (p= .481), ET-NA was associated with significantly higher LRR rate compared to RT alone or ET-A (p<.05). The rate of ET non-adherent rate was 21.4%. Conclusion:. RT yielded LRR equivalent to overall ET and superior to ET non-adherence. For patients with early stage ER+ breast cancer, a prospective randomized trial comparing RT to ET and evaluating quality of life (QoL) is needed. In light of emerging data, a five-day course of RT can be considered as an alternative to five years of ET, and RT should be strongly considered if ET adherence is in doubt. Table 1.Patient, tumor and treatment characteristicsRT alone (n=86)ET alone (n=154)Median follow-up (months)50.6 (1-135)48 (3-114)Age (median)63 (39-91)74 (50-87)StageT176 (88.4%)142 (92.2%)T210 (11.6%)12 (7.8%)HistologyGrade 38 (9.3%)9 (5.8%)+LVI5 (5.8%)3 (2.0%)Endocrine Therapy (ET)ET duration (median, months)-57 (1-101)ET-Adherent-102 (66.2%)ET-Non adherent-33 (21.4%)ET duration not available-19 (12.3%) Citation Format: Seung Won Seol, Travis Pflederer, Lauren Weller, Chelain Goodman, Eric D Donnelly, John P Hayes, Jonathan B Strauss. Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence [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 P1-13-03.

Background: Neoadjuvant endocrine therapy (NET) has long been limited to patients who were deemed medically unfit for immediate surgery or on clinical trials. Coronavirus disease 2019 (COVID-19) resulted in a global pandemic, which led to deferral of elective surgeries including breast surgeries for early stage breast cancer patients during March - June 2020. Institutional guidelines were developed based on societal recommendations, including NCCN, to use NET as a bridge to surgery. Objective: Primary objective was to establish a database of early stage HR+ Her2/neu- breast cancer patients diagnosed during COVID-19 who were treated with NET as a bridge to surgery. Secondary endpoints include correlation between duration of NET and changes in pathological variables. Method: This was a single institution, retrospective observational study from Perlmutter Cancer Center at NYU Langone Hospital and NYU Langone Hospital - Long Island of DCIS and early stage breast cancer patients diagnosed from March 15, 2020 - June 1, 2020 during COVID-19 pandemic. Inclusion criteria were males and females older than 18 years of age and initial diagnosis of DCIS or early stage HR+ Her2/neu- breast cancer who did not require neoadjuvant chemotherapy by established guidelines. Descriptive statistics were calculated separately by DCIS and invasive breast cancer using SAS version 9.4. Results: From March 15 - June 1, 2020, 13 patients who were diagnosed with DCIS and 41 patients with early stage HR+ Her2/neu- invasive breast cancer received NET (Table 1). Of the 41 patients with invasive breast cancer, 19 (46%) had Oncotype DX assay on biopsy specimens; 12/19 (63%) had scores 10-14 and 7/19 (37%) had scores 15-25. 38/41 (92.7%) had post-surgery Ki-67% and 16/38 (42.1%) demonstrated maturation arrest (Ki-67 <2.7%). 26/41 (63%) invasive breast cancer patients had pre and post Ki-67% checked while on aromatase inhibitors (AI); 21/26 (81%) had a decrease in Ki-67%, 2/26 (7.7%) patients had no change, and 3/26 (11.5%) had an increase. Of those 21 patients, the percent change of Ki-67% from baseline was mean 69.15% ± 22.58 and median 71.83%. No significant associations with changes (pre to post) in Ki-67%, T stage, ER% and PR% in NET for ≤4 weeks and >4 weeks (Table 2). Median duration of NET in invasive breast cancer was 6.85 weeks. 1 patient had a complete pathological response after NET and 2 patients were upstaged from DCIS to invasive carcinoma at the time of surgery. Conclusion: While the sample sizes are small, this is a unique cohort of early stage surgically resectable breast cancer patients who were treated with NET during the COVID-19 pandemic. This real-world data confirms pathological changes, especially decrease in Ki-67% even with short duration use of NET that has been reported in trials of neoadjuvant AI. Long term follow-up for survival outcome is planned. Table 1.Demographics of early stage breast cancer patients diagnosed during COVID-19.DCIS (n=13)Invasive Breast Cancer (n=41)Total (n=54)Menopause status (n, %)Pre-menopause7 (53.8)6 (14.6)13 (24.1)Post-menopause6 (46.2)35 (85.4)41 (75.9)Diagnosis (n, %)Self-Palpated08 (19.5)8 (14.8)Screening13 (100)33 (80.5)46 (85.2)Age (n, %)≤503 (23.1)5 (12.2)8 (14.8)50+10 (76.9)36 (87.8)46 (85.2)Clinical Stage (n, %)Tis13 (100)013 (24.1)I037 (90.2)37 (68.5)II04 (9.8)4 (7.4)NET in weeks (n, %)≤43 (23.1)11 (26.8)14 (25.9)4+10 (76.9)30 (73.2)40 (74.1)Genomic Testing (n, %)Oncotype DX019 (86.4)19 (86.4)ProSigna03 (13.6)3 (13.6)Mammaprint000 Table 2.No significant associations with changes in pre to post in T stage, ER%, PR% or Ki-67% in patients treated with NET for ≤4 weeks and >4 weeks.≤4 weeks>4 weeksp-valueChange in T stage0.5810Decrease2 (27.27%)8 (26.67%)No change7 (63.64%)15 (50%)Increase1 (9.09%)7 (23.33%)Change in ER%0.2444Decrease4 (36.36%)9 (30%)No change4 (36.36%)5 (16.67%)Increase3 (27.27%)16 (53.33%)Change in PR%1.0000Decrease7 (70%)21 (70%)No change2 (20%)5 (16.67%)Increase1 (10%)4 (13.33%)Change in Ki-67%0.3224Decrease4 (66.67%)17 (85%)No Change1 (16.67%)1 (5%)Increase1 (16.67%)2 (10%) Citation Format: Julie Huang, Joshua Feinberg, Bahram Dabiri, Jordan Baum, Meredith Akerman, Anthony Pasquarella, Abhinav Rohatgi, Shubhada Dhage, Amber Guth, Nina D'Abreo. Neoadjuvant endocrine therapy (NET) as bridge therapy for early stage breast cancer during COVID-19: A single institution experience [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 P2-15-03.

Background: Adjuvant hormonal therapies for early-stage breast cancer significantly reduce the risk of recurrence, incidence of contralateral breast cancer and death from breast cancer. Optimal compliance to prescribed therapies is associated with improved patient outcomes. However, non-adherence to adjuvant tamoxifen and aromatase inhibitors (AIs) has been reported to range from 17-49% and 19-31% respectively.Objective: To evaluate medication adherence for a large population of post-menopausal women with HR+ early stage breast cancer that were prescribed initial adjuvant hormonal therapies in a publicly funded health care system, and to assess for predictive factors associated with higher rates of non-adherence.Methods: A retrospective cohort of post-menopausal patients diagnosed with HR+ stage I-III breast cancers referred to the BCCA between 2005-2008 whom were prescribed initial adjuvant hormonal therapies (either tamoxifen or an AI) were identified using the British Columbia (BC) Breast Cancer Outcomes Unit database. Cases were matched with the provincial BCCA pharmacy data repository to evaluate patterns of prescription filling. Factors including age, stage, tumor characteristics, use of chemotherapy, hormonal agent prescribed, and prescribing physician were pre-identified as potential factors predicting for non-adherence. Non-adherence was defined as less than 80% of days covered with a prescription.Results: A total of 4,592 patients were prescribed adjuvant hormonal therapies through the BCCA from 2005-2008. 2,414 patients were available for analysis after applying pre-defined inclusion criteria. Overall non-adherence rate was 40%, with non-adherence to tamoxifen and aromatase inhibitors at 42% and 37% respectively. The non-adherence cohort were older, had smaller tumor size, less nodal involvement, lower grade and lower rate of initial chemotherapy (all p<0.001). Non-adherence rates specific to individual physician prescribers ranged from 16% to 67% (p<0.001), and non-adherence rates between specialist provider groups were 34% among medical oncologists compared with 47% in radiation oncologists (p<0.001).Conclusion: Overall non-adherence to adjuvant tamoxifen and AIs in this large population of postmenopausal women with HR+ positive early stage breast cancer was 40%. This likely represents a true reflection of both non-adherence and multiple factors associated with non-adherence given the population size, public health care setting and follow-up strategies. The non-adherent cohort may be the group that is most likely to benefit from hormonal therapy (lower tumor grade) and require hormonal therapy (less adjuvant chemotherapy). Future directions should include interventions directed at physicians in addition to patients given the discrepancy in non-adherence rates among prescribers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 36.

Background: At the height of the COVID19 pandemic, many surgical procedures across the country including at Dartmouth-Hitchcock Medical Center (DHMC) were postponed to redirect resources. The American Society of Breast Surgeons shared guidelines to manage patients experiencing surgical delays. For estrogen receptor positive (ER+), HER2- early-stage tumors, recommendations were to use neoadjuvant endocrine therapy (NET). NET is usually under-utilized for locally advanced hormone receptor-positive breast cancer (BC) despite literature concluding that chemotherapy and NET have comparable clinical response rates but with lower toxicity for the latter. The COVID19 pandemic thus presented a unique occasion to extend the use of NET for localized BC. Herein, we examined the rate of adoption of NET and associated patient/tumor characteristics at DHMC during the lockdown. Methods: A retrospective analysis of patients diagnosed with early-stage ER+, HER2- BC between December 2019 and June 2020. Data extracted from chart review included age, menopausal status, tumor stage/grade, body mass index (BMI), and adherence to adjuvant endocrine therapy (ET). A “delay in surgery” was defined as days between surgical consult and surgery over 14 days. Descriptive statistics were applied to data collected on patient/tumor characteristics, and the number of patients accepting or declining NET. Results: 109 cases were identified within the study period, with 42 found with surgical delay. The median age of the delayed group was 62 and the majority of patients were post-menopausal. 36 patients received NET with most started on an aromatase inhibitor. Median BMI was 28.5. Median duration of treatment was 39.5 days. Three cases were noted to have some decrease in cellularity for pathologic partial response and four had no definite response. The majority of patients on NET had no change in pathological grade. Out of the 36 patients who had NET, 30 (83.3%) remain on adjuvant ET. In contrast, only 59% (43 out of 73 patients) of those who did not receive NET were on adjuvant ET at the median follow up time of 2.75 years post-therapy initiation. Of note, 16 (out of 73) patients who were not on NET were either lost to follow up, had their care transferred to another health network or were not offered ET. Results are reported in Tables 1 and 2. Conclusions: Delays in surgery during the COVID19 crisis resulted in increased use of NET in early-stage BC. Impact of NET use includes possible increase in long-term adherence to adjuvant ET with a trend towards statistical significance (odds ratio of 3.25, p=0.08). A larger sample size is needed to evaluate this finding and a prospective trial is in progress (NCT04568616). NET is a viable treatment option during surgical delays and may help increase long-term adherence to adjuvant ET. Table. Patient and tumor characteristics Table. Number of patients on adjuvant ET Citation Format: Mary Chamberlin, Todd Miller, Marie Anne Christine Buteau, Steven Tau. Effects of neoadjuvant endocrine therapy on early-stage breast cancer: a retrospective cohort study of patients during the COVID19 pandemic [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 PO4-01-14.

Introduction During the coronavirus 2019 (COVID-19) pandemic in USA, NET use has been recommended to allowsafe deferral of surgical treatment in early stage, estrogen receptor positive breast cancer (ER+BC) In suchcircumstances, after NET use there is limited guidance on locoregional treatment, especially with management of the axilla We aimed to evaluate patterns of care in early stage ER+BC during the first several months of theCOVID-19 pandemic Method A cross-sectional, 30-item survey was developed using a standardized surveydevelopment framework The survey was administered May 8 - June 12, 2020 to a convenience sample of medicaloncologists (MO), radiation oncologists (RO), and surgeons (SO) - breast committee members of two nationalcooperative groups (Alliance and SWOG) with additional participation through chain referrals Providers were presented with general questions on NET use before and during the pandemic They were asked their propensity foromitting axillary lymph node dissection (ALND) after NET if 1 micrometastatic node is found on sentinel lymph nodebiopsy, based on duration of NET Results 114 providers from 29 US states completed the survey - 42 (37%) MO, 14(12%) RO, and 58 (51%) SO, the majority (N=73/96, 76%) with practices dedicated ≥ 75% to BC, at NCI designatedcomprehensive cancer centers 52% (N=48/94) and in large cities (N=49/94, 52%) Prior to COVID-19, most rarely(N=49/107, 46%) or sometimes (N=36, 33%) used NET for early stage ER+BC Nearly half were willing to delay surgery up to 2 months (46%) and 3 months (21%) without use of NET (Table 1, p<0 05) Most providers wouldperform a genomic assay on the biopsy specimen on all or select patients prior to NET initiation, more frequently byMO compared to RO and SO (90% vs 75% and 60%, p<0 05) The most preferred regimen was tamoxifen (withoutovarian suppression) for premenopausal patients and aromatase inhibitor for postmenopausal patients Mostplanned to use NET for as little time as possible until surgery could proceed When stratified by specialty, more MOstated they would vary the duration of therapy based on patient's risk of cancer progression Most providersrecommended omitting ALND after 1, 2, or 3 months of NET (1 month N=56/93, 60%;2 months N=54/92, 59%;3months N=48/90, 53%) With longer duration of therapy, the propensity for omitting ALND decreased (definitely omitafter 6 months N=25/91, 27%;probably omit after 6 months N=38/91, 42%;definitely omit after 1 year N=26/92,28%;probably omit after 1 year N=29/92, 32%) Omitting ALND was not associated with provider's years in practice,percent of practice dedicated to BC, practice type or setting, participation in multidisciplinary tumor board, or numberof COVID-19 cases in the provider's practicing state ConclusionMost providers changed their management of early stage ER+BC during the COVID-19 pandemic by utilizing NET until surgery could proceed As the duration of NET extended, more providers favored ALND in low volume axillary metastatic disease in early stage ER+BC Additional data to inform the care on post-NET locoregional management is needed

The role of hormone therapy as a neoadjuvant to radical prostate radiotherapy.

Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis

Background: Coronavirus disease 2019 (COVID-19) resulted in a global pandemic, which led to deferral of surgeries for early stage breast cancer during March - June 2020. Institutional guidelines were developed to use neoadjuvant endocrine therapy (NET) as a bridge to surgery. As a follow up to initial data presented at SABCS 2020 demonstrating patient acceptance of NET, the present study provides results from a survey which explored psychosocial factors associated with medication compliance. Objective: Primary objective was to identify any barriers to compliance with NET. Method: This was a single institution, prospective study that surveyed patients diagnosed with DCIS and early stage breast cancer at Perlmutter Cancer Center at NYU Langone Hospital and NYU Langone Hospital - Long Island from March 15, 2020 - June 1, 2020. Questions were based on the Beliefs about Medicines Questionnaire specific for endocrine therapy (BMQ-AET) and the Medication Adherence Report Scale. Responses were recorded on a Likert scale and included 7 questions regarding perceptions about breast cancer treatment, 10 questions addressing experience with NET, and 5 questions gauging at adherence to NET. Inclusion criteria were males and females older than 18 years old, with an initial diagnosis of DCIS or early stage HR+ Her2/neu- breast cancer, who were prescribed NET. Descriptive statistics were calculated and subgroups were compared using Fisher’s exact tests. Analyses were performed using SAS version 9.4. Results: From March 15 - June 1, 2020, 13 patients were diagnosed with DCIS and 29 patients with HR+ Her2/neu- breast cancer for whom NET was recommended. Demographics are shown in Table 1. All 42 patients were female with an average age of 60.9 years. Majority of patients were post-menopause (74%) and predominantly white (64%), with an income of less than $60,000 (52.4%). Average NET duration was 6.7 weeks. Survey responses displayed in Table 2 indicate statistically significant p values in bold. Patients &amp;gt;50 years old, post-menopause and invasive breast cancer had a stronger belief that NET would be helpful, resulting in greater perception to breast cancer treatment and higher adherence to NET. Patients treated with NET for greater than 4 weeks also felt that NET would make them feel well compared to ≤4 weeks. Interestingly, no significant differences in responses based on education or income level were observed. Conclusion: COVID-19 pandemic presented a unique opportunity to use NET, which is often underutilized outside of clinical trials. In this single institution prospective study, we found that post-menopause patients greater than 50 years old with invasive breast cancer perceived hormonal therapy as beneficial to their health, resulting in increased medication compliance. These findings can be used when counseling patients currently treated with NET as well as those patients may be appropriate for NET in the post-COVID era. Table 1.Demographics of early stage breast cancer patients diagnosed during COVID-19.DCIS (n=13)Invasive Breast Cancer (n=29)Total (n=42)Menopause Status (n, %)Pre-menopause7 (53.8)4 (13.8)11 (26.2)Post-menopause6 (46.2)25 (86.2)31 (73.8)Diagnosis (n, %)Self-Palpated06 (20.7)6 (14.3)Screening13 (100)23 (79.3)36 (85.7)Age (n, %)≤504 (30.8)4 (13.8)8 (19)50+9 (69.2)25 (86.2)34 (80.9)Average Age (range)54.9 (40 – 72)63.6 (32 – 85)60.9 (32 – 85)Race (n, %)White7 (53.8)20 (69%)27 (64.3)Non-White6 (46.2)9 (31%)15 (35.7)Education (n, %)K-121 (7.7)6 (20.7)7 (16.7)College and Graduate12 (92.3)23 (79.3)35 (83.3)Income (n, %)$0 – $60,0005 (38.5)17 (58.6)22 (52.4)$&amp;gt;60,0017 (53.8)12 (41.3)19 (45.2)No response1 (7.7)01 (2.4)NET in Weeks (n, %)≤45 (38.5)7 (24.1)12 (28.6)4+8 (61.5)22 (75.9)30 (71.4) Table 2.Perceptions of breast cancer and hormonal therapy.Perceptions About Hormonal TherapyPerceptions About Breast Cancer TreatmentAdherence To Hormonal TherapyMy health at present depends on me taking hormone treatment (p-value)Hormone treatment is a mystery to me (p-value)My health in the future will depend on me taking hormone treatment (p-value)Taking hormone treatment makes me feel I am taking positive steps to remain well (p-value)How much do you feel that your current hormone therapy can help? (p-value)How much do you feel that you need your current hormone therapy? (p-value)I miss out on a dose (p-value)I stop taking medication for a while (p-value)Age &amp;gt;50 vs. ≤500.04020.56510.00580.08330.04770.87370.04831.0000Post-Menopause vs. Pre-Menopause0.00330.02720.00530.13380.00060.24520.01661.0000Invasive vs. DCIS0.00381.00000.00450.16480.01810.00011.00000.0133Non-White vs. White0.47420.04340.76400.05220.91430.77730.61280.1369Duration of NET: ≤4 vs. &amp;gt;4 weeks0.43190.49971.00000.02840.11390.75430.05220.8833Screening vs. Self-Palpated0.51100.02560.62571.00000.44230.05930.47760.6353K-12 vs. College/Graduate0.43660.65400.16151.00000.41450.67531.00000.8321Income: ≤$60,000 vs. &amp;gt;$60,0000.54590.27860.59900.85690.09530.07000.78980.0581 Citation Format: Julie Huang, Joshua Feinberg, Meredith Akerman, Anthony Pasquarella, Abhinav Rohatgi, Bahram Dabiri, Jordan Baum, Shubhada Dhage, Amber Guth, Nina D'Abreo. Neoadjuvant endocrine therapy (NET) during COVID-19: Single institution survey of patients’ perspectives [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 P5-14-20.

Background: Pre-clinical and clinical data suggest that CDK4/6 inhibitors can promote an immunogenic tumor microenvironment (TME) and when combined with programmed cell death ligand 1 (PD-L1) inhibitors synergistic anti-cancer effects are observed. To understand the differential effects of CDK4/6 inhibition in the context of immunotherapy we designed a study evaluating neoadjuvant endocrine therapy (ET) with a PD-L1 inhibitor (avelumab) with or without a CDK4/6 inhibitor (palbociclib, palbo) in patients (pts) with stage II/III endocrine receptor (ER)-positive breast cancer. Methods: In this randomized phase 2 pilot study, pts with stage II/III ER+, HER2-negative breast cancer were randomized 2:1 to ET (aromatase inhibitor, AI, for post-menopausal pts; tamoxifen+/-ovarian function suppression for pre-menopausal pts) with avelumab, with or without palbo (palbo vs. control arms). Avelumab was added after a 1-month lead-in of ET +/- palbo, and all drugs were continued for additional 3-month-long cycles prior to surgery. We obtained tumor tissue and breast MRIs on C1D1, C2D1, and at the end of treatment. Imaging assessment was done according to RECIST 1.1 criteria at each time point. The primary endpoint was clinical complete response (cCR) by MRI in the palbo arm (H0: cCR=10% vs. 40% at a two-sided alpha level of 0.1). Secondary endpoints included pathologic CR (pCR), overall response rates (ORR), percent sum diameter changes, and adverse effects (AE). We report descriptive statistics on patient characteristics, clinical response rates, and changes in the sum of the longest diameters of the target lesions (SLD). Translational correlatives including imaging mass cytometry, spatial transcriptomic assessments, and other pathologic biomarkers will be reported at the meeting. Results: From 2018-2023, 33 pts were enrolled, and 30 were eligible for the primary analysis, including 20 pts on the palbo arm (1 pt with bilateral breast cancer, response to each breast cancer evaluated separately) and 10 to the control arm (1 pt with missing data). Clinical and pathologic characteristics were well balanced between arms, however, there was a higher proportion of patients with node-positive disease on the palbo arm (80% vs 60%). The study did not meet its primary endpoint as only 1 pt achieved a cCR and pCR in the palbo arm (cCR/pCR rate 4.8%) vs. no pts in the control arm. ORR was numerically higher in the palbo arm, 42.9% vs. 11.1% (p=0.204). After 1-month of ET+palbo, the mean SLD decreased by 11.6% compared to 9.4% in the ET-only control group (p=0.704). After avelumab was added to both arms, the mean SLD decreased by a further 15.2% in the palbo arm in contrast to a 6.9% increase in the control arm (p=0.018). Subgroup analysis in the palbo arm did not identify clinical or pathologic variables significantly associated with responses. No new safety or toxicity signals were observed. Notably, however expected, grade 3 or higher immune-related adverse events were observed including autoimmune diabetes (n=1), hepatitis (n=1), and colitis (n=1). Conclusions: As shown in previous studies, the addition of palbo to ET did not improve responses in the neoadjuvant setting; however, increased responses to palbo+ET were seen after PD-L1 inhibition, whereas not to ET, suggesting synergy between ET/palbo and avelumab. Translational correlative analysis will aim to decipher TME changes that augment PD-L1 inhibitor responses. Future studies in high-risk pts, where the toxicity of immunotherapy is acceptable, are warranted. Citation Format: Phaedon Zavras, Ruizhe Chen, Hanfei Qi, Mary Kate Jones, Ann Folmer, Hayden Chae, Allen Khodab, Ashley Cimino-Mathews, Lisa Jacobs, Lisa Mullen, Christie Hiton, Ahmed Elkhanany, Katia Khoury, Massimo Cristofanilli, Elizabeth Jaffee, Vered Stearns, Cesar Santa-Maria. Neoadjuvant endocrine therapy and avelumab with or without palbociclib in stage II/III endocrine receptor-positive breast cancer: the ImmunoADAPT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-09.

For postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer, neoadjuvant endocrine therapy (NET) is an underutilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates (1). Several studies from a decade or more ago showed marked improvements in breast conservation after 3 to 4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation. More recently the American College of Surgeons Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast-conserving surgery after 16 to 18 weeks of AI treatment (2). Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to NET such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET (3). Z1031 therefore provided an opportunity to further evaluate the PEPI. This study was run in two phases, Z1031A enrolled postmenopausal women with stage II/III ER+ (Allred 6 to 8) breast cancer (BC) whose treatment was randomized to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For Z1031B the protocol was amended to include a tumor Ki67 determination after 2-4 weeks of AI. If the Ki67 was &amp;gt;10%, patients were switched to neoadjuvant chemotherapy because the chance of a PEPI=0 score (best prognostic group) is very low in this subpopulation. A pCR rate of &amp;gt;20% was the predefined efficacy threshold. Only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7-19.1%). After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI=0 score relapsed versus 49 of 341 (14.4%) PEPI&amp;gt;0 patients, recurrence hazard ratio (PEPI=0/PEPI&amp;gt;0) = 0.27 (p=0.014; 95%CI: 0.092-0.764). Chemotherapy efficacy was therefore lower than expected in ER+ tumors exhibiting AI-resistant proliferation. For patients with PEPI=0 disease the relapse risk over 5 years was only 3.6% without chemotherapy supporting the study of adjuvant endocrine monotherapy in this group (4). These Ki67 and PEPI triage approaches are being definitively studied in new studies. In particular, new approaches are needed for the poor responders given the low efficacy of chemotherapy. Preliminary studies demonstrate that tumors that exhibit AI-resistant proliferation in the neoadjuvant setting often remain sensitive to CDK4/6 inhibition (5). Serial Ki67 monitoring could logically be considered as an approach to tailored use of adjuvant CDK4/6i treatment. Finally, serial sampling of the tumor inherent in the PEPI approach allows us to study of the genomic evolution of the tumor and to identify new therapeutic targets (6) and monitor tumor evolution in response to AI therapy (7).

Background: For women with early stage hormone receptor positive breast cancer, adjuvant treatment with tamoxifen reduces their 15-year risk of death from breast cancer by about one third. Aromatase inhibitors (AIs) are even more effective than tamoxifen in post-menopausal women but, used alone, are ineffective in pre-menopausal women due to compensatory ovarian oestrogen production. Several trials have assessed whether, if administered with ovarian suppression, AIs may also be more effective than tamoxifen at preventing breast cancer recurrence in premenopausal women but trial results have been inconsistent. Methods: Individual patient data were available from four randomised controlled trials, including 7,030 pre-menopausal women with estrogen receptor positive (ER+) breast cancer. All women received ovarian suppression or ablation and were randomised to receive either an AI or tamoxifen for 3 years (in ABCSG XII) or 5 years in other trials (SOFT, TEXT and HOBOE). Primary outcomes for the meta-analysis were time to invasive breast cancer recurrence (distant, loco-regional, or new contralateral breast primary) and breast cancer mortality. Log-rank analyses were used to estimate first-event rate ratios (RR) and their confidence intervals (CIs). Results: Overall, the annual rate of recurrence averaged 21% lower (RR 0.79, 95% 0.69-0.90, p=0.0005) for women allocated AI compared to tamoxifen. The main benefit from AI was seen in years 0-4 (RR 0.68, 99% CI 0.58-0.80), during the period when treatments differed, with no further benefit, or loss of benefit, in years 5-9 (RR 0.98, 99% 0.73-1.32), and as yet limited follow up data available beyond year 10. The 5-year absolute risk of breast cancer recurrence was 3.2% lower in the AI group than the tamoxifen group (6.9% vs 10.1%, p=0.0005). Although distant recurrence was reduced with AI (RR 0.83, 95% CI 0.71-0.97, p=0.02), there was no difference in breast cancer mortality although longer follow up is needed to assess effects on mortality reliably. The proportional reduction in recurrence during the period when treatments differed did not vary by age, BMI, or by tumour size, tumour grade, histological subtype, or presence and absence of chemotherapy. In contrast to the findings of the meta-analysis of AI vs tamoxifen in postmenopausal women, AI appeared ineffective in N4+ disease (RR=0.49 in N0, RR=0.56 in N1-3, RR=1.03 in N4+; p for trend =0.0009). The only other apparent heterogeneity was between the four trial results (p=0.03), and between HER2-negative and positive disease (p=0.05), which may be chance findings given the borderline statistical significance. There were more bone fractures in women receiving AI (5.0% AI vs 3.8% Tam, p=0.02). Among these younger women, few non-breast cancer deaths occurred: 0.9% AI vs 0.7% Tam (RR 1.30, 95% CI 0.75-2.25), and the incidence of endometrial cancer was low (0.2% AI vs 0.3% tamoxifen, p=0.14). Conclusion: Using an AI rather than tamoxifen, in premenopausal women receiving ovarian suppression, reduces the risk of breast cancer recurrence by about 20%. If the surprising lack of benefit in N4+ disease is a chance finding, then the absolute benefits will be larger for women at a higher absolute risk of recurrence. Citation Format: Rosie Bradley, Jeremy Braybrooke, Richard Gray, Robert K Hills, Zulian Lui, Hongchao Pan, Richard Peto, Jonas Bergh, Sandra M Swain, Prudence Francis, Michael Gnant, Francesco Perrone, Meredith M Regan. Aromatase inhibitors versus tamoxifen in pre-menopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised 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 GS2-04.

The Optimal Adjuvant Treatment in Older Patients with Hormone Receptor Positive Early Stage Breast Cancer (BC) is Breast Radiation (RT) not Endocrine Therapy (ET)

Background: HR+ early stage breast cancer (ESBC) is associated with suboptimal pathologic complete response rate (pCR, ~10%) following neoadjuvant cytotoxic chemotherapy. Neoadjuvant endocrine therapy with aromatase inhibitors (AI) may serve as an effective alternative as gauged using the surrogate Ki67 cell proliferation histologic marker. Patients with poor Ki67 response (defined as Ki67&amp;gt;10%) following neoadjuvant AI exhibit poor prognosis and therapeutic resistance to both endocrine therapy and chemotherapy. In a genomic analysis of Ki67-high HR+ tumors, we identified 8-fold upregulation of BIRC5 (survivin), a gene that regulates apoptosis and the cell cycle and is associated with poor clinical outcome. Maveropepimut-S (MVP-S) leverages the non-aqueous, lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from Survivin. Treatment with MVP-S and intermittent, low-dose cyclophosphamide (CPA) has shown to increase tumor infiltration of survivin-specific T cells. Previous clinical trials have shown that MVP-S is well-tolerated, immunogenic, and could lead to clinical response in several cancer indications. Further exploration of the regimen in breast cancer could extend the application of this immunotherapy for the unmet medical need of improving clinical response in high ki67 HR+ ESBC prior to surgery. Trial Design: NCT04895761 is phase I trial evaluating the safety and immunologic effects of neoadjuvant MVP-S plus letrozole (arm A, n=6), with/without tumor-directed MR-guided radiotherapy (arm B, n=6), or intermittent low-dose cyclophosphamide (CPA, arm C, n=6). Postmenopausal patients with T1c+ HR+HER2- breast cancer with Ki67&amp;gt;10% will receive two doses of MVP-S and 7 weeks of neoadjuvant letrozole prior to surgery (all arms), arm B will be treated additionally with concurrent 10Gy x 2 tumor boost radiation to facilitate immunogenic cell death, and arm C (n=6) will be treated additionally with intermittent low-dose CPA (50mg BID) to facilitate regulatory T cell depletion. Specific Aims: The primary objective is safety. Biomarker objectives are to evaluate for each treatment arm: 1) systemic type I survivin-specific immune response, as measured by IFN-γ ELISPOT; 2) changes in immune environment by GeoMx digital spatial genomic profiling; 3) and changes in tumor infiltrating lymphocytes (TILs) and Ki67. These data will be used to identify the most immunogenic MVP-S combination therapy for study in phase II trial powered to assess clinical outcome (pCR). Accrual: 3 of 6 patients in the MVP-S+ letrozole arm have been enrolled. Arm B and C will enroll after completion of arm A. Citation Format: Sasha E. Stanton, Lisa D. MacDonald, Stephan Fiset, Staci Mellinger, Nicole Moxon, Heather Hirsch, Tracy L. Kelly, Kristina H. Young, David B. Page. Neoadjuvant survivin immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor positive (HR+) early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-20-01.