Preoperative Endocrine Therapy Research Articles

Overtreatment and Undertreatment of Early-Stage Breast Cancer in Older Women: Evaluating the POWER Trial

IntroductionRadiation therapy (RT) omission is acceptable in older women with early-stage estrogen receptor + breast cancer treated with breast-conserving surgery (BCS) and adjuvant endocrine therapy (AET). However, RT rates in this population remain high, causing concern for overtreatment. Conversely, patients who omit RT and do not complete a course of AET are at risk of undertreatment. In the Pre-Operative Window of Endocrine Therapy to Inform Radiation Therapy Decisions (POWER) trial, participants receive 90 days of preoperative endocrine therapy to assess tolerance before deciding about RT. This study aimed to determine the rates of undertreatment and overtreatment institutionally and among POWER trial participants. MethodsData were retrospectively collected from medical records of women aged ≥ 65 years diagnosed with invasive, estrogen receptor +/human epidermal growth factor receptor 2- breast cancer, ≤ 3 cm, who had BCS between 2012 and 2022. Patients were categorized as undertreated (BCS alone), overtreated (BCS + RT + AET), or appropriately treated (BCS + RT or BCS + AET). ResultsThe cohort included 478 patients, of whom 62 (12.97%) were undertreated, 202 (42.26%) were overtreated, and 214 (44.77%) were appropriately treated. Appropriately treated patients were more likely to be aged 70-79 years (P < 0.0001) and have high health literacy (P = 0.0003). Of the 37 patients (7.71%) in the POWER trial, more were appropriately treated than patients not in the POWER trial (81.1% versus 44.8%) (P < 0.0001). ConclusionsDespite long-standing guideline changes, RT utilization remains high. This study highlights how a novel patient-centered approach to guide adjuvant therapy decisions may increase the number of appropriately treated patients.

Metaplastic Carcinoma Breast in Polycythemic Octogenarian – Lessons Learnt: Case Report

An 80-year-old lady presented with lump Left breast of 8 months duration. Clinically was aT4b lesion, sonomammogram showed BIRADS V lesion and core needle breast biopsy features were suggestive of metaplastic carcinoma breast of adenosquamous type, ER, PR-Positive, Her2Neu-Negative. Patient received preoperative hormonal therapy followed by modified radical mastectomy and postoperative adjuvant chemotherapy and hormonal therapy. Post operative patient showed good clinical recovery and was recurrence free at 6 months follow up although patient had all the poor prognostic factors with large size, LN involvement and high Ki 67. This article is a rare example of metaplastic breast carcinoma presenting in geriatric age group and showing good recovery despite presence of all poor prognostic factors. Hence this report is to enlighten the medical caregivers about the existence of this rare entity and challenges involved in management of this entity.

P-022 Klinefelter syndrome couples are expected higher live birth rates than unexplained NOA couples after ICSI with testicular spermatozoa

Abstract Study question What are sperm retrieval rates (SRR) by microdissection TESE (micro TESE), fertilization rates, and pre- and post- implantation development in Klinefelter syndrome (KS) couples? Summary answer In KS couples, SRR, clinical pregnancy rates (CPR) per embryo transfer (ET), and live birth rates (LBR) per patient were higher than unexplained NOA couples. What is known already Micro TESE, in combination with ICSI, is presently used to treat infertility in cases of NOA including KS, which is the most common sex-chromosome disorder among infertile males, with a prevalence of 1 in 660 men and is a frequent cause of hypogonadism and infertility. There were few reports regarding ICSI outcomes in the couples of KS. The aim of this study is to assess the prevalence and the significance including SRR by micro TESE of ICSI outcomes with embryonic development in KS couples. Study design, size, duration A retrospective study was conducted in 212 patients with non-mosaic KS and 963 unexplained NOA patients with 46, XY without past history (unexplained NOA; not including after orchidopexy, KS, cryptozoospermia, post chemotherapy, mumps orchitis, etc) who underwent micro TESE and ICSI with fresh or cryopreserved testicular spermatozoa for their wives between September 2013 to November 2023. Participants/materials, setting, methods A total of 2204 azoospermic patients were examined for chromosomal analysis. We evaluated SRR of microdissection TESE, two pronuclei (2PN) rates, blastocyst development rates, good-quality blastocyst (Grade 3BB and above on day 5 by the Gardner scoring) rates, CPR per ET, and LBR per couple patient who underwent micro TESE. We did not undergo preoperative hormonal therapy for KS patients. Statistical analysis was performed using unpaired t-tests and chi-squared tests. Main results and the role of chance We identified 212 KS out of 2204 azoospermic patients (9.6%). SRR of the first attempt micro TESE in KS (91/175=52.0%) was significantly higher than unexplained NOA (166/768=21.6%) (p &amp;lt; 0.001). 2PN, blastocysts development, and good-quality blastocysts rates were 49.2%, 42.9%, 16.9% in KS and 50.8, 45.8%, 21.0% in unexplained NOA respectively. Only good-quality blastocysts rate of KS was significantly lower than that of unexplained NOA (p &amp;lt; 0.01). Taking into account deflection of wives age, each result was calculated at their age 38 or under, but they were the same. CPR and LBR per ET in KS (42.6%, 30.4%) were significantly higher than unexplained NOA (33.1%, 23.7%) (p &amp;lt; 0.01, p &amp;lt; 0.05). The couples were 26.4% (56/212) in KS and 12.0% (116/963) in unexplained NOA (p &amp;lt; 0.001) who have given birth or ongoing pregnancy up to now after underwent micro TESE. That is, KS couples were significantly easier to give birth than unexplained NOA. Rates of congenital disorders had no significant difference between KS and unexplained NOA. Limitations, reasons for caution We did not show the data using ejaculated sperm with KS. The natal outcomes and development of these children has not been fully investigated, long-term follow-up of babies of the KS couples is needed. Wider implications of the findings Micro TESE is particularly helpful for KS cases, but embryonic development depend on the quality of spermatozoa. However, if a blastocyst can be obtained, the expectation of having a child is considered to be high. These results were shown to be useful in informing azoospermic couples undergoing micro TESE. Trial registration number not applicable

Predictive Factors for Early Biochemical Recurrence Following Robot-assisted Radical Prostatectomy.

The primary objective of this study was to identify predictors for biochemical recurrence (BCR) within 2 years following robot-assisted radical prostatectomy (RARP). Identifying predictors will enable insights that enhance personalized patient management and facilitate the ongoing refinement of postoperative therapy strategies. This retrospective study included patients undergoing RARP from September 2014 to January 2021. Exclusion criteria were preoperative endocrine therapy, BCR beyond 2 years post-surgery, and incomplete postoperative data. Multivariate analyses were conducted to evaluate predictors of BCR, focusing on preoperative prostate-specific antigen (PSA) level, pathological tumor (pT) stage, Gleason score (GS), extraprostatic extension (EPE), and surgical margin status. Among 374 patients, 40 experienced BCR within 2 years. Significant predictors of early BCR included initial PSA level ≥10 ng/ml, pT3 or greater, GS ≥8, EPE, and positive surgical margins (RM1). Multivariate analysis identified pT3 or higher, GS ≥8, and RM1 as independent risk factors for early BCR. Early BCR after RARP is significantly associated with advanced pathological stage, high GS, and positive surgical margins. These findings emphasize the need for tailored postoperative management strategies and highlight the importance of precision in surgical technique to improve patient outcomes.

The pre-operative window of endocrine therapy to inform radiation therapy decisions (POWER) trial: Baseline patient beliefs about breast cancer and endocrine therapy.

11115 Background: The POWER Trial (NCT04272801) aims to determine whether pre-operative endocrine therapy (pre-ET) impacts physician recommendations and patient preferences for adjuvant radiation (RT) and endocrine therapy (AET) among women who qualify for RT omission. While physicians characterize this population as low-risk, they often still recommend RT. The POWER trial captures baseline patient perspectives regarding recurrence and medication tolerance using patient-reported outcome surveys and examines how these influence treatment choices. Methods: POWER Trial participants received 90 days of pre-ET before surgery and treatment decisions regarding RT. Women ≥ 65 years old with ER+ tumors ≤ 2 cm, node negative were eligible. Patient beliefs about their cancer and medications were assessed at baseline using the Beliefs About Illness Questionnaire (BIP-Q), Beliefs About Medicine Questionnaire-ET (BMQ-ET), and Perceived Sensitivity to Medicines (PSM) scale. An additional novel, non-validated questionnaire was created to further evaluate patients’ beliefs. Results: The study cohort included 48 women with mean age of 73.7. Few patients (14.6%) viewed their breast cancer as having a high threat to their health. While half (50.0%) of the participants worried a lot about the return of their breast cancer, only 35.4% thought that a cancer recurrence would be devastating. Participants who worried more about their breast cancer returning were more likely to feel a recurrence would be devastating (Pearson Correlation Coefficient = .67). There was no association between baseline beliefs and RT omission. Most patients (81.3%) did not consider themselves sensitive to medications. Although 81.3% reported side effects as important when deciding to continue or stop medications, almost all participants (95.8%) stated they would continue medications, despite side effects, if it would help lower their risk of recurrence. When specifically asked about AET, 70.8% reported a low level of concern about taking the therapy and 72.9% felt it was necessary. Of study participants, 27 (56.3%) omitted RT and initiated AET, 10 (20.8%) had RT and declined AET, 10 (20.8%) completed RT and initiated AET, and 1 (2.1%) declined RT and AET. Conclusions: This analysis shows that many early-stage ER+ breast cancer patients have a low level of worry about breast cancer recurrence, which may support treatment de-escalation such as RT omission. Most participants are open to taking AET despite the potential for side effects, yet historical data demonstrate low rates of adherence to AET. This discrepancy highlights that patients’ baseline beliefs about themselves and their medications may not align with their actual adherence. Future analysis from the POWER trial will examine how long-term AET adherence relates to baseline patient beliefs. Clinical trial information: NCT04272801 .

Molecular profiling after short-term preoperative endocrine therapy to identify oestrogen receptor positive (ER+)/HER2+ early breast tumours with favourable prognosis.

560 Background: The impeded anti-proliferative response of Estrogen Receptor positive (ER+) HER2+ breast cancer (BC) to endocrine therapy (ET) has been considered negated by treatment with anti-HER2 therapies but residual disease after anti-HER2 therapy remains at risk of recurrence. Studying the molecular changes (MolC) of ER+HER2+ BC in response to ET will provide clinical insights to treatment options. Methods: POETIC was a phase III trial of post-menopausal patients with ER+ BC randomized 2:1 to 2-weeks of peri-operative aromatase inhibitors (POAI) vs control, followed by standard-of-care. Paired pre-treatment (B) and on-treatment (2wk) samples from 313 ER+HER2+ BC (213 POAI/100 controls) were gene expression profiled (BC 360 codeset; NanoString). Association of MolC with Early biological response to AI was assessed by residual Ki672wk (low ≤10%; high &gt;10%) by T-test, multiple testing corrected by Benjamini &amp; Hochberg (FDR); with time to recurrence (TTR) was estimated using multivariable Cox regression models adjusted for post-surgery clinicopathological variables and age as adjuvant treatment surrogate. Results: In POAI tumours, immunity-related signatures and mammary stemness were significantly upregulated in responders while proliferation, DNA-damage repair (DDR), TP53mutational status and ER-signaling were downregulated (FDR&lt;0.05). Controls had exclusive downregulation of PDL1 and upregulation of hypoxia (FDR &lt; 0.05). We previously identified 5 new molecular subgroups based on baseline gene expression (1- Immune high, ESR1 low; 2- ECM, ESR1 low, highest ERBB2; 3- DDR deficiency, 4- Endocrine signalling high and 5- Endocrine and PI3K/MAPK/RAS signalling high) which were associated with different response to AI and differential outcome. Endocrine-signalling, PI3K/MAPK/RAS signalling, tumour-immunity and chemokines were upregulated at a higher magnitude in AI sensitive subgroups (3 and 4) while the molecular subgroup with early resistance to AI and poorer outcome at baseline (2) did not show significant changes. Intrinsic subtype (IS) shifting was significantly more prevalent in treated (37%, 79/213) than in controls (14%, 14/100) (p &lt;0.001). In POAI most Luminal B (LumB) shifted to Luminal A (LumA; 79%, 59/75), driven by a reduction in proliferation. LumA2wk was associated with better outcome compared to LumB2wk (HR 0.2; CI95% 0.06-0.72, p=0.01). IS2wk provides additional information predicting TTR, than ISB (AIC value = 217.2 vs 221.6). Conclusions: We provide a comprehensive picture on how ER+HER2+ BC gene expression profile changes in response to ET. Most LumB BC shift to LumA, being LumA2wk IS significantly associated with better outcome. There is a clinical utility of peri-operative ET for ER+HER2+ BC, guiding who would have good prognosis for adjuvant ET and who may need additional therapy. Clinical trial information: NCT02338310 .

Linking the companion diagnostic function of cancer genome profiling to therapy: Investigation of TMB-high predictors.

e13033 Background: Based on the companion diagnostic function of the Comprehensive Cancer Genome Profiling (CGP) test in Japan, pembrolizumab is the standard treatment for patients with Tumor Mutational Burden (TMB)-high (H) solid tumors. In this report, we attempted to extract predictive factors of TMB-H from CGP test results. Methods: We carried out a retrospective cohort study of 42 patients with malignant breast tumors (excluding circulating tumor DNA in the blood) who underwent CGP testing between June 1, 2019, and November 30, 2023, at our hospital and affiliated institutions. We analyzed the association between clinicopathological factors, the number of analyzed cancer-related gene mutations (SNV, InDel), and TMB-H using univariate and multivariate statistical analysis. Results: Of the 42 cases (27 positive and 15 negative for estrogen receptor (ER), respectively), seven (16.7%) were TMB-H. Samples significantly associated with TMB-H according to univariate analysis were submitted as pathology specimens (non-primary (16.7%) vs. primary (0%), p = 0.011), ER (positive (16.7%) vs. negative (0%), p = 0.044), letrozole (LET) (yes (11.9%) vs. no (4.8%), p = 0.008), and previous treatment (after 6th line (14.3%) vs. before (2.4%), p = 0.041). Multivariate analysis showed that LET had a significant effect on TMB-H in Aromatase inhibitor agents (LET + Anastrozole + Exemestane) (LET: OR, 19.9; 95% CI, 2.2–183.5; p = 0.008) and the number of cancer-related gene mutations (PIK3CA+TP53) were significantly affected (PIK3CA: OR, 3.8; 95% CI, 1.1–13.2; p = 0.032. TP53: OR, 0.08; 95% CI, 0.01–0.66; p = 0.015). Single regression analysis showed a significant association between the number of PIK3CA mutations and LET. (β, 0.31; SE, 0.11; p = 0.008). Conclusions: ER positivity, history of LET use, prior therapy after the 6th line, and submission of pathology specimens from non-primary tumors to CGP testing are predictive factors for TMB-H. In multivariate analysis, the history of LET use and the number of PIK3CA mutations were significantly associated with TMB-H. Research shows that PIK3CA mutations are most frequent in patients who have undergone preoperative endocrine therapy with LET (Breast Cancer Res Treat. 2020 Nov;184(1):123–133.), suggesting that an increased number of PIK3CA mutations due to LET contributed to TMB-H. Although immune checkpoint inhibitors (ICIs) are not indicated for ER-positive breast cancer, TMB-H may be a predictor of ICI efficacy in such cases. The limitations of our research were the small sample size, and the study population only included Japanese. For the next steps needed to continue in this research, clinical trials should take place to test whether TMB-H is a predictor of ICIs in a wider population of ER-positive breast cancer.

Abstract LBO1-05: Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334)

Abstract Background: In HR+/HER2- early breast cancer (EBC), short preoperative endocrine therapy (ET) is a promising tool for ET-efficacy assessment based on Ki67-decrease after 2-4 weeks of ET. Low post-endocrine Ki67 (Ki67post) is associated with good prognosis in large prospective trials. WSG-ADAPT demonstrated that ET-response is a valid criterion for decisions in uncertain adjuvant chemotherapy indications, e.g., in premenopausal patients (pts) with N0 and Recurrence Score (RS, Oncotype DX®) RS 16-25 or with N1 and RS ≤25. Preliminary results from the phase III ADAPTcycle trial indicated higher efficacy of preoperative ET in premenopausal pts. if ovarian function suppression (OFS) was used together with tamoxifen (TAM) or aromatase inhibitors (AI). In the final screening population, we are now able to confirm these results and investigate the influence of age subgroups, RS, individual biological markers, and OFS on ET-response. Methods: In ADAPTcycle (n=5,290 screened, 1,670 randomized by 06/23; 84 sites in Germany), N0-1 pts with RS &amp;gt;25 or N2-3 pts with RS ≤25 and ET-response were randomized to (neo)adjuvant chemotherapy (CT) followed by ET vs. ribociclib + AI (premenopausal: +GnRH). In premenopausal pts, participation with N1-disease and RS ≤25 or N0 and RS 16-25 was allowed irrespective of ET-response, but randomization recommended only for ET-responders; in the preoperative phase, OFS+TAM or AI for ET-response assessment was protocol-recommended. Results: This analysis includes all pts with complete baseline characteristics (including RS) and ET-response data (n=4,334); ET-response was defined as Ki67post ≤10% (central pathology) after 2-4 weeks (if OFS: 4 weeks) of therapy. ER, PR, and HER2-levels were analyzed by IHC and mRNA. Median age was 56 years (22-87y). 55% had cT2-4 tumors; 28% had cN+ disease; 42% were G3 (central lab). Median RS was 20, median baseline Ki67 25%. n=1,368 were ≤50y and premenopausal (“≤50y”): n=314 (23.0%) and 255 (18.6%) were treated by AI+OFS and TAM+OFS, respectively. 2,966 were &amp;gt;50y or postmenopausal (“ &amp;gt;50y”), of whom 2,565 received AI (86.5%). ET-response occurred in 48.2% of “≤50y” vs. 72.7% in “ &amp;gt;50y” pts (p&amp;lt; 0.001). We observed significant differences in ET-response rates between “≤50y” vs. “ &amp;gt;50y” with TAM alone (34.7% vs. 46.4%); In “≤50y” pts, 55.7% ET-response occurred with TAM+OFS vs. 76.4% with AI+OFS, comparable to 76.8% in “ &amp;gt;50y” patients with AI. Moreover, OFS led to higher ET-response rates (by uni- and multivariable analysis) even in the small (n=78) group of premenopausal pts &amp;gt;50y. Remarkably, even in pts with RS &amp;gt;25, substantial ET-response rates were observed with AI: 66.7% (“≤50y”, AI+OFS), 55.6% (“ &amp;gt;50y”, AI) vs. lower rates with TAM alone (&amp;gt;50y: 18.2%; &amp;lt; 50y: 15.8%). ET-response rate in “≤50y” pts was associated with ET type, RS, and baseline Ki67 in both uni- and multivariable analysis, but not age subgroup (≤40 vs. 41-50y). ER, PR, and HER2 expression by IHC or RT-PCR were associated with ET-response by univariable (but not multivariable) analysis. In “ &amp;gt;50y” pts, by uni- and multivariable analysis, again ET-type, RS, and baseline Ki67, as well as ER-expression (by IHC) and ESR1, PR, and HER2-expression (by RT-PCR) were associated with higher ET-response rates. Conclusions: With about 10,000 pre- and postmenopausal pts, ADAPT and ADAPTcycle provide the largest international database regarding ET-response. ADAPTcycle confirms ADAPT ET-response rates in pts receiving TAM or AI; adding OFS to either improves ET-response, irrespective of RS. ET-response measurement adds value in therapy decisions, particularly in ≤50y N0-1 pts. ET-response might provide key information even in pts with high RS; outcome data of ADAPTcycle will reveal potential clinical consequences. Optimal preoperative ET, especially in premenopausal pts, might even enable sparing chemotherapy in additional pts. Citation Format: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Katarzyna Jozwiak, Sandy Burmeister, Rick Baehner, Peter Schmid, Hans-Heinrich Kreipe, Nadia Harbeck. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334) [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 LBO1-05.

Abstract PO3-18-10: Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter WSG-ADAPTcycle trial (n=5,290)

Abstract Background In HR+/HER2- early breast cancer (EBC), short preoperative endocrine therapy (ET) offers a promising tool for assessment of ET-efficacy based on Ki67-decrease after 2-4 weeks of treatment. Low post-endocrine Ki67 (Ki67post) is associated with good prognosis in several large prospective trials. WSG-ADAPT demonstrated that Ki67post is a promising tool for decision making in cases with uncertain adjuvant chemotherapy indication, e.g., in premenopausal patients (pts.) with N0 and Recurrence Score (RS, Oncotype DX®) RS 16-25 or N1 and RS ≤25. Preliminary results from the phase III ADAPTcycle trial indicated higher efficacy of preoperative ET in premenopausal pts. if ovarian function suppression (OFS) was used together with tamoxifen (TAM) or aromatase inhibitors (AI). In the ADAPTcycle screening population, we are now able to validate these results and investigate the influence of age subgroups, Recurrence Score, and individual biological markers, as well as OFS on ET-response. Methods In ADAPTcycle (n=5,290 screened until 06/23 at 84 sites in Germany), N0-1 pts. with RS &amp;gt;25 or N2-3 pts with RS ≤25 and ET-response (Ki67post ≤10%) were randomized to (neo)adjuvant standard chemotherapy (CT) or ribociclib + AI +/- GnRH-analog (n=1,670 randomized). Participation of premenopausal pts. with N1-disease and RS ≤25 or N0 and RS 16-25 was allowed irrespective of ET-response, but randomization recommended only for ET-responders. Use of OFS + TAM or AI for ET response assessment in the preoperative phase was protocol-recommended. This analysis includes all patients with baseline RS and data on ET-response. Ki67-response is defined as Ki67post ≤10% (central pathology assessment) after 2-4 weeks of therapy (OFS-use recommended for 4 weeks). ER-, PR-, and HER2-levels are analyzed by IHC and mRNA. Results Results on ET-response according to age and clinicopathological as well as tumor biological characteristics will be presented at the meeting. So far, ADAPTcycle with &amp;gt;5,000 pts. screened is the largest trial worldwide to look at ET response assessment in pre- and postmenopausal pts. with HR+/HER2- EBC. The results thus have the potential to impact clinical practice. Contact Information oleg.gluz@wsg-online.com Citation Format: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Peter Schmid, Rick Baehner, Hans-Heinrich Kreipe, Nadia Harbeck. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter WSG-ADAPTcycle trial (n=5,290) [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 PO3-18-10.

Abstract PO3-01-10: Changes in Patient-Reported Outcomes with 3 Months of Pre-operative Endocrine Therapy in the POWER Trial

Abstract Background: The Pre-Operative Window of Endocrine Therapy to Inform Radiation Therapy Decisions Trial (POWER, NCT04272801) aims to determine whether 3 months of pre-operative endocrine therapy (pre-ET) affects decision-making regarding adjuvant radiation therapy (RT) among older women with early-stage, estrogen receptor (ER) positive breast cancer. The goal of the present study is to evaluate changes in patient-reported outcomes (PROs) during the course of pre-ET. We hypothesize that PROs will change over the course of pre-ET and that those changes can be used to identify patients who are at-risk for long-term noncompliance to adjuvant ET and who may benefit from RT. Methods: Participants in the POWER Trial receive 3 months of pre-ET prior to breast-conserving surgery and final treatment decisions regarding adjuvant RT. Health-related quality of life (HRQOL) (EORTC QLQ-C30 and QLQ-BR23), depression (Center for Epidemiologic Studies Depression Scale Revised), and general symptom burden (Breast Cancer Prevention Trial Symptom Checklist (BCPT-SCL)) are assessed at baseline and at day 90 after pre-ET. Perceived sensitivity to medicine (Perceived Sensitivity to Medicine (PSM) survey) is assessed at baseline. The BCPT-SCL was used to examine common ET side effects, including hot flashes, musculoskeletal symptoms, cognitive problems, weight gain, and bladder control. Graphical methods are used to display results. Results: The first 46 participants who completed pre-ET in the POWER trial were included in this preliminary assessment. From baseline to day 90, there was notable variability in HRQOL and no definitive shift towards worsening HRQOL with a median change (IQR) of 0 (-8.33, 8.33). Similarly, the median change in symptom profiles for the whole cohort was 0 over the 90 days of pre-ET. However, a subset of patients experienced changes in symptom burden throughout the 90-day period. Approximately one-fourth of participants reported an increase in hot flashes and musculoskeletal symptoms from baseline to day 90. There does not appear to be worsening fatigue, depression scores, cognitive problems, or weight gain. After stratifying by self-perceived sensitivity to medicine, patients with high PSM scores have a greater median change (0.5 and 0.33) in symptoms compared to those with low PSM scores (0 and 0) for hot flashes and musculoskeletal symptoms, respectively (Figure 1). Conclusions: When looking at this cohort, there was no change in symptoms or quality of life after the 3-month course of pre-ET. Evaluation of the changes in PROs identified a subset of participants with worsening symptoms after pre-ET. Future analyses, when trial accrual is complete, will examine the relationship between PROs and long-term adherence to adjuvant ET and will elucidate if the patients who experience worsening BCPT-SCL symptoms during the 90-day period are more likely to opt for RT. Figure 1 Change in symptoms after pre-ET Change in hot flash burden and musculoskeletal symptom burden is greater in patients with high perceived sensitivity to medicine. Citation Format: Trish Millard, Lena Turkheimer, Christiana Brenin, David Brenin, Patrick Dillon, Einsley Janowski, Anneke Schroen, Gina Petroni, Shayna Showalter. Changes in Patient-Reported Outcomes with 3 Months of Pre-operative Endocrine Therapy in the POWER 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 PO3-01-10.

Abstract PO2-19-07: PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET

Abstract Background During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) with 0 to 3 positive lymph nodes. In case of a low genomic risk, there is strong consensus in favor of endocrine treatment (ET) alone for postmenopausal patients, regardless of clinical risk (supported by data from planB, ADAPT, RxPonder, TailorX, MINDACT). However, there is still uncertainty regarding optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database on how to optimally treat these patients. Eligibility Criteria PROOFS (NCT05792150) aims at the long-term follow up of pre- or perimenopausal patients with HR+/HER2- EBC with an intermediate to high clinical risk of recurrence and low genomic risk measured by MammaPrint(R). Additional endocrine response assessment (Ki67) after a short preoperative endocrine therapy is encouraged. Up to 25% of the study population may have node-positive disease. Participants undergo standard-of-care treatment at physician´s discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. Specific Aims PROOFS aims to give insights in the real-world use of OFS and to confirm an excellent outcome in pre-/perimenopausal women with HR+/HER2- early BC with an intermediate to high clinical risk of recurrence and low genomic risk treated by ET +/- OFS alone (without CT). In addition, quality of life is captured. Statistical Methods The primary objective is to demonstrate the 5-year distant recurrence-free interval (dRFI) in patients treated by ET +/- OFS alone. The null hypothesis H(0) is: 5-year dRFI &amp;lt; 92%. Secondary endpoints for all patients are 5- and 10-year dRFI, distant disease-free survival (dDFS), overall survival (OS), breast cancer-free interval (BCFI), quality of life (QLQ BR23 and QLQ-C30) and therapy adherence. Cox regression models, Kaplan-Meier method and log-rank tests will be applied for survival analysis. Linear mixed models will be utilized to quantitatively describe the course of quality of life-scores as well as therapy adherence, and to conduct group comparisons. Present and Target Accrual The study is open for recruitment of 1500 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany (June 2023: 24 open for recruitment). Funding AGENDIA N.V., Amsterdam Contact Information rachel.wuerstlein@med.uni-muenchen.de Citation Format: Rachel Wuerstlein, Lotta Ada Fischer, Nadia Harbeck, Monika Graeser, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Christine zu Eulenburg, Matthias Warm, Oleg Gluz. PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET [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 PO2-19-07.

Impact of the preoperative hormone therapy duration on the satisfaction of transgender men after chest masculinization surgery

Introduction Chest masculinization is currently the most commonly performed gender-affirming surgery. It is often preceded by testosterone replacement therapy, whose duration is not agreed upon before surgery. Our study evaluates the postoperative satisfaction of transgender men who have undergone chest masculinization surgery according to their preoperative hormonal treatment duration. Material and methods We conducted a single-center prospective study conducted from 2021 to 2022. All transgender men older than 18 years who had chest masculinization surgery were included. Demographic data, medical history, operative data, and duration of preoperative hormone therapy were collected. Participants completed the BREAST-Q© and BODY-Q© questionnaires pre- and postoperatively. Results Forty-six patients were included, with a median age of 21 years (18–45 years). The median preoperative testosterone duration was 596 days (186–4479 days). A significant improvement was found in BREAST-Q© (psychosocial, sexual and physical well-being; satisfaction with chest) and BODY-Q© (satisfaction with chest and nipples) parameters (p < 0.01). There was no significant correlation between preoperative hormone therapy time and chest satisfaction of BREAST-Q© (ρ = 0.069; R2 = 0.002; p = 0.647) and BODY-Q© (ρ = –0.114; R2 = 0.007; p = 0.450). Conclusion All patients in our study were exposed to exogenous testosterone for at least six months. Our study suggests that satisfaction remains unchanged with a longer duration of usage, indicating that an extended period of hormone impregnation may not be necessary before performing chest masculinization surgery in transgender men. Furthermore, the findings confirm a significantly high post-operative satisfaction rate among participants, emphasizing the positive impact of this type of surgery.

ASO Visual Abstract: The POWER-PAK Score Characterizes Tumor Response to 3 Months of Preoperative Endocrine Therapy.

ASO Visual Abstract: The POWER-PAK Score Characterizes Tumor Response to 3 Months of Preoperative Endocrine Therapy.

Therapy decision-making after pre-operative endocrine therapy in HR+ HER2- early breast cancer.

e12520 Background: Nowadays, the right way for therapy decision-making in HR+ HER2- early breast cancer (BC) includes the complex of validated multigene assays (VMA) result with clinical and IHC evaluation. Given the inability to use VMA in routine clinical practice, the short-term pre-operative endocrine therapy (P-ET) allows to estimate more precisely plan the further adjuvant therapy (AT) in the patients (pts) with early HR+ HER2- BC. Our work is aimed to share of pts with P-ET benefit, or tumor phenotype reversion for proper treatment planning in pts with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 and any grade (G) have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in A.S. Loginov MCSC, Russia. Enrollment period was Jun’20 - Jan’23. The study was aimed to access P-ET efficiency in pts with baseline Ki67&gt;10% downgrading to ≤10% (1), tumor ET sensitivity in the whole group (2) and/or phenotype transformation during P-ET followed by changing AT strategy (3). Results: At the data cut-off (Jan’23) 998 pts (5 pts were men) with HR+ HER2- BC were enrolled with median age 63,5 (range:26-85). The median time of P-ET was ≈19,5 days (range: 14-42). Pts flow according to tumor Ki67 level dynamic is show. 54% (434) pts with initially Ki67 level &gt;10% decreased Ki67≤10% after P-ET in whom 36% (314) pts avoided adjuvant chemotherapy. In Ki67≤10% baseline group (n=187) tumor Ki67 level after P-ET increased &gt;30% in every fifth case (n=35, 19%), that may reflect the initial ET resistance. Ki67 level dynamic change under P-ET was observed regardless of the TAM/IA use. 4% (38) pts has resulted the phenotype change to HER2+ BC (n=32) and TNBC (n=6) with subsequent AT decisions (anti-HER2-based or dose dense regimens, respectively). In this group there weren’t any Ki67 decrease after P-ET that additionally confirms the unmet need for treatment plan correction. Conclusions: In HR+ HER2- BC pts the results of P-ET with TAM or IA before surgery helps to estimate pts prognosis and further AT strategy: to identify the pts population of whom chemotherapy can be avoided while maintaining treatment efficacy with a better quality of life (1), to assess the initial ET tumor sensitivity (Ki67 baseline level independently) (2), to radically change the planned AT to achieve optimal treatment results (3). Mature data of long-term pts outcome are awaited. [Table: see text]

57. Safety of Hormonal Therapy Prior to DIEP Reconstruction: A Matched Cohort Analysis

PURPOSE: Hormone therapy is a mainstay in the treatment of receptor positive breast cancers. There have been conflicting reports regarding the effects of pre-operative hormonal therapy on outcomes after autogenous breast reconstruction (ABR). Here, we present a matched cohort analysis to determine if hormonal therapy truly affects outcomes following ABR. Method: A review was conducted of patients undergoing bilateral deep inferior epigastric perforator flaps (DIEP) between 2016-2020. Patients were split into two cohorts: hormonal therapy (HT) (tamoxifen or aromatase inhibitor), and not on hormonal therapy (NH). A 1:1 propensity match was conducted based on risk factors for complications following DIEP, including BMI, smoking, history of radiation and diabetes. RESULTS: A total of 356 patients were entered in the analysis. From this, 108 patients were matched into the HT and NH cohorts. Overall, patients in the HT cohort were significantly more likely to develop a complication (HT: 44 (41%) vs NH: 25 patients (23%); p=0.006). Incidence of intraoperative thrombosis was similar between the cohorts as was incidence of post-operative total flap loss (HT: 3 patients (2.8%) vs NH: 2 patients (1.9%); p=0.65). HT patients were at a significantly increased risk of venous thromboembolism (VTE) when compared to NH patients (HT: 3.7 % vs NH 0%; p=0.04). CONCLUSION: This is the first study examining the effect of pre-operative hormonal therapy on DIEP breast reconstruction, with matched cohorts to control for comorbidities. HT patients had a significantly higher risk of complication and VTE, suggesting patients should discontinue hormonal therapy prior to surgery.

Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study

PurposeThe B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources.MethodsThis multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis.Results1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm [IQR − 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month’s duration of BrET.DiscussionThis study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.

Abstract TC1-3-1: Ki 67 Ki67 – a clinically relevant biomarker or just nice to have information?

Abstract Ki67 is an immunohistochemical marker indicating the growth fraction of cycling cells from G1 to S-phase in tumor specimens. In breast cancer, Ki67 is a prognostic marker with high values indicating poor outcome. Over the last decades, obstacles for its wide-spread use in clinical practice included lack of methodological standardization and lack of specific cut-off values for clinical decision making, i.e. discrimination of luminal A vs. B early breast cancer (EBC), chemotherapy indication in HR+/HER2- EBC. However, recently, the International Ki67 working group has put forward consensus statements for a standardized methodology. In general, reproducibility of Ki67 values at extreme sides of the spectrum such as 10% or ≥ 35% is much higher than in the intermediate range and quality assurance programs substantially improve laboratory performance. Moreover, clinical utility has also become apparent in two specific settings of HR±/HER2- EBC. First, the monarchE trial evaluating adjuvant abemaciclib in node-positive high-risk disease used a Ki67 cut-off of 20% as a criterion for aggressive disease and as a sole inclusion criterion for patients with 1-3 lymph nodes (cohort2). While data for this cohort have not yet been reported, Ki67 was a strong prognostic factor in the overall trial population with patients with high Ki67 having worse outcome than those with Ki67 &amp;lt; 20%. Benefit from abemaciclib was independent of Ki67 index. Nevertheless, some health authorities included Ki67 in their abemaciclib label as the absolute benefit was greater in tumors with Ki67 ≥ 20%. Second, Ki67 response after a short (2-4 week) preoperative endocrine therapy allows endocrine response assessment by determining Ki67 in the surgical specimen. This information is widely used in drug development. Ki67post 10% has been defined as endocrine response. In the POETIC trial, endocrine response was associated with improved outcome compared to tumors with Ki67 ≥ 10% after 2-weeks of preoperative AI in postmenopausal patients. In the WSG ADAPT trial, patients with 0-3 lymph nodes, Recurrence Score 25 and endocrine response had excellent outcome with adjuvant endocrine therapy alone independent of menopausal status (5-year dDFS ≥ 95%). In postmenopausal women, probability of endocrine response with an AI is around 80% whereas in premenopausal patients with tamoxifen it is only around 40%. Yet, in premenopausal women addition of GnRH substantially improves endocrine response probability reaching about 80% with GnRH and AI as recently shown by interim analysis of the WSG ADAPTcycle trial (about 2500 patients). Endocrine response probabilities seen in the ADAPT trial (≥ 5000 patients) were validated in ADAPTcycle demonstrating clinical validity of this biomarker. In conclusion, Ki67 is a clinically relevant biomarker that can be used for clinical decision making, particularly in HR+/HER2- EBC. As there is no single generally accepted Ki67 cut-off value to discriminate prognostically favorable from aggressive EBC, Ki67 needs to be used in the context of tumor burden and tumor biology. Currently, next to its use in allocating patients to adjuvant abemaciclib in countries where Ki67 index is included in the label, it provides clinically important information after short-term preoperative endocrine therapy regarding endocrine response in HR+/HER2 EBC. Given its easy and inexpensive determination method, its analytical validity within quality assurance programs, and its clinical usefulness, Ki67 needs to be integrated in our biomarker portfolio in EBC. Citation Format: Nadia Harbeck, Torsten Nielson. Ki 67 Ki67 – a clinically relevant biomarker or just nice to have information? [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 TC1-3-1.

Abstract P4-02-08: Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-Positive Breast Cancer

Abstract Pre-operative endocrine therapy use in post-menopausal women with localized, ER-positive breast cancer affords comparable rates of response and breast preservation, but lower toxicity relative to chemotherapy. Pre-operative endocrine therapy exerts selective pressure on cancer cells and promote evolution and/or enrichment of pathogenic alternations such as ESR1 mutations and other cellular adaptations. How such endocrine therapy-induced adaptations alter response to radiation therapy remains poorly defined. In this study, we show that diverse mechanisms that confer endocrine therapy resistance also drive radiation resistance by reprogramming of DNA repair pathways. We also show that BRD4, a member of bromodomain and extraterminal domain (BET) family of proteins, mediates such DNA repair reprogramming. BRD4 also plays a key role in trascriptional reprogramming in ER-positive breast cancer cells that confers endocrine therapy resistance. Thus, OTX015, a BET inhibitor with a favorable safety profile in early stage clinical trials, reverses both endocrine therapy resistance and radiation resistance in ER-positive breast cancer cells and tumors. Our findings are also consistent with reports that tamoxifen-resistant breast cancer cells are resistant to DNA damaging chemotherapeutic agents such as adriamycin and cisplatin. Overall, our findings suggest that endocrine therapy resistance in the pre-operative setting serves as a biomarker for reduced response to adjuvant radiation therapy, and that pharmacological BET inhibition reverses radiation resistance in such patients. The increasing use of “window of opportunity” studies to assess response to endocrine therapy in the pre-operative setting will further facilitate personalization of radiation treatments in these patients based on their response to endocrine therapy. Thus, we provides a therapeutic rationale for personalization of radiation treatments in breast cancer patients based on their response to endocrine therapy. We also provide a molecularly targeted approach for reversing radiation resistance in such patients. Thus, our study provides a framework for advancing Precision Radiation Oncology in breast cancer patients. Citation Format: SM Nashir Udden, Asal Rahimi, Dong W. Nathan Kim, Prasanna Alluri. Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-Positive 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 P4-02-08.

Unchartered waters: Significance of fall in Ki67 index after short-term preoperative endocrine therapy in early breast cancers.

Endocrine treatment for breast cancer acts largely by inhibiting tumor cell proliferation. The biomarker Ki67 is linked to the proliferative index of the tumour. To identify the factors affecting the fall in Ki67 value in early-stage hormone receptor (HR) positive breast cancer patients receiving short-term preoperative endocrine therapy in an Indian cohort. Women with hormone receptor positive, invasive, nonmetastatic, and early breast cancer (<T2, <N1) were assigned to short-term preoperative tamoxifen 20 mg daily (pre-menopausal women) or Letrozole 2.5 mg daily (post-menopausal women) for a minimum of 7 days after noting the baseline Ki67 value from the diagnostic core biopsy specimen. The postoperative Ki67 value was estimated from the surgical specimen, and the factors determining the extent of fall were evaluated. The short-term preoperative endocrine therapy resulted in a reduction in the median Ki67 index, which was significantly greater among postmenopausal women who received Letrozole (63.25 (31.94-80.5)) than among premenopausal women who received Tamoxifen (0 (-28.99-62.25)) (p-value 0.001). The fall in Ki67 value was particularly marked for patients with low-grade tumors with high Estrogen and progesterone receptor expression (p-value < 0.05). The duration of treatment (<2 week or 2-4 week or >4 week) did not affect the fall in Ki67. Preoperative therapy with Letrozole resulted in a more significant fall in Ki67, as compared to therapy with Tamoxifen. Determining the fall in Ki67 value in response to preoperative endocrine therapy could provide an insight into the response to endocrine therapy in luminal breast cancer.

A retrospective study to evaluate the effect of preoperative hormonal therapy on continence recovery.

To evaluate whether different preoperative hormonal therapy options affect postoperative continence and to identify risk/protective factors for continence recovery. This is a retrospective analysis of several clinical trials (NCT04356430, NCT04869371, NCT04992026 and NCT05406999). Data from patients treated with hormonal therapy followed by RARP were collected and analyzed. Continence was defined as 0 pad/day or one safety pad. The study included 230 patients with adequate information. The median time to continence recovery is 8 weeks. A total of 216 (93.9%) participants recovered to urinary continence within 12 months after surgery. 21 (9.1%) participants achieved immediate continence. 69, 85, 27 and 14 participants restored continence at 1 month, 1-3 month, 3-6 month, 6-12 month, accounting for 30.0%, 40.0%, 11.7% and 6.1% accordingly. No difference in continence recovery was found among different preoperative hormonal treatment options (p=0.821). Cox regression showed that membranous urethral length (MUL) was the only independent factor influencing urinary continence recovery either in the univariate analysis (OR=1.13, 95%CI: 1.04-1.22, p=0.002) or in the multivariate analysis (OR=1.12, 95%CI: 1.04-1.20, p=0.002). Different preoperative treatment options were not associated with urinary recovery. More advanced preoperative T stage (OR=0.46, 95%CI: 0.24-0.85, p=0.014) delayed the recovery of immediate continence. MUL was associated with continence restoring at 1 month (OR=1.20, 95%CI: 1.03-1.39, p=0.017), 3 month (OR=1.27, 95%CI: 1.07-1.51, p=0.006), 6 month (OR=1.34, 95%CI: 1.07-1.67, p=0.011) and 12 month (OR=1.36, 95%CI: 1.01-1.84, p=0.044). There is no difference in postoperative continence recovery among ADT, ADT+Docetaxel and ADT+Abiraterone preoperative treatment options. More advanced T stage indicated poor immediate continence recovery. Longer membranous urethral length was a promotional factor for both short-time and long-time continence recovery.