Adjuvant Endocrine Therapy Research Articles

Adherence to adjuvant hormone therapy in hormone-sensitive breast cancer: Insights from the Medical Oncology Department at Hassan II University Hospital, Morocco.

e12505 Background: Adjuvant endocrine therapy (AET) improves long-term survival for hormone-sensitive breast cancer; However, suboptimal adherence is prevalent, with many women failing to follow prescribed dosage and frequency. Long-term adherence patterns to AET are poorly understood. Additionally, there is a lack of data regarding the adherence to AET among Moroccan women and the factors that may influence it. Objectives: The primary objective of the study was to assess the adherence rate to AET in patients with HR-positive early breast cancer being treated at Hassan II University Hospital of Fez, Morocco. Secondary objectives included determining factors associated with poor adherence and assessing the adverse events associated with AET and their prevalence. Methods: We conducted a cross-sectional study involving 335 breast cancer patients undergoing AET. Eligible patients, who had received at least one dispensing of AET, participated in the study through a direct questionnaire survey after providing signed consent. The questionnaire comprised sections covering patient demographics, clinical data (stage, type of AET, duration of therapy), side effects or symptoms related to AET, other factors that may impact adherence. Adherence to AET was assessed at three points of measurement: 1 year, 3 years, and ≥ 5 years after the initiation of therapy. The study was carried out with respect to the Moroccan regulation in effect. Results: The study included 335 cases with an average age of 54 years. Participants were predominantly illiterate (62%) and post-menopausal (50.7%). Most were classified as stage II UICC (53.5%). Mastectomy was performed in the majority (74%). Neo(adjuvant) CMT was given to 79.4%, and adjuvant radiotherapy to 86.9%. Tamoxifen was administered to 55.4%, and aromatase inhibitors to 44.6%. Medical castration was associated with 12.5%, and 35 patients switched AET over time. Only 12.8% exceeded 5 years of AET during recruitment. Adherence assessment revealed an overall adherence rate of 53.4%. Notably, 67.2% claimed never to forget their medication, and about 20% temporarily stopped it, primarily due to lack of information. Most participants used a reminder strategy, notably alarms (43.3%). Treatment tolerance varied, with hot flushes and arthralgia being predominant side effects. Statistical analyses found a significant link between treatment lasting over 5 years and non-adherence (p = 0.003). However, the use of an alarm as a reminder strategy strengthened adherence (p = 0.021). No statistically significant differences were noted in other variables. Conclusions: Despite the benefits, ensuring adjuvant hormone therapy adherence is challenging. Our analysis, estimating a 53.4% global adherence, found that only treatment duration and recall strategy significantly correlated with adherence.

Comprehensive clinical characteristics and ctDNA mutational profile analysis of endocrine resistance/sensitivity to adjuvant ET therapy in luminal breast cancer from the GEICAM/2014-03_RegistEM registry.

1011 Background: Patients (pts) with hormone receptor-positive (HR) early breast cancer (BC) may develop resistance to adjuvant endocrine therapies (ET), with relapse occurring months (m) to decades after surgery. Our study explores clinical characteristics, prognosis, and oncogenic drivers in circulating tumor DNA (ctDNA) at relapse in HR+ BC pts, based on their sensitivity to adjuvant ET. Methods: In the REGISTEM study, we identified 805 primary HR-positive BC pts who developed metastatic relapse. These cases were classified based on their sensitivity to adjuvant ET, according to the 5th ESO-ESMO ABC Guidelines: 1ET-resistance (1ET-R, relapse within the first 2 years of adj ET; n=138), 2ET-resistance (2ET-R, relapse after the first 2 years or <12 m after completing adj ET; n=284), and ET-sensitive (ET-S, relapse after >12 m of completing adj ET; n=383). Out of this cohort, 139 individuals had plasma samples obtained prior to the initiation of the first-line treatment for advanced disease, and these samples were analyzed using the AVENIO ctDNA assay. Results: Pts with 1ET-R were significantly more likely to have grade 3, stage III, and highly proliferative tumors (Ki67>20%). The median time to distant relapse was 24 m for 1ET-R, 52.8 m for 2ET-R, and 124 m for ET-S cases. For first-line treatment, the median PFS was 8.1 m for 1ET-R, 13 m for 2ET-R, and 21.2 m for ET-S relapse (p<0.0001). With a median follow-up in the advanced setting of 34 m, median OS was 28 m for 1ET-R, 46 m for 2ET-R, and 55 m for ET-S relapses (p<0.0001). Pts with ET resistance had more mutations (mut) and higher mut allele frequency than ET-sensitive relapse. Pts with ET resistance showed higher incidence of mut in TP53, ESR1, PTEN, andhigh copy number in EGFRand ERBB2 than ET-sensitive, but similar incidence of mut in PIK3CA.Mut in ESR1 and high copy number in EGFR were correlated with poorer PFS, while ESR1 mut were additionally associated with worse OS, although these associations were not independent of the ET relapse groups (Table). Furthermore, mut in PIK3CA were associated to worse PFS only in ET-R pts. Conclusions: In HR-positive BC, both primary and secondary resistance to adjuvant ET represents a highly aggressive disease with enriched actionable genetic alterations detected at the time of diagnosis of metastatic relapse. Addressing these alterations has the potential to mitigate the unfavorable prognosis associated with these cases. Clinical trial information: NCT02819882 .[Table: see text]

Exploring factors impacting quality of life in patients with breast cancer undergoing adjuvant hormone therapy: Experience of the Medical Oncology Department-CHU Hassan II-FEZ University Hospital.

e12507 Background: Considering that the recommended duration of adjuvant hormone therapy in localized breast cancer is at least 5 years, it becomes crucial to investigate the quality of life (QOL) of these patients and the factors influencing it. Objectives: To assess the quality of life (QOL) and identify factors impacting it in patients with localized hormone-sensitive breast cancer receiving adjuvant hormone therapy. Methods: We surveyed 335 patients with localized hormone-sensitive breast cancer undergoing adjuvant hormone therapy using the Moroccan Arabic dialect version of the EORTC QLQ-C30 questionnaire. Written informed consent was obtained from all participants. Confidentiality of participant data was maintained. The study was carried-out with respect to the Moroccan regulation in effect. Results: The overall quality of life (QOL) in our patient population was moderate, with positive scores for social functioning, followed by physical, cognitive, and emotional functioning. Financial difficulties emerged as the most influential factor affecting patients' QOL, followed by fatigue, pain, and other symptoms. Age-related declines in physical functioning were observed, with symptoms more prevalent, especially diarrhea, in patients aged 70 and above (p = 0.009). Urban patients faced a greater financial impact on QOL than rural patients (p = 0.025). Higher education correlated with improved QOL, particularly in physical functioning (p = 0.025). Married individuals demonstrated better overall QOL and fewer symptoms (p = 0.027). Menopausal patients exhibited lower ability and a higher loss of appetite (p = 0.027). No significant correlation was found between UICC stage and QOL. Patey-mastectomy was associated with more pain than tumorectomy (p = 0.024). Previous chemotherapy had no overall QOL impact, but users reported less diarrhea (p = 0.016). Hormone therapy type did not significantly affect overall health status, except for tamoxifen users who demonstrated improved functional roles (p = 0.008). The duration of adjuvant hormone therapy (<5 years or >5 years) showed no significant difference in patient QOL. Associated castration had a significant impact on overall health and role functioning, favoring non-castration (p = 0.034 and p = 0.011). Effective treatment tolerance positively influenced overall QOL, leading to better physical, emotional, and cognitive functioning (p < 0.0001), with fewer pronounced symptoms. Conclusions: Our study indicate that the overall QOL of patients with localized breast cancer under AET was moderate, and several factors were identified as major influences, each affecting the QOL in distinct ways.

Associations between HIV infection status, psychosocial factors, and adjuvant endocrine therapy adherence among South African women with early-stage breast cancer.

522 Background: South African (SA) women living with comorbid estrogen receptor positive (ER+) breast cancer (BC) and HIV have higher mortality than other SA women with ER+ BC. We aimed to evaluate for associations between HIV status, psychosocial factors, and adjuvant endocrine therapy (AET) adherence as a potential contributor to this disparity. Methods: From Chris Hani Baragwanath Hospital, Johannesburg, we enrolled adult women with stage I-III ER+ BC in remission and currently prescribed tamoxifen or an aromatase inhibitor to a prospective cohort study. We performed AET pill counts at enrollment, 12 weeks, and 24 weeks, and calculated adherence ratios from the difference in pills between visits divided by the number of days between visits. Women completed questionnaires on sources of social support, beliefs about medication, health literacy, and self-efficacy at enrollment and questionnaires about mental health (depression, anxiety, and acute stress) symptom burden and AET-related side effects at the 12- and 24-week visits. We also collected household wealth data and clinical data on BC and HIV. AET adherence ratios were compared between women with and without comorbid HIV using Wilcoxon rank sum testing. We also used structural equation modeling techniques to refine and evaluate an a priori model of AET adherence with latent variables for mental health, socioeconomic (SES) status, healthcare savvy, and AET side effect burden and subgroup analyses of the resulting model in women with and without HIV. Results: Between April 26, 2022, and July 11, 2023, we enrolled 239 women, 63 (26.4%) of whom had co-morbid HIV. Adherence data was available from 106 women at 12 and 24 weeks, from 22 women at 12 weeks only, and from 111 women at 24 weeks only. Comparing women with and without HIV, median AET adherence ratio was 0.88 vs 0.89, respectively (p = 0.65). Our final model of AET adherence achieved good fit (comparative fit index = 0.96, RMSEA 90% CI: 0.03-0.06). In the full cohort, SES quintile showed a trend towards association with AET adherence (β 0.02, SE 0.01, p=0.09); mental health, healthcare savvy, and side effect burden latent variables were not significantly associated with adherence. In the subgroup of women living with HIV, SES quintile (β 0.04, SE 0.02, p=0.08) and mental health (β -0.02, SE 0.01, p=0.10) showed trends toward association with adherence; these relationships did not persist for women without HIV. Conclusions: HIV status is not predictive of AET adherence among SA women with ER+ BC, but in women with both diagnoses, decreasing SES status and increasing mental health symptoms trended towards an association with decreased adherence. Interventions to improve the mental health of SA breast cancer patients living with HIV may promote AET adherence.

Assessment of endocrine therapy adherence in a nurse-led cancer survivorship clinic: Results from the Linking You to Support and Advice (LYSA) trial.

1627 Background: The care of those living with and beyond a cancer diagnosis requires dedicated cancer survivorship services to ensure optimal symptom control and quality of life. Supporting adherence to adjuvant endocrine therapy is also an essential component of care. We examined endocrine therapy adherence rates, and factors associated with non-adherence, in patients with early-stage breast cancer enrolling in a survivorship trial (LYSA). Methods: Women with early-stage hormone positive breast (n=168) cancers within 12 months of completing primary therapy, were enrolled in a randomized control trial with parallel arms (PMID 36357934). Experimental arm had access to nurse-led symptom management, dietetic consultation, and undertook bimonthly electronic patient reported outcome (ePRO). Active comparator group had access to conventional care and ePRO was completed at beginning and end of study. Endocrine therapy adherence was reported as the ability to take medication as prescribed over prior 4 weeks (Michigan Oncology Quality Consortium Adherence Tool), with response quantified as Excellent (adherence close to 100%), Very Good (80%), Good (60%), Fair (40%) and Poor (20%). Adherence Objective (Secondary) was adherence rate at 12 months after study entry in both arms, and factors associated with non-adherence. Results: A total of 148/168 women with breast cancer who completed the LYSA study reported adjuvant endocrine therapy use (74 experimental arm, 74 active comparator) during study conduct. Therapies included aromatase inhibitors (53%), tamoxifen (39%) and ovarian suppression combinations (8%). At study entry ≥ 80% adherence was reported in 74% of overall cohort (75% experimental, 72% comparator, p=0.7), with 1.6% reporting not taking any medication. By end of study (12 months), ≥ 80% adherence was reported in 74% overall (77% experimental, 71% comparator, p=0.4), while non-adherence rates were 2.9%. Among the pre-specified reasons for non-adherence at study end, “simply missing it” ranked highest (10%), and 5% “experienced side effects”. Post-menopausal patients were more likely than pre-menopausal to report excellent (versus sub-excellent) adherence at study end (OR 4.60, 95%CI 1.45 – 16.13, p = 0.012, adjusted for arm, age, and ECOG). Additional exploration of reasons for non-adherence will be presented. Conclusions: Adjuvant endocrine therapy adherence rates in both arms at 12 months after study entry collected via ePRO were good (≥ 90% reporting excellent or very good adherence). Additional factors potentially associated with non-adherence are being analyzed including self-care agency, symptom burden and quality of life. Clinical trial information: NCT05035173 .

Benefit of perioperative chemotherapy in the patients with loco-regional recurrence of HR-positive HER2-negative breast cancer: A multi-institutional retrospective cohort study.

526 Background: Loco-regional recurrence (LRR) in breast cancer (BC) is addressed with multimodal treatment, yet the prognosis remains unfavorable. The benefit of adjuvant chemotherapy for the hormone receptor-positive, HER2-negative (HR+HER2-) subtype of BC is controversial. Methods: We performed a multi-institutional retrospective cohort study under the Japan Clinical Oncology Group. This study focused on patients without distant metastasis who developed HR+HER2- ipsilateral breast tumor recurrence (IBTR) or other LRR (oLRR) including recurrence in skin, chest wall, or regional lymph nodes. The patients received curative surgery for LRR between 2014 and 2018. Patients were divided into two groups: the chemotherapy group and no chemotherapy group before/after LRR. We performed a Cox proportional hazards model to evaluate invasive disease-free survival (iDFS) between the two groups. Sensitivity analysis was conducted using propensity score (PS) matching and IPTW. Results: A total of 967 patients were registered from 41 institutions, and 958 patients concordant with inclusion criteria were analyzed. There were 509 patients (53%) of only IBTR and 449 patients (47%) of oLRR. Neoadjuvant/Adjuvant chemotherapy was administered to 235 patients (25%), while 722 (75%) did not receive it. Compared to the no-chemotherapy group, the chemotherapy group included a higher number of patients aged 41-60, oLRR, and recurrences during adjuvant endocrine therapy. At a median follow-up of 5.2 years (Interquartile range: 4.1-6.5), the 5-year iDFS rate was 75.4% (95% CI: 72.4-78.2). Multivariate analysis showed an improvement in iDFS for the chemotherapy group (HR: 0.70, 95% CI: 0.49-0.99, p = 0.045). Sensitivity analysis also consistently suggested the effectiveness of chemotherapy (PS matching HR 0.76, IPTW HR 0.75). In the subgroup analysis, the chemotherapy group showed more significant iDFS improvement in cases with oLRR, recurrences during adjuvant endocrine therapy for primary BC, and those without perioperative chemotherapy for primary BC. Conclusions: Our study showed improvement in iDFS in patients who received perioperative chemotherapy for HR+HER2- LRR. This improvement was particularly notable in patients with oLRR, recurrences during adjuvant endocrine therapy, and those without perioperative chemotherapy for primary BC. [Table: see text]

Treatment outcomes and survival of patients with breast cancer aged 75 and older: A comparative study using propensity score-adjusted analysis.

e13763 Background: With an aging society, the incidence of breast cancer among elderly patients is expected to rise. We aimed to explore treatment outcomes in breast cancer patients aged 75 and older at our institution. The lack of consensus on whether adjuvant therapy for elderly breast cancer patients should mimic that for younger patients prompted our investigation. Methods: We conducted a comparative study using data from 1553 breast cancer surgery cases (stage 0-3) treated between April 2007 and August 2021. Patients were divided into two groups: those aged 75 and older (n=184) and those aged 74 and younger (n=1369). Variables investigated included mean age, tumor size, stage, and subtype; surgical procedures and adjuvant therapies; overall survival (OS); and OS in the 75 and older group, considering the presence or absence of hormone therapy, and propensity score-adjusted OS. Results: Comparing the group aged 74 and younger with the group aged 75 and older revealed: Mean age: (55.5 years vs. 79.6 years), tumor size: (2.4 cm vs. 2.3 cm), stage (0/1/2/3) (%): (7.3/43.1/44.1/4/6 vs. 7.6/43.4/43.4/5.7), subtype (Luminal A/Luminal B/TN/HER2) (%): (60.0/16.7/11.3/7.9 vs. 63.5/10.7/15.7/5.7). Except for age, no significant differences were observed. Mastectomy (%): 45.9 vs. 50.8, axillary lymph node dissection (%): 33 vs. 22.3, adjuvant therapy (%): 93.2 vs. 65.7, adjuvant hormone therapy (%): 90 vs. 68, adjuvant chemotherapy (%): 68 vs. 14. The group aged 75 and older received significantly less adjuvant hormone therapy and chemotherapy. Kaplan-Meier 10-year OS rates: 90.3% vs. 77.5%, showing a trend toward lower survival in the group aged 75 and older, albeit not statistically significant. No significant differences were found in overall survival rates by subtype. In the group aged 75 and older, hormone therapy was omitted in 44.6% and administered in 55.4%, resulting in a significant difference in 10-year OS rates (63.5% vs. 84.7%). Following propensity score adjustment for age, stage, and subtype, the hormone therapy-free group exhibited a higher 10-year OS rate of 100%, in contrast to 84.7% in the hormone therapy group. Conclusions: Breast cancer cases in patients aged 75 and older show similar biological characteristics to those aged 74 and younger. The absence of adjuvant therapy does not impact OS, even though elderly patients aged 75 and older are less likely to receive adjuvant hormone therapy and chemotherapy.

Effect of timing of recurrence on outcomes in patients with metastatic breast cancer treated with CDK4/6 inhibitors.

e13067 Background: CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) comprise the standard 1st line treatment for ER+ HER2- metastatic breast cancer (MBC). However, there is a gap in understanding how timing of MBC recurrence affects clinical outcomes on CDKi. We conducted a study to compare clinical outcomes of MBC patients on CDKi based on timing of MBC recurrence. Methods: This retrospective study enrolled ER+ HER2- MBC patients diagnosed from Jan 2015 to Jan 2023, who received CDKi + ET as 1st line treatment for MBC. Patients were categorized as de novo MBC (dMBC), if they had 1. Stage 4 disease at initial diagnosis or 2. MBC diagnosed < 6 months of the primary breast cancer (PBC) diagnosis and before starting any systemic treatment for PBC. Patients with distant recurrence occurring < 5 years, 5-10 years, and >10 years from PBC were categorized as early, intermediate, and late MBCs (eMBC, iMBC, laMBC). Endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) from MBC diagnosis. Baseline variables were compared using t-tests (continuous) and Chi-square tests (categorical). Endpoint analyses were conducted using Kaplan-Meier method and compared using Log rank test. Multivariate analyses were performed using Cox models. Results: Out of 280 patients enrolled, 67 were dMBC, 75 eMBC, 56 iMBC, and 82 laMBC. The laMBC group had a higher mean age (years) compared to other groups (71 vs. 62 in dMBC+ eMBC + iMBC, p<0.001). 64.5% of laMBC had visceral disease compared to 50.5% of dMBC + eMBC + iMBC (p=0.031). 65.7% of dMBC patients were treated with palbociclib compared to 80.8% of eMBC + iMBC + laMBC (p=0.010). Higher % of eMBC were PR- vs other cohorts (41.3 vs 23.9 dMBC + iMBC + laMBC, p<0.001). Among the 3 non dMBC groups, prior ET sensitivity (no recurrence for 2 years on adjuvant ET) was lower in eMBC (45.3%) compared to iMBC + laMBC (81.9%, p<0.001). 61.3% of eMBC patients were on adjuvant ET at recurrence compared to 17.4% of iMBC + laMBC (p<0.001). Other variables were similar. Table shows unadjusted endpoint analyses. In multivariate analyses, the risk of PFS events were not significantly different among cohorts (age<=65, ECOG performance status (PS) >=2 and PR- were independently associated with shorter PFS); risk of death was higher in eMBC vs laMBC (HR 1.73, p=0.047). Conclusions: In this retrospective study of ER+ HER2- MBC patients treated with 1st line CDKi + ET, timing of MBC recurrence was not associated with PFS differences after adjusting for other variables. However, patients with MBC recurring < 5 years of PBC had the higher likelihood of death compared to those recurring >10 years of PBC. [Table: see text]

Evaluation of recurrence rate in Canadian patients with stage II/III HR+/HER2- early breast cancer in the real-world setting.

e23303 Background: Breast cancer is the most prevalent cancer and second leading cause of cancer-related mortality among Canadian women. Most of cases belong to the HR+/HER2- subtype, representing approximately two-thirds of all instances. Treatment for this subtype encompasses a multifaceted approach with a curative intent. This real-world evidence study aims to comprehensively analyze the clinical outcomes of Canadian patients diagnosed with early-stage HR+/HER2- breast cancer, focusing on recurrence rates after initiation of adjuvant endocrine therapy to identify opportunities for enhancing patient care. Methods: This is a retrospective, longitudinal cohort study involving 541 patients enrolled in the pan-Canadian cancer patient registry PMT (Personalize My Treatment), with newly diagnosed or recurrent stage II or III HR+/HER2- breast cancer between January 1st, 1996, and May 31st, 2022. We evaluated disease recurrence rates, time to recurrence, and overall survival (OS). Furthermore, the study explored duration of endocrine therapy (ET) in the adjuvant setting. Results: 409 patients received adjuvant ET representing 75.6% of the total cohort, emphasizing the role of ET as standard of care for adjuvant treatment in this patient population. The median duration of adjuvant ET was 4.5 years. In the overall adjuvant patient population, recurrence rates progressively increased over time from 13.2% after 2 years, 21.4% after 3 years, 30.3% after 5 years, and peaking at 58.4% after 10 years. Median time to recurrence for the overall patient population on ET was 7.76 years. OS rate for patients on ET was 94.6% at 5 years and 78.3% at 10 years. Conclusions: This study marks a pioneering real-world analysis utilizing pan-Canadian EHR data, demonstrating increasing recurrence rates over time in HR+/HER2- early breast cancer. It highlights the high unmet need in stage II and stage III breast cancer, with 1 patient out of 3 recurring after 5 years, and more than half recurring after 10 years despites adjuvant treatment with ET alone. This indicates the need for more efficacious and tolerable treatment options to reduce short- and long-term recurrence and to prolong survival, not only in the higher risk patient population, but in the overall HR+/HER2- breast cancer patients at increased risk of recurrence.

Real-world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer.

The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.

Ki67 as a prognostic factor in male breast cancer (male BC): Results from a large GEICAM Spanish cohort of male BC.

556 Background: Male BC management is based, by default, on evidence produced from female BC. There is a high need to validate gender specific performance of established prognostic biomarkers. We present here descriptive results from a large, country specific, registry of Male BC. Methods: GEICAM/2016-04 (NCT03800355) is a retrospective, observational study including Male BC pts diagnosed from 2000 to 2019 in 51 Spanish sites. Data from BC diagnosis until 10-Mar-2020 was collected from medical charts; biological specimens were obtained. Pts and tumors characteristics, therapies, and outcomes were analyzed. Molecular subtypes were categorized as hormonal receptor positive (HR+)/HER2 negative (HER2−), triple negative (TN) (HR−/HER2−), and HER2+ (any HR). Results: 773 pts were analyzed, at first diagnosis, 721 (93%) had early BC (EBC) (stages I [28%], II [41%], III [21%]), and 52 (7%) de novo metastatic BC; median age was 66 (23-96) years; median body mass index was 28 (18-50) Kg/m2 (overweight), with obesity in 4% as prior medical history. Previous history of other cancers: 20 (3%) pts were diagnosed with prostate cancer (PC) and 20 (3%) pts with skin cancer (melanoma and non-melanoma). BC family history was reported in 212 (35%) pts, 56 (9%) PC, and 35 (6%) ovarian cancer. Germline genetic testing for hereditary risk was performed in 238 (31%) pts, with BRCA1/2 mutations present in 46 (19%) pts (BRCA1 in 6, BRCA2 in 39, and both in 1); BRCA1/2 mutations were observed in 9 (33%) HER2+ pts and 32 (18%) HR+/HER2− pts. Of EBC pts, 322 (45%) were node-positive, 274 (38%) had T2 tumors; 4% had breast conserving surgery, and 42% sentinel lymph node biopsy; 42% received adjuvant radiation therapy; 336 (47%) adjuvant and 44 (6%) neoadjuvant chemotherapy, 609 (84%) adjuvant endocrine therapy, mainly tamoxifen (72%); and 6% pts did not receive any systemic therapy. Morphologically, invasive carcinoma of no special type was reported in 89% pts, and 52% were grade 2. Per local pathological assessment, 97% estrogen receptor positive (ER+), 90% progesterone receptor positive (PgR+), 84% androgen receptor positive; 51% presented Ki67 index expression ≥20%, and 11% HER2+. Frequency according to molecular subtype: 599 (77%) HR+/HER2−, 75 (10%) HER2+, 6 (1%) TN, and 93 (12%) unknown. With a median follow-up of 64 months, medians of invasive disease-free survival (iDFS) and distant DFS (dDFS) were not statistically different in HR+/HER2− vs HER2+ pts and according to levels of Ki67 index expression (&lt;20% vs. ≥20%). In a Cox multivariate model, stage I-II vs III and age were statistically significant (p&lt;0.05) for both iDFS and dDFS. Conclusions: HR+/HER2− is the most common Male BC subtype, with ER and PgR highly positive, and 20% as median Ki67 index. No statistically significant differences were observed in terms of iDFS and dDFS based on level of Ki67 index expression. Clinical trial information: NCT03800355 .

Effects of plant-based diet (PBD) and exercise therapy (Ex) on weight and body composition in patients with primary hormone receptor (HR) positive breast cancer: A phase 2 randomized controlled trial.

548 Background: Obesity increases breast cancer recurrence and mortality. Strategies that induce weight loss may improve clinical outcomes. We investigated the feasibility and efficacy of personalized energy restricted PBD plus Ex on weight and body composition in primary HR-positive breast cancer (NCT04298086). Methods: Postmenopausal women with body mass index (BMI) ≥ 27 kg/m2 on adjuvant endocrine therapy were randomized (1:1) to PBD plus Ex or attention control for 24 weeks. PBD plus Ex received individualized caloric goals adjusted weekly to target 1.5 lbs/week weight loss. PBD targeted 500 kcal/day goal deficit achieved via nutrition coaching and meal delivery. Ex sessions targeted 250 kcal goal expenditure via remotely delivered treadmill walking 3-5 days/week with real-time monitoring. Attention control received a home treadmill and monthly check-in calls. Baseline to post-intervention changes in weight and body composition, measured by dual energy X-ray absorptiometry (DXA), were compared between arms using linear mixed models. Results: 43 women were randomized between 8/2020 and 4/2023. Weight data was available for all participants (35 measured at follow-up, 8 abstracted from clinical documentation); 37 completed post-intervention DXA. At baseline, mean BMI was 34 (SD 4) kg/m2. Intention-to-treat results are presented in the Table. Mean weight loss in PBD plus Ex was –13% (SD 6%) compared with –5% (SD 6%) in attention control (mean between group difference –8 kg, 95% CI –11, –4). Mean fat loss in PBD plus Ex was –6 kg compared with –2 kg in attention control (mean between group difference –4 kg, 95% CI –6, –2). Lean mass increases were greater in PBD plus Ex (P&lt;0.001). Weekly energy deficit goal compliance was 95% in month 1 and 64% in month 6. No serious adverse events were observed. Baseline and post-intervention tissue samples were available on 37 (86%) patients, which will undergo biologic correlative analysis. Conclusions: Personalized PBD plus Ex led to substantial weight loss and favorable changes in body composition during endocrine therapy for HR-positive breast cancer. Clinical trial information: NCT04298086 . [Table: see text]

Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC): NATALEE trial.

512 Background: NATALEE assessed ribociclib (RIB) + non-steroidal aromatase inhibitor (NSAI) vs NSAI alone in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease, and showed a statistically significant invasive disease-free survival (iDFS) benefit. We report BL characteristics, efficacy, and safety for the N0 subgroup. Methods: Pts with stage II/III HR+/HER2− EBC were randomized (R) 1:1 to RIB 400 mg/d (3 wk on/1 wk off for 36 mo) + NSAI (letrozole or anastrozole for ≥60 mo) or NSAI alone. Men and premenopausal women received goserelin. Pts could receive any standard (neo)adjuvant endocrine therapy (ET) ≤12 mo before randomization. In the intent-to-treat (ITT) population, 78% of pts completed 3y of RIB treatment (tx) or discontinued early with 21% still on tx at the time of this analysis (data cutoff: July 21, 2023; median follow up, 33 mo). The N0 subgroup included pts with T2N0 (stage IIA; with grade [G]3, or G2 disease and Ki-67 ≥20% or high genomic risk [HGR]), T3N0 (stage IIB), and T4N0 (stage IIIB); T1N0 was excluded. Results: Of 2549 pts R to RIB + NSAI and 2552 to NSAI alone, 285 (11%) and 328 (13%) had N0 disease, respectively. BL characteristics for the N0 subgroup were balanced across arms. Most pts were premenopausal (RIB + NSAI: 67% vs NSAI alone: 63%). Pts with N0 disease had anatomic stage IIA (RIB + NSAI: 74% vs NSAI alone: 73%), stage IIB (17% vs 13%), or stage IIIB (9% vs 12%) disease (Table). Most pts received prior chemotherapy (RIB + NSAI: 72% vs NSAI alone: 71%); prior ET was received by 59% vs 62% of pts with RIB + NSAI vs NSAI alone. For pts with T2N0 disease treated with RIB + NSAI vs NSAI alone, 49% vs 45% had G3 disease and 49% vs 53% had G2 disease (54% vs 56% with T2N0, G2 &amp; Ki-67 &gt; 20%; 13% vs 23% with T2N0, G2, Ki-67 ≤20%/missing &amp; HGR). Consistent with the ITT population, RIB + NSAI improved iDFS (HR, 0.72; 95% CI, 0.41-1.27; 3y rate with RIB + NSAI vs NSAI alone, 93.2% vs 90.6%), distant disease–free survival (DDFS; HR, 0.70; 95% CI, 0.38-1.29; 3y rate, 94.3% vs 91.5%), and distant recurrence–free survival (DRFS; HR, 0.58; 95% CI, 0.29-1.17; 3y rate, 96.3% vs 92.5%) in pts with high-risk N0 disease. The safety profile of RIB in the N0 subgroup was consistent with the ITT population. The rate of discontinuation due to all grade adverse events was 24% vs 8% with RIB + NSAI vs NSAI alone. Conclusions: This analysis showed a consistent efficacy benefit and manageable safety profile of RIB + NSAI vs NSAI alone in pts with N0 disease in NATALEE. The 3y iDFS, DDFS, and DRFS rates in the control arm at this early follow-up underscore the risk of recurrence for the N0 subgroup. These findings support the use of RIB in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease. Clinical trial information: NCT03701334 . [Table: see text]

Identification of patients with DCIS with low-risk clinicopathology who benefit from radiation therapy with and without endocrine therapy after breast-conserving surgery assessed with the 7-gene biosignature.

528 Background: Ductal carcinoma in situ (DCIS) accounts for 20% of breast cancers. For most patients with DCIS, the standard treatment involves breast-conserving surgery (BCS) followed by radiotherapy (RT). Adjuvant endocrine therapy (ET) is typically recommended for hormone receptor-positive disease. However, prospective trials have failed to identify a low-risk CP group not benefitting from RT with respect to ipsilateral breast recurrence (IBR), with no modern trials evaluating ET. We utilized the 7-gene predictive DCIS biosignature to assess the effects of RT and/or ET on 10yr IBR in women with low-risk CP DCIS. Methods: Women (n=926) from four DCIS cohorts treated with BCS had tissue samples analyzed at a CLIA lab (Laguna Hills, CA). Low-risk CP was defined with RTOG 9804-like criteria (margin negative by no-ink on tumor) or MSKCC-like criteria using nomogram-weighted factors (low-risk score&lt;220, excluding number of re-excisions, using negative margin, and RT treatment). Women with either low-risk CP criteria were classified as molecular Low Risk (DS≤2.8, no Residual Risk subtype, RRt) or High Risk (DS&gt;2.8 +/- RRt) using the 7-gene DCIS biosignature. Ten-year IBR Kaplan-Meier rates and Cox proportional hazard ratios (HR) were calculated for ET and RT. Results: Overall, 66% of 926 women were classified as low risk by one of the CP criteria. Patients with low-risk CP treated without ET (n=315) had 10yr IBR rates of 13% after BCS without RT and 7% with RT (HR=0.51, p=.10), while those treated with ET (n=291) had 10yr IBR rates of 9% after BCS without RT and 4% with RT (HR=0.39, p=.09). Overall, 37% of women were classified as low risk (n=338) by the biosignature and had a 10yr IBR rate of 5.6% after BCS with no significant ET (HR=0.66, p=.41) or RT benefit (HR=0.88, p=.78) in multivariable analysis. Of patients with low-risk CP, 48% of those treated without ET were classified as High Risk by the biosignature and had elevated 10yr IBR rates without RT (21%) and a substantial RT benefit (HR=0.31, p=.03, n=151), while 59% of those treated with ET after BCS were classified by the biosignature as High Risk and had elevated 10yr IBR rates without RT (14%) and a 9% absolute reduction from RT (HR=0.22, p=.02, n=173). Patients with concordant low-risk CP and biosignature Low Risk (n=269) had a 5.5% 10yr IBR rate after BCS and no significant RT (HR=1.10 95% CI 0.33 to 3.7, p=.87) or ET benefit (HR=0.44, 95%CI 0.1 to 1.6, p=.22) in multivariable analysis. Conclusions: The 7-gene biosignature provided better identification of patients with low 10yr IBR rates and no significant RT benefit compared to using CP low-risk criteria. Importantly, the biosignature classified over half of women with low-risk CP treated with ET as High Risk. This group received a substantial benefit from RT, while those with biosignature Low Risk did not.

A window-of-opportunity (WOO) trial of giredestrant +/- LHRHa vs anastrozole+LHRHa in premenopausal women with ER+/HER2- early breast cancer (EBC; IBCSG 67-22; PREcoopERA).

TPS628 Background: Adjuvant endocrine therapy (ET) for premenopausal women with ER+/HER2- EBC often includes ovarian function suppression (OFS) via a GnRH or LHRH agonist (LHRHa) plus an aromatase inhibitor (AI) or tamoxifen. Younger age is associated with lower rates of ET adherence indicating side effects are less acceptable to these women. The development of drug regimens without OFS are clearly an unmet medical need in this setting. New oral selective ER degraders (SERDs) are emerging as potentially useful ETs in the (neo)adjuvant settings. Giredestrant is an efficient and potent SERD and a full antagonist, which translates into better anti-proliferation activity than known SERDs. PREcoopERA is a WOO trial aiming to determine, among premenopausal women with ER+/HER2- EBC: if giredestrant+LHRHa provides greater anti-proliferative activity than anastrozole+LHRHa; and if giredestrant without LHRHa provides similar (non-inferior) anti-proliferative activity to giredestrant+LHRHa. Results would provide rationale for subsequent (neo)adjuvant clinical trials. Methods: PREcoopERA (NCT05896566) is a randomized, open-label, 3-arm, WOO trial evaluating the anti-proliferative activity and safety of the oral SERD giredestrant +/- LHRHa triptorelin, as compared to the AI anastrozole + triptorelin. Eligible are premenopausal women with untreated ER+/HER2- operable stage I-III (excl. T4) EBC, with Ki-67 ≥10%. 220 women will be randomized in 2:2:1 ratio to giredestrant (30 mg/d po for 4 weeks until rebiopsy) + triptorelin (3.75 mg IM on D1); giredestrant alone; or anastrozole (1 mg/d po) + triptorelin. Rebiopsy is planned for D29, either during primary surgery or standalone procedures. The primary endpoint is change in Ki-67 labeling index between pre-treatment diagnostic tumor biopsy and post-treatment rebiopsy, as assessed by the IBCSG Pathology Office. Sample size of 80:80:40 randomized women are planned to test superiority of 4 weeks giredestrant+triptorelin vs anastrozole+triptorelin to reduce Ki-67 (hypothesized percentage changes -80% vs -65%) and to test non-inferiority of 4 weeks giredestrant vs giredesrant+triptorelin (within 10% as non-inferiority margin). The trial was activated on 9 October 2023. The first woman was enrolled on 25 January 2024. Clinical trial information: NCT05896566 .

Combination of predicted sensitivity to endocrine therapy (SET2,3 index) and the Recurrence Score in node-positive breast cancer: Independent validation in the PACS-01 trial.

565 Background: SET2,3 index measures hormone receptor-related transcriptional activity (SETER/PR) adjusted for a baseline prognosis index (BPI) derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4). SET2,3 added prognostic information to the 21-gene Breast Recurrence Score (RS) in the SWOG 8814 trial (1). To confirm this, we independently evaluated both tests performed on node-positive, hormone receptor-positive (HR+) cancers from the PACS-01 trial (Roche et al, JCO 2006, PMID: 17116941) that evaluated the addition of adjuvant docetaxel to anthracycline-based chemotherapy. Adjuvant endocrine therapy became standard for premenopausal patients during PACS-01, justifying a sensitivity analysis in the population who received adjuvant endocrine therapy. Methods: SET2,3 was measured with the QuantiGene Plex bead-based hybridization assay (ThermoFisher) using an aliquot of residual RNA from prior RS testing in 791 HR+ tumor samples. Pre-defined cut points defined higher risk if RS &gt;25 or SET2,3 &lt;2.10. SETER/PR index and BPI, individual components of SET2,3 index, were evaluated as continuous variables. The primary endpoint was distant recurrence-free interval (DRFI). Multivariable Cox proportional hazards models were used to calculate hazard ratios with 95% confidence interval (HR, 95%CI) adjusted for treatment arm, and the likelihood ratio (LR) of benefit from addition of SET2,3 to RS with LR test for significance at p &lt;0.05. Results: Of 791 tumor samples, 760 (96.1%) passed quality control (QC) for the SET assay; 724 had pathologic information to calculate SET2,3 index; and 659 had results for RS and SET2,3. At a median follow-up of 8 years, distant recurrence occurred in 144 of 659 (21.9%) patients overall, and 94 of 490 (19.2%) patients in the sensitivity population. Overall, high RS status (HR 2.33, 1.60-3.39) and high SET2,3 (HR 0.43, 0.30-0.62) were independently prognostic. SET2,3 was high in 303/377 (80.4%) patients with RS ≤25, with 5-year DRFI of 93.7% [95%CI 90.2;95.9]; and SET2,3 was low in 171/282 (60.6%) patients with RS &gt;25, with 5-year DRFI 64.6% [95%CI 56.9;71.3]. SETER/PR index of endocrine transcriptional activity and the BPI, each contributed additional prognostic information to RS status in the sensitivity population (Table). Conclusions: SET2,3 index added prognostic information to the Recurrence Score in this independent blinded validation study of the PACS-01 trial for node-positive breast cancer. 1. Speers et al, JCO 2023, PMID: 36649570. [Table: see text]

Relevance of timing intake of everolimus (EVE) combined with adjuvant endocrine therapy (ET) in patients (pts) with high-risk early breast cancer: Results of a sub-study of the UCBG-UNIRAD trial.

542 Background: We reported the benefit of taking evening tamoxifen compared to morning/afternoon as adjuvant treatment for high-risk breast cancers in the UNIRAD phase III trial (NCT01805271) (1). Here, we examine the relevance of EVE timing intake in this trial. Methods: 1,277 pts with high-risk HR+/ HER2- primary BC were randomly assigned to adjuvant ET with placebo or EVE (1). Patients prospectively reported in a diary the daily timing for ET and EVE intake among four 6-h slots (06:00 to 11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The association between EVE, ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial. Results: EVE timing was recorded by 513 of 632 patients (81.2%). Patients declaring EVE intake in the morning (n= 248, 48 %) or in the afternoon (n=52, 10%) were older than those declaring evening (n=207, 40 %) or night (n=6,1%) intakes ( p&lt;0.001). They were more likely to be postmenopausal (p=0.001) and to take AI rather than tamoxifen (p = 0.03). Only 17 patients (3%) changed EVE intake timing throughout the study. EVE intake dialy times were binned into 2 categories for analyses: morning/afternoon group (n=300) and evening/night group (n = 213). The patients who took morning/afternoon EVE chose another timing for ET in 38% of the cases compared to 17.1% in evening/Night EVE group (p&lt;0.01). The timing of EVE intake was not significantly associated with definitive EVE withdrawal ( p=0.62) in the whole population. Time to EVE withdrawal was significantly longer in the patients taking tamoxifen rather than AI (17.2 vs 10.9 months, p = 0.0047). Prolonged duration of EVE treatment was associated with evening/night intakes of both EVE and tamoxifen, compared to other drug timing modalities (p = 0.04). With a median follow-up of 85months, 15 patients relapsed locally (3%), 55 developed metastases (11%), 36 patients died (7%). Overall, EVE intake timing was not associated with DFS (HR=0.84 [95% CI, 0.53 - 1.35], p=0.4). There was a significant interaction between EVE timing intake and ET type ( P interaction= 0.001). Patients on evening/night EVE combined with tamoxifen had a reduced likelihood of relapse compared to those taking morning/afternoon EVE (HR = 0.17 [0.05- 0.59], p = 0.005). In contrast, no significant EVE effect was found in the AI group (HR = 1.56 [0.92 2.64], p = 0.1). Evening/Night intake of EVE plus tamoxifen was independently associated with DFS (HR 0.13 [0.03-0.6], p = 0.002) after adjustment for age, nodal status, tumor size, ET timing intake, and EVE dose (2.5, 5 or 10 mg). Conclusions: These exploratory results are consistent with a role of circadian rhythm in the efficacy of EVE when given with tamoxifen in pts with high risk early breast cancer. 1. S. Giacchetti et al, Abst 546, ASCO 2023. Clinical trial information: NCT01805271 .

Retrospective observational study of patients with luminal breast cancer in early stages: 10-year follow-up—Which luminal breast cancer relapse?

e12586 Background: Luminal BC is a heterogeneous group of breast cancer (1), with molecular signatures of better prognoses and others of worse prognoses being found. Prosigna test provide the molecular BC subtype, an individualized prognostic score called “ROR score”. Our main objective is to analyze in 10 years which Luminal early BC patients have local and distant relapses. See if there is a correlation between ROR and relapse. As second objective is select this group of patients who relapse and analyze the presence of CAF S1 for a future study. Methods: We performed a retrospective observational study from the two main hospitals in Málaga (Spain) We included 415 women 43-79 years with EBC defined as T1 or T2 primary breast cancer &lt;30 mm in the largest dimension) node negative. Molecular BC subtype analyzed by IHC and genomic platform Prosigna) The patients were treated with breast-conserving surgery with clear excision margins hypofractionated radiotherapy and adjuvant endocrine therapy. We followed them from 2014 to the present. Results: 415 patients. We made genetic platform Prosigna to all of them luminal A 55%, Luminal B 37%, Basal like 4.8% and Her2 3.6%. The median follow-up was 9.1 years. The cumulative incidence of recurrence in Luminal BC was 2.29% (44.4% locoregional 55.55% distant recurrence). In 55.55% of the patients that relapsed had a Prosigna test with high ROR score, in 11.11% of the patients that relapsed had a Prosigna test with an intermediate ROR score and in 33.33 of the patients that relapsed had a Prosigna test with a low ROR score. Conclusions: In our study the cumulative incidence of recurrence in Luminal BC was 2.29 % and the ROR score provided a good estimate of the risk of relapse. Currently we use genomic platforms as Prosigna to estimate the ROR and adapt treatments to the risk. However, until now there is no biological or translational study focusing on T1N0 luminal BC. Subsequently, there exists a real need for new strategies to determine the long-term prognosis of these patients. We selected a group of patients to analyze the presence of CAF S1 fibroblast for a future study. Distant recurrence in T1N0 Luminal BC is strongly associated with the presence of CAF-S1 fibroblast The determination of CAF-S1 could more accurately predict recurrence in this subgroup of patients and could be a target for future treatments.

LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer.

1052 Background: Following promising outcomes in hormone receptor (HR)-positive, HER2-negative endocrine-resistant advanced breast cancer (BC) with lerociclib plus fulvestrant, this study assesses the efficacy and safety of lerociclib and letrozole in HR+/HER2- advanced or metastatic BC. Methods: This randomized, double-blind, placebo-controlled phase III study involved HR+/HER2- advanced or metastatic BC patients without prior systemic therapy for advanced disease. Participants were allocated 1:1 to either lerociclib (150mg twice daily) with letrozole or placebo with letrozole. The primary endpoint was progression-free survival (PFS) as assessed by investigators. Secondary endpoints included PFS (assessed by Blinded Independent Central Review (BICR)), response rates, overall survival (OS), and safety. The interim analysis was planned approximately 80 PFS events. Results: By September 20, 2023, 279 patients were randomized (137 to lerociclib + letrozole, 142 to placebo + letrozole), with a median follow-up of 12.91 months. Baseline characteristics were comparable across groups. At the data cutoff, 83 PFS events were reported. The lerociclib significantly improved PFS versus placebo (median: not reached (NR) versus 16.56 months; hazard ratio: 0.464; 95% CI: 0.293-0.733; p=0.0004). BICR analysis confirmed these results (median: NR versus NR; hazard ratio: 0.457; 95% CI: 0.274-0.761; p=0.0011). Subgroup benefits were consistent, including in patients with visceral metastases, extensive metastatic sites and previous (neo)adjuvant endocrine therapy, etc. For patients with measurable disease, lerociclib plus letrozole showed a higher objective response rate (62.3%) compared to placebo group (48.5%). OS data were immature at the cutoff. Adverse events were primarily hematological toxicity, with higher incidences of grade 3/4 neutropenia (grade 3: 41.6% vs. 0.7%; grade 4: 5.1% vs. 0%) and leucopenia (grade 3: 27.0% vs. 0%; grade 4: 1.5% vs. 0%) in the lerociclib group. All of neutropenia and leukopenia were considered to be treatment related. Grade 3 diarrhea was infrequent, only 1 case (0.7%) was reported in lerociclib group. QTc prolongation was reported comparable between lerociclib group (4.4%, Grade 3:1.5%) and placebo group (3.5%, Grade 3:0.7%). No venous thromboembolism was reported. Serious AEs were slightly higher in the lerociclib group (13.1% vs. 7.7%). Treatment discontinuation due to AEs was rare (1 patient [0.7%]) with lerociclib. Conclusions: Lerociclib with letrozole had an excellent safety profile and significantly prolonged PFS in HR+/HER2- advanced or metastatic BC patients. This benefit was consistent across all clinically relevant subgroups, suggesting lerociclib as a viable first-line therapeutic option with a favorable benefit-risk balance. Clinical trial information: CTR20212139; NCT05851014.

Association between PIK3CA mutations and disease-free survival in patients with HR+, HER2- tumors treated with adjuvant hormonal therapy: A real-world study in Croatia.

e12512 Background: Disease recurrence of early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one-quarter of patients with early disease will present with the disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene have a high prevalence of 30% to 40% in HR+/HER2- advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine this association and impact of PIK3CA mutation status on disease free survival (DFS) in HR+/ HER2- early breast cancer patients. Methods: We conducted a multicentric, retrospective cohort study in five Croatian institutions from July 2020 to December 2021. Study included initially early HR+/HER2- breast cancer patients who have been diagnosed with disease recurrence during adjuvant hormonal treatment or within first six years of follow up. The Cobas PIK3CA Mutation Testing Kit was used for real-time PCR-based amplification and mutation detection on the Cobas z 480 analyzer. We have analyzed differences in DFS from initiation of adjuvant endocrine therapy, using Cox, proportional hazard regression. Results: There was total of 186 patients, out of which 40.9% tested positive for the PIK3CA mutation. Primary and adjuvant treatment and in particular adjuvant endocrine treatment was similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with positive PIK3CA status and with H1047 PIK3CA mutation had significantly lower hazard for disease recurrence in comparison to patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p = 0.024; HR 6.52; 95% CI 1.15; 36.95; p = 0.034 respectively; false discovery rate, FDR &lt; 10%) and higher odds for late recurrence (p = 0.001, FDR &lt; 5%). Conclusions: This study highlights the potential impact of PIK3CA mutations on disease recurrence during/following adjuvant endocrine treatment and by that potentially opens the door for further investigation of possibly more personalized treatment strategies.