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Background: All intrinsic molecular subtypes are represented among HER2-positive breast cancer, with implications on clinical outcome and treatment sensitivity. The impact of molecular subtypes on the pattern and site of relapse is largely unexplored. Methods: 677 patients with HER2-positive early breast cancer from the Shorther trial (n=437), the CherLOB trial (n=84) and two Institutional cohorts (Istituto Oncologico Veneto IRCCS Padova n=39 and Hospital Clinic Barcelona n=117) were included. Only patients with available PAM50 intrinsic molecular subtyping were considered. We analyzed the incidence of distant relapse (at any site and at specific sites) as the first event. Cumulative incidence was estimated according to competing risk analysis (Fine and Gray’s method). Competing risk regression was used to calculate the subdistribution Hazard Ratios (subHR) and their 95% Confidence Interval (CI). Results: The distribution of molecular subtypes was: 130 LumA (19%), 75 LumB (11%), 347 HER2-e (51%), 46 Basal (7%), 79 Normal (12%). Median follow up was 8.4 years (95%CI 8.2-8.6). The 10-yr cumulative incidence rates of distant relapse as first event were: LumA 7.9%, LumB 14.8%, HER2-e 14.7%, Basal 15.5%, Normal 10.4% (HER2-e vs LumA: SubHR 2.21, 95%CI 1.05-4.64, p=0.037). Table 1 shows the 5-yr and 10-yr cumulative incidence rates of distant metastases at specific sites (as first event) according to intrinsic subtype. HER2-e enriched and Basal tumors were more prone as compared to other subtypes to develop brain and lung metastasis as first event, respectively. Isolated brain metastases without extracranial disease occurred only in patients with HER2-e tumors. All brain metastases as first event occurred within 5 years from diagnosis. Bone-only disease as first event was less frequent in HER2-e and Basal subtype (subHR HER2-e vs LumA: 0.32, 95%CI 0.10-10.4. p=0.058). Next, we analyzed the frequency of site-specific first metastasis among patients who experienced a distant metastasis as first event (n=77). Lung metastases were more frequent in Basal tumors (LumA 25.0%, LumB 20.0%, HER2-e 24.4%, Basal 71.4%, Normal 0.0%, p=0.037) and bone metastases were more frequent in Luminal tumors (LumA 100.0%, LumB 60.0%, HER2-e 31.1%, Basal 42.9%, Normal 57.1%, p=0.006). Among 45 HER2-e patients with a first distant relapse, 25.6% were diagnosed with a brain metastasis and 15.6% had brain-only disease. Conclusions: Molecular subtypes influence the metastatic behaviour of clinically HER2-positive breast cancer. These results, if further validated, may have implication in planning personalized monitoring strategies. Table 1. 5-yr and 10-yr cumulative incidence rates of distant metastasis at specific sites (as first event) according to intrinsic subtype. Citation Format: Maria Vittoria Dieci, Giancarlo Bisagni, Stefania Bartolini, Antonio Frassoldati, Daniele Giulio Generali, Federico Piacentini, Gaia Griguolo, Enrico Tagliafico, Fara Brasó-Maristany, Nuria Chic, Francesca Porra, Roberto Vicini, Roberto D’Amico, Sara Balduzzi, Aleix Prat, PierFranco Conte, Valentina Guarneri. Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts. [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 P2-11-12.

Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Baseline characteristics of the patients included (PIK3CA cohort) or not (no-PIK3CA cohort) in the PIK3CA analysis.

Purpose:We explored the prognostic effect of PIK3CA mutation in HER2+ patients enrolled in the ShortHER trial.Patients and Methods:The ShortHER trial randomized 1,253 patients with HER2+ breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform.Results:A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56–1.27; P = 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n = 232): 5-year DFS 91.8% versus 76.1% (log-rank P = 0.049; HR, 0.46; 95% CI, 0.21–1.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68–0.99; P = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65–0.99; P = 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53–0.99; P = 0.042 for MYBL2 expression).Conclusions:PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes.

Purpose:The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer is underexplored.Patients and Methods:The neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II–IIIA premenopausal patients with Luminal B (LumB)-like breast cancer (HR-positive/HER2-negative, Ki67 ≥ 20%, and/or histologic grade 3). Patients received: three 21-day cycles of epirubicin/cyclophosphamide followed by eight 14-day cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathologic complete response (pCR; ypT0/is, ypN0).Results:A pCR was achieved by 7/43 patients [16.3%; 95% confidence interval (CI), 7.4–34.9]; the rate of residual cancer burden class 0–I was 25.6%. pCR rate was significantly higher for patients with PAM50 Basal breast cancer (4/8, 50%) as compared with other subtypes (LumA 9.1%; LumB 8.3%; P = 0.017). Tumor-infiltrating lymphocytes (TIL), immune-related gene-expression signatures, and specific immune cell subpopulations by multiplex immunofluorescence were significantly associated with pCR. A combined score of Basal subtype and TILs had an AUC of 0.95 (95% CI, 0.89–1.00) for pCR prediction. According to multiplex immunofluorescence, a switch to a more immune-activated tumor microenvironment occurred following exposure to anthracyclines. Most common grade ≥3 treatment-related adverse events (AE) during nivolumab were γ-glutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all grades 1–2; including adrenal insufficiency, n = 1).Conclusions:Luminal B-like breast cancers with a Basal molecular subtype and/or a state of immune activation may respond to sequential anthracyclines and anti–PD-1. Our data generate hypotheses that, if validated, could guide immunotherapy development in this context.

Consort diagram of ShortHER patients for the different analyses described in the present work.

Supplementary Data from Neoadjuvant Chemotherapy and Immunotherapy in Luminal B-like Breast Cancer: Results of the Phase II GIADA Trial

IntroductionPatients with triple-negative breast cancer (TNBC) achieving a pathological complete response (pCR) after neoadjuvant chemotherapy have a better event-free survival. The role of gut microbiome in early TNBC is underexplored.MethodsMicrobiome was analyzed by 16SrRNA sequencing.ResultsTwenty-five patients with TNBC treated with neoadjuvant anthracycline/taxane-based chemotherapy were included. Fifty-six percent achieved a pCR. Fecal samples were collected before (t0), at 1 (t1), and 8 weeks (t2) from chemotherapy. Overall, 68/75 samples (90.7%) were suitable for microbiome analysis. At t0, pCR group showed a significantly higher α-diversity as compared with no-pCR, (P = .049). The PERMANOVA test on β-diversity highlighted a significant difference in terms of BMI (P = 0.039). Among patients with available matched samples at t0 and t1, no significant variation in microbiome composition was reported over time.ConclusionsFecal microbiome analysis in early TNBC is feasible and deserves further investigation in order to unravel its complex correlation with immunity and cancer.

Background We evaluated the impact of the type of endocrine therapy on disease-free survival (DFS) in patients with HR-positive/HER2-positive BC enrolled in the phase III ShortHER trial. Methods Short-HER randomized 1254 patients with HER2-positive early BC to 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI), or tamoxifen (TAM). The use of gonadotropin-releasing hormone analogues (GnRHa) was also collected. DFS was calculated from randomization to disease recurrence, second primary tumor, or death. Results 784 patients with HR-positive BC were included: 60.5% postmenopausal, median age 55 years. The pattern of endocrine therapy was: 59.6% AI, 23.8% TAM, 16.6% TAM-AI. At a median follow up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4% vs 79.7%, log-rank P = 0.013 (HR 1.52, 95%CI 1.09–2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07–2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤ 45 years (97% receiving TAM or TAM-AI), the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2% vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19–0.88). Conclusions In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in young premenopausal patients suggests benefit with ovarian suppression. Trial registration: NCI ClinicalTrials.gov number: NCT00629278. Registered 5 March 2008. Retrospectively registered (first patient in December 2007).

Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/mBetween April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred.Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer.

Background: Hormone-receptor (HR)+/HER2- breast cancer (BC) is a biologically heterogeneous disease. Homologous recombination deficiency (HRD) and BRCA mutations have been previously reported to be associated with worse outcomes in HR+/HER2- metastatic BC patients receiving CDK4/6 inhibitors and endocrine therapy. Here, we assess the relation between HRD and RB-loss signatures, intrinsic subtyping, the PAM50-based chemo-endocrine score, and response to chemotherapy-based therapy and endocrine treatment in HR+/HER2- early BC. Methods: GIADA is a multicentric neoadjuvant phase II trial that treated premenopausal patients with Luminal B (LumB)-like BC (HR-positive, HER2-negative, with Ki67>20% and/or histologic Grade 3) with a combination of chemotherapy, immunotherapy and endocrine treatment. Expression of 758 genes on baseline tumor samples from all 43 patients was quantified by nCounter platform. The LETLOB phase II trial randomized postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 out of 92 pts enrolled. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. A published HRD signature (Peng, Nat Commun 2014) and a signature of RB loss (RBsig), previously reported to potentially predict resistance to CDK4/6 inhibitors in HR+/HER2- BC (Malorni, Oncotarget 2016) were computed. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate chemosensitivity. Association between genomic signatures was assessed through Pearson’s correlation coefficient. Association of genomic signatures with pCR was assessed through logistic regression and association with PEPI scores was assessed through Kruskal-Wallis test. Results: HRD signature levels were significantly higher in non-luminal (Basal-like and HER2-enriched) tumors as compared to Luminal (A or B) tumors (p>0.001 in the GIADA trial, p=0.021 in the LETLOB trial). Moreover, higher levels of HRD signature were associated with higher levels of RB-loss signature (Pearson correlation 0.355, p=0.020 in the GIADA trial; Pearson correlation 0.942, p< 0.001 in the LETLOB trial), higher levels of Basal-like signature (Pearson correlation 0.502, p< 0.001 in the GIADA trial; Pearson correlation 0.373, p=0.002 in the LETLOB trial) and lower levels of CES (Pearson correlation -0.422, p=0.005 in the GIADA trial; Pearson correlation -0.763, p< 0.001 in the LETLOB trial), indicative of higher chemosensitivity. In the GIADA trial, higher levels of HRD signature (p=0.018) and RBloss signature (p=0.073) and lower levels of CES (p=0.007) were associated with higher pCR rates after chemo, endocrine and immunotherapy. In the LETLOB trial, lower levels of HRD signature (p=0.068) and RBloss signature (p=0.042) and higher levels of CES (p=0.050) were associated with higher sensitivity to endocrine treatment (lower PEPI scores, 0 vs 1-3 vs 4 or more, after neoadjuvant letrozole). Conclusions: In HR+/HER2- early BC, HRD gene signatures, RB-loss gene signatures and non-luminal (especially Basal-like) intrinsic subtyping are associated with each other and associated with higher sensitivity to chemotherapy-based therapy and lower sensitivity to endocrine treatment. These observations might help correctly tailor systemic therapy, including biologic agents, in patients with HR+/HER2- early and advanced BC. Citation Format: Gaia Griguolo, Federica Miglietta, Laia Paré, Daniele G. Generali, Antonio Frassoldati, Antonino Musolino, Simon Spazzapan, Grazia Vernaci, Tommaso Giarratano, Marcello Lo Mele, Giancarlo Bisagni, Federico Piacentini, Enrico Tagliafico, Katia Cagossi, Francesca Schiavi, Claudia Pinato, Aleix Prat, Valentina Guarneri, Maria Vittoria Dieci. Homologous recombination deficiency, RB-loss gene signatures, intrinsic subtype and response to neoadjuvant treatment in HR+/HER2- early breast cancer: a correlative analysis of two phase II trials [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 P4-02-13.

Introduction: More than 2 years after the WHO declaration of a pandemic, SARS-Cov-2 still represents a public health problem The pandemic has increased the complexity of cancer treatments including breast cancer. These difficulties were highlighted in adjuvant treatments but above all in metastatic disease. Vaccination has been one of the most important public health factors that has reduced deaths, hospitalizations and the severity of symptoms related to infection. In metastatic breast cancer hormone receptor positive and HER2/neu negative currently the first line of treatment is given by the association between cyclin 4/6 inhibitors and hormone therapy (aromatase inhibitors or fulvestrant) A well-known and frequent side effect of this therapy is the reduction of white blood cell values and neutrophils. The hypothesis that this study is to evaluate whether treatment with cyclin inhibitors initiated before the period of vaccinations may have influenced, due to the reduction in white blood cell values, an increased risk of infection in these patients. Materials and methods: In our study, we selected patients who had started treatment with cyclin inhibitors before starting the vaccination cycle (in Italy up to the fourth dose in cancer patients) and continue it without evidence of disease progression. All patients were offered a vaccination cycle with mRNA COVID vaccines and were followed during their cancer treatments. All patients, at least 90 days after the last dose of vaccine, have been tested for antibodies against SARS CoV-2 (trimeric spike protein) with a value expressed in binding antibodies unit (BAU) according to international standard WHO During the observation period (starting from the first dose of vaccine administered) the patients were clinically checked and in case of suspicion of infectious pathology with symptoms suggestive of SARS-COV-19 infection, they were tested with molecular swab Results: We evaluated 52 patients who started cyclin treatment before the vaccination course and who are currently without signs of disease recurrence During the study period we found 14 SARS-COV19 infections (28% of patients) and one patient with two infectious episodes. No patients needed treatment in a hospital or resuscitation setting. All patients have fully recovered from the infection and at most after 21 days have resumed the treatment still in place Statistically, a linear regression calculation was applied to evaluate a functional relationship between variables measured on the basis of sample data. We did not find a relationship between spikes or infections compared to the start date of the vaccination cycle; instead we observed a relationship between the value of the spike and the date of last immunization (considered as an active infection or fourth dose of vaccine) with a reduction in the values the further you go away Conclusion: The data of the study show that there is a correlation between the time elapsed between the last vaccination and the risk of getting sick. For this reason, the fourth recall represents a strong help to reduce this risk. We did not find any ranges we could refer to regarding the dosage of trimeric spike protein. Considering the positivity rate of infections that does not exceed the general vaccinated population and the absence of serious infectious symptoms with hospitalization, treatment with cyclin inhibitors appears to be a safe treatment even in a pandemic period. Last day immunization and spike with IA or fulvestrant Last day immunization and spike with IA or fulvestrant Citation Format: Filippo Giovanardi, Edoardo Carretto, Giancarlo Bisagni, Claudia Degli Esposti, Elisa Gasparini, Alessandra Bologna, Roberto Di Cicilia, Gabriella Moretti, Carmine Pinto. Cyclin-dependent kinase 4/6 inhibitor in advanced breast cancer during the COVID pandemic period: efficacy in relation to vaccination for SARS-COV 19 [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 P3-03-04.

547 Background: Optimal adjuvant endocrine therapy for HER2+/HR+ patients treated with chemotherapy and trastuzumab is still unclear. We evaluated the impact of the type of endocrine therapy on DFS in patients with HER2+/HR+ breast cancer enrolled in the phase III ShortHER trial. Methods: The Short-HER study randomized 1254 patients with HER2+ early breast cancer to receive 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected every 6 months during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI, in case of both drugs were administered for at least 1 year each), or tamoxifen (TAM). For premenopausal patients, the use of GnRH analogue was also collected. DFS was calculated from randomization to disease recurrence (locoregional or metastatic), second primary invasive cancer, or death. Results: 853 patients with HR+ BC (ER and/or PgR >10%) were included: 60% postmenopausal, 40% premenopausal. The pattern of endocrine therapy was: 55% AI, 22% TAM, 15% TAM-AI (8% missing data). Among premenopausal patients, 51% received GnRH. At a median follow up of 8.7 years (IQR 7.6-9.0), patients who received AI had a significantly better DFS as compared to patients who received TAM or TAM-AI: 7-yr DFS 87.3% vs 81.7%, log-rank P=0.017 (HR 1.46, 95%CI 1.05-2.03). In multivariate analysis including menopausal status, stage, and treatment arm, the type of endocrine therapy maintained a significant association with DFS (Table). In the subgroup of premenopausal patients, the use of GnRH was associated with numerically improved DFS: 86.6% vs 81.6%, log-rank P=0.168 (HR=0.70, 95%CI 0.43-1.16). Conclusions: In this post-hoc analysis of the ShortHER trial, adjuvant treatment with aromatase inhibitor was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests potential benefit with ovarian suppression. Clinical trial information: NCT00629278. [Table: see text]