Duration Of Adjuvant Endocrine Therapy Research Articles

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.

Fine-Tuning Adjuvant Endocrine Therapy for Early-Stage Breast Cancer: An Expert Consensus on Open Issues for Future Research.

After decades of research, improving the efficacy of adjuvant endocrine therapy (ET) for early-stage breast cancer becomes increasingly difficult. Beyond technological breakthroughs and the availability of new classes of drugs, further improvement of adjuvant ET will require applying a rigorous research approach in poorly investigated areas. We critically discuss some key principles that should inform future research to improve ET efficacy, including identifying specific subgroups of patients who can benefit from escalating or de-escalating approaches, optimizing available and new treatment strategies for different clinical contexts, and dissecting the direct and indirect biological effects of therapeutic interventions. Four main issues regarding adjuvant ET were identified as relevant areas, where a better application of such principles can provide positive results in the near future: (i) tailoring the optimal duration of adjuvant ET, (ii) optimizing ovarian function suppression for premenopausal women, (iii) dissecting the biological effects of estrogen receptor manipulation, and (iv) refining the selection of patients to candidate for treatments escalation.

Abstract P1-04-09: Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence between Breast Cancer Index (BCI) and 21-gene Oncotype DX Recurrence Score (RS)

Abstract Background: The 21-gene Recurrence Score (Oncotype DX) is a genomic assay that provides prognostic information for distant recurrence risk and is predictive of adjuvant chemotherapy benefit in hormone receptor (HR)-positive, HER-2 negative early-stage breast cancer (EBC). The Breast Cancer Index (BCI) is another molecular gene expression-based assay that evaluates the utility of extending adjuvant endocrine therapy (ET) from 5 to 10 years and predicts risk of distant recurrence. In January 2021, the National Comprehensive Cancer Network (NCCN) Guidelines added BCI to guide duration of adjuvant ET as a category 2A recommendation. The goal of this study was to evaluate the association between BCI and RS in terms of their predicted benefit for adjuvant therapy and risk of distant recurrence. We also assessed the association of various anatomic and biologic tumor features with BCI. Methods: We performed a retrospective chart review of all patients with HR-positive EBC who had a BCI and Oncotype DX performed between 2007-2021. Demographics, tumor characteristics and BCI and RS results were extracted from the electronic medical record. Patients were categorized by BCI predictive of extended ET (formerly BCI high) versus not (formerly BCI low) and RS of low (0-10), intermediate (11-25) and high (26-100). Numerical values for distant recurrence risk were recorded for both BCI and Oncotype DX tests. Multivariable regression models were used to assess the relationship between BCI and Oncotype DX as well as factors associated with each. Results: We identified 153 women with HR-positive EBC with both RS and BCI performed. The median age of the population was 57 years and 25% were premenopausal. 32% (n=49) had a BCI result predictive of benefit from extended adjuvant ET. When comparing patients with BCI predictive of extended ET versus those with BCI not predictive of extended ET, there was no association between BCI and RS based on multivariate logistic regression models, p=0.7. A similar distribution of RS was observed between patients who had a BCI result predictive of benefit from extended ET versus not predictive. Among 49 patients with a BCI predictive of extended ET, 35% had high RS, 63% intermediate RS and 2% low RS. Among 104 patients with a BCI not predictive of extended ET, 24%, 73% and 3% had high, intermediate, and low RS, respectively. Multivariate regression models revealed an association between poorly differentiated tumors and BCI result predictive of extended ET, p=0.002. No associations were observed between BCI and menopausal status, ER%, PR%, tumor size or lymph node positivity. Regarding risk of recurrence, there was an association between BCI and Oncotype DX in terms of their predicted numerical risk of recurrence, p< 0.001. Higher percentage of PR positivity, poorly differentiated tumors, and lymph node positivity were associated with a higher risk of recurrence on the BCI. Conclusions: In our patient population selected to have Oncotype DX and BCI performed, we found no association between the two genomic assays in terms of their predictive benefit. However, there was an association between Oncotype DX and BCI in terms of their prognostic ability. Given the increased use of BCI since its inclusion in national guidelines, it is important to understand its relationship with other genomic assays especially when used to guide clinical decisions and estimate prognosis. Citation Format: Rima Patel, Nicole Casasanta, Zhiqiang Li, Melanie Kier, Julia Blanter, Sophie Sohval, Malin Hovstadius, Catherine Wu, Marc Fink, Xiang Zhou, Brittney Zimmerman, Krystal Cascetta, Rong Chen, William Oh, Amy Tiersten. Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence between Breast Cancer Index (BCI) and 21-gene Oncotype DX Recurrence Score (RS) [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 P1-04-09.

Abstract P1-07-08: Prediction of breast cancer late recurrence according to Clinical Treatment Score post-five years (CTS5) and progesterone receptor in a wider patient population

Abstract Background The duration of adjuvant endocrine therapy remains a continuous challenge in hormone-receptor positive (HR+) early breast cancer. The Clinical Treatment Score post-five years (CTS5) is an online model used to predict late distant metastasis for women with HR+ breast cancer who are recurrence-free 5 years after endocrine therapy (ET). It incorporates patients age, tumor size, grade, and number of positive lymph nodes, and is an important tool to help in this treatment decision. There is a paucity of data in premenopausal women and whether other variables could add additional information. Methods A single-center retrospective analysis of patients that have received adjuvant ET for 5 years, between January 2007 and December 2008 at the Instituto Nacional de Cancer (INCA), Brazil. Disease-Free Survival (DFS) was compared between the low, intermediate, and high-risk subgroups. Data analysis was descriptive and exploratory. Kaplan-Meier estimates and Cox regression models were used. Results A total of 183 patients were enrolled, 26.5% being premenopausal. Median age at diagnosis was 66 years. Tumor stage: I (44%) and II (56%). ET consisted of tamoxifen (88%), anastrozol (6%), and a switch (6%). There were 39.5%, 39.5% and 21% of patients in the low, intermediate, and high-risk (L/I/H) subgroups, respectively. Progesterone-receptor was ≥ 20% in 71% of tumors and in 55%, 49% and 34% in the L/I/H subgroups, respectively. Median follow up was 88.9 months. After 5 years, the median DFS was 100%, 96.3% and 68.2% in L/I/H subgroups (p < 0,001). Progesterone-receptor was also an independent prognostic factor for late recurrence (p < 0,05). Conclusion CTS5 performed well in a wider patient population including premenopausal women. Progesterone-receptor was an independent prognostic factor for DFS and should be further considered into the model. Citation Format: Giselle S. Carvalho, GUSTAVO O. BRETAS, Daniel Musse, Victor Gondim, José Bines. Prediction of breast cancer late recurrence according to Clinical Treatment Score post-five years (CTS5) and progesterone receptor in a wider patient population [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 P1-07-08.

Abstract 515: Single-cell transcriptomic analysis of HR+/HER2- breast cancer identifies gene signatures that predict outcomes of luminal A and B subtypes

Abstract Introduction: Patients with luminal A and B early-stage ER+/HER2- breast cancer (BrCa) are uniformly treated with adjuvant endocrine therapy (ET) (±chemotherapy). A better understanding of drivers of ET resistance is required as subsequent lethal metastatic disease remains a major clinical problem. Therefore, there is an unmet clinical need to identify biomarkers that select low- and high-risk patients who may benefit from de-escalation of current treatments or alternative therapeutic interventions. In the present study, we hypothesized that while luminal A and B tumors both arise from normal hormone-responsive cells, they are transcriptionally distinct, hence allowing the identification of unique gene signatures that can predict outcomes in each subtype. Methods: Tumors from 10 early-stage ER+/HER2- BrCa patients were subjected to single-cell RNA-sequencing (scRNA-seq) analysis (10X Genomics); 6/10 tumors were classified as luminal A and 4/10 as luminal B based on combined PAM50 and immunohistochemical classification (Ki67 cut-off=20%). We performed a direct transcriptional comparison between luminal A and B tumors, using well-established signatures and unbiased differential gene expression analysis. To identify unique luminal A and B tumor-specific genes, we compared the gene expression profile of each luminal subtype with 10 non-neoplastic breast tissues. A predictive model (LASSO) was applied to select genes with the highest frequency using a training dataset. This resulted in 5- and 4-gene signatures for luminal A and B, respectively, which were used to calculate risk scores that divided each subtype into low- and high-risk groups. The prognostic value of the above signatures was validated in an independent dataset. Results: The integrated scRNA-seq analysis of luminal A and B tumors revealed transcriptionally distinct tumor cell clusters while tumor microenvironment (TME) clusters were well intermixed. Luminal B tumors had higher cell cycle and BrCa-specific scores, low ER pathway-gene expression scores, and increased 8q amplifications. IFNγ, OXPHOS, p53, hypoxia and MYC targets were the most upregulated pathways in the luminal B subtype. The TME of luminal B tumors was comprised of lower CD4+ and CD8+ T cell but higher Treg levels. Comparison with normal breast tissues revealed that early-stage ER+ BrCa arises from hormone-responsive epithelial cells and provided a number of tumor-specific genes that were used to generate prognostic signatures. These signatures were capable of differentiating high- from low-risk patients within each subtype and predicting survival outcomes in two large-scale training and validation cohorts. Conclusions: We developed a novel prognostic tool that can be used to determine duration of adjuvant ET and/or new therapeutic strategies for high-risk luminal A and B patients in the early-stage ER+/HER2- setting. Citation Format: Sofia Mastoraki, Jerome Lin, Xiayu Rao, Sophie R. Liu, Harsh Batra, Maria G. Raso, Edwin R. Parra Cuentas, Akshara S. Raghavendra, Komal S. Rasaputra, Min Yi, Jing Wang, Aysegul Sahin, Debasish Tripathy, Kelly K. Hunt, Nicholas E. Navin, Khandan Keyomarsi. Single-cell transcriptomic analysis of HR+/HER2- breast cancer identifies gene signatures that predict outcomes of luminal A and B subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 515.

Real-world assessment of quality-of-life in patients with breast cancer treated with adjuvant endocrine therapy.

Objective: The aim of this study was to investigate quality-of-life (QoL) in breast cancer (BC) patients treated with adjuvant endocrine therapy (AET). Methods: Wedesigned a cross-sectional study of 233 BC patients treated with AET andused the Functional Assessment of Cancer Therapy - Breast questionnaire. Results: No significant difference was observed between endocrine agents. Duration of AET did not affect QoL. In the entire cohort, multivariate analysis determined age (p=0.034) and switching treatment from tamoxifen to aromatase inhibitors (p=0.049) as significant positive coefficients of QoL, while comorbidity (p=0.072) tended to be associated with lower scores. Education level (p=0.001) and chemotherapy (p=0.04) were significant predictors of QoL in the tamoxifen group, while comorbidity (p=0.04), surgery type (p=0.02), radiotherapy (p=0.006) and stage (p=0.009) had a significant impact on QoL in aromatase inhibitors group. Conclusion: Evaluating the well-being of BC patients by QoL questionnaires is of great importance to identify particular subgroups that may require supportive care.

Physicians’ acceptance of extended or intermittent adjuvant endocrine therapy (AET): A survey on breast cancer (BC) physicians.

e12515 Background: The results from the GIM4, SALSA, and SOLE trials are potentially practice-changing, but it was unknown whether physicians would accept these trial results and adjust their AET prescriptions for postmenopausal women with BC. Methods: A cross-sectional survey involving 77 BC physicians in China was conducted. The survey questions were developed based on the GIM4, SALSA, and SOLE trial results, as well as referred to the latest NCCN guidelines. Statistical analyses were performed using SPSS version 28.0. Results: Almost half (48%) of the respondents were breast surgeons, 19% were breast specialists, 8% were medical oncologists, and 2% were general surgeons. Forty-five percent of the respondents had a clinical experience of ≥15 years, and the mean ± SD number of BC patients managed annually was 762.10 ± 1,254.50. For pN0, tumor size ≤0.5cm, postmenopausal patients, respondents with ≥15 years of clinical experience were more likely to prescribe a longer duration of AET as compared to those with <15 of clinical experience (p=0.025 and p=0.038 for patients receiving prior 4-5 years of tamoxifen [TAM] and prior 5 years of aromatase inhibitor [AI], respectively). More than half (57.1%) did not agree with the hypothesis that AI resistance can be reversed by intermittent letrozole treatment (the SOLE trial hypothesis), but 50.6% considered intermittent letrozole as an acceptable option, especially for patients with ≤3 positive nodes (79.5%), tumor grade 1 (84.6%), tumor size ≤2cm (82.1%), HER2 negative disease (74.4%). Conclusions: A high proportion of the BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal women with BC, especially for those with higher risk. Intermittent letrozole was considered as an acceptable option for low-risk patients.[Table: see text]

Who Needs Extended Endocrine Therapy for HR+ Breast Cancer?

For patients with hormone receptor–positive (HR+) breast cancer, the recommended duration of adjuvant endocrine therapy ranges from 5 to 10 years. For

Molecular Assays to Determine Optimal Duration of Adjuvant Endocrine Therapy in Breast Cancer.

Hormone receptor (HR) positive breast cancer has a high propensity for late recurrences that might be prevented with longer durations of endocrine therapy (ET). However, trials evaluating extended adjuvant ET have produced somewhat conflicting results. Additionally, ET is associated with not only day to day side effects that can impact quality of life, but more detrimental effects that can cause significant morbidity. Although patients with higher stage disease are at greater risk of late recurrences, even patients with stage 1 disease have a significant risk of recurrence after 5years. Current guidelines recommend extending therapy for patients with node-positive disease, but recommendations for patients with node-negative disease are less clear. This has led to the development of various genomic tests to aid oncologists in further individualizing their approach when it comes to deciding which subpopulation of patients with HR-positive breast cancer may benefit from extending their endocrine therapy beyond 5years. There are several assays that are prognostic of recurrences years 6 to 10 following diagnosis. Additionally, the breast cancer index has been shown to be predictive of extended ET in patients who have completed 5years of tamoxifen. None of the available assays are, to date, predictive of recurrence after 10years. Genomic testing is not appropriate for all patients, especially if the results will not predict the choice of further treatment. Ultimately, genomic testing should help facilitate shared decision making between the patient and oncologist.

Adjuvant endocrine treatment for estrogen receptor (ER)-positive/HER2-negative breast cancer.

Approximately 70% of women with breast cancer worldwide receive a diagnosis of ER-positive/ HER2-negative disease. Recurrence-free survival of the node-negative population of these women is approximately 85%, and most are treated with endocrine chemotherapy. Endocrine treatment for ERpositive/HER2-negative early breast cancer is a major treatment strategy. Breast cancer clinicians have gained much experience with this issue, but new data regarding adjuvant endocrine therapy have recently been accumulated. In the integrated analyses of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials, the addition of ovarian function suppression (OFS) to tamoxifen showed a significant improvement in both 8-year disease-free survival [hazard ratio (HR) 0.76, 95% confidence interval (CI): 0.62-0.93] and overall survival (HR 0.67, 95% CI: 0.48-0.92) compared with tamoxifen alone for premenopausal patients with breast cancer, with the assumption of 5 years as an appropriate duration for OFS. The ATLAS trial showed that, compared with 5 years of tamoxifen, 10 years of tamoxifen provided further benefit to women with HR-positive early breast cancer in recurrence [5-9 years: rate ratio (RR) 0.90, 95% CI: 0.79-1.07; ≥10 years: RR 0.75, 95% CI: 0.62-0.90; and all years: log-rank P=0.002] and breast cancer mortality (5-9 years: RR 0.97, 95% CI: 0.79-1.18; ≥10 years: RR 0.71, 95% CI: 0.58-0.88; and all years: log-rank P=0.01), particularly after reaching 10 years, which is considered a "carry over" benefit. In this review, adjuvant endocrine treatment for ER-positive/HER2-negative early breast cancer is discussed. Particular areas of focus are premenopausal patients, especially regarding the addition of OFS, postmenopausal patients, the duration of adjuvant endocrine therapy, the treatment implications of multigene expression assays, and adjuvant endocrine therapy for ductal carcinoma in situ. Some of this evidence supports the clinical management of breast cancer patients as well as clinical studies in the future.

Abstract P2-11-02: Breast Cancer Index predicts benefit from extended endocrine therapy in HR+ breast cancer

Abstract Background: Optimizing the duration of adjuvant endocrine therapy in patients diagnosed with early stage hormone receptor-positive (HR+) breast cancer requires improved approaches to individualize disease profile and to reduce any unnecessary treatment burden for patients. Current clinical practice guidelines recommend 10 years of adjuvant endocrine therapy for most patients unless there are characteristics of low risk disease. However, approximately 2/3rds of patients have favorable long-term outcomes after completing 5 years of adjuvant therapy. Therefore, consideration of the risk-benefit profile for each patient is critical to identify who may be spared extended endocrine therapy (EET) and its associated toxicities, and which patients will benefit from an additional 5 years of endocrine therapy. The Breast Cancer Index (BCI) is a gene expression-based signature that stratifies patients based on the risk of overall (0-10y) and late (post-5y) distant recurrence (DR) and predicted the likelihood of benefit from extended endocrine therapy in MA.17. The translational-aTTom (Trans-aTTom) study is a multi-institutional, prospective-retrospective study to validate the predictive ability of BCI by HOXB13/IL17BR (H/I) status for EET benefit in early stage HR+, N0 and N+ breast cancer. Methods: Patients treated in the aTTom (Adjuvant Tamoxifen - To Offer More?) trial with available primary tumor tissue were eligible. Biospecimens were retrospectively collected from aTTom study sites and centrally assessed for ER, PR and HER2 status. Median follow-up was 12.6 years. Primary and secondary endpoints were recurrence-free interval (RFI) and disease-free interval (DFI), respectively. Statistical significance level was set at 0.0336 as per statistical analysis plan. Weighted Kaplan-Meier and Cox proportional hazards regression analysis with time-varying coefficients were used to test the predictive activity of BCI by HOXB13/IL17BR (H/I) status (High vs Low). Likelihood ratio test based on Cox regression was used to evaluate treatment by biomarker interaction. Results: Archived tumor specimens from 3328 patients were collected across 62 aTTom trial sites, representing 48% of the parent trial population. Central testing and assessment of ER, PR, HER2, and BCI resulted in 2445 HR+ patients (1367 N0, 789 N+, 289 nodal status unknown) in the overall cohort. At final analysis, the study remained underpowered for evaluating BCI predictive performance in the overall cohort due to an observed limited effect size that was smaller than planned and did not recapitulate the parent aTTom trial. However, evaluation of BCI predictive performance in the updated N+ subset (N=789) showed that patients classified as BCI(H/I)-High (N=404, 51%) experienced a statistically significant benefit from 10y vs 5y of tamoxifen (9.7% RFI: HR=0.33 [95% CI 0.14-0.75]; P=0.016), whereas those classified as BCI(H/I)-Low showed no significant benefit (-1.2% RFI; HR=1.11 [95% CI 0.76-1.64]; P=0.58). A statistically significant interaction between continuous BCI(H/I) and treatment was demonstrated (P = 0.036) adjusted for age, tumor size and grade, whereas no significant interaction was observed between treatment and quantitative ER (P=0.939) or PR (P=0.138) expression. Conclusion: BCI by high H/I expression was predictive of endocrine response and identified a subset of HR+, N+ patients with significant benefit from 10 vs. 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, for BCI as a predictive biomarker of benefit from extended endocrine therapy. Findings from the Trans-aTTom strengthen the clinical validity of BCI for prediction of endocrine response and its clinical utility in optimizing duration of endocrine therapy. Citation Format: John Bartlett, Dennis Sgori, Kai Treuner, Yi Zhang, Tammy Piper, Ranelle Shalunga, Ikhlaaq Ahmed, Lucy Doos, Sarah Thornber, Elena Brachtel, Sarah Pirrie, Catherine Schnabel, Daniel Rea. Breast Cancer Index predicts benefit from extended endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-02.

Abstract P4-01-16: Detection of plasma tumor DNA (ptDNA) in patients with hormone receptor-positive HER2-negative (HR+HER2-) early breast cancer (EBC) in clinical remission

Abstract Background: Detection of ptDNA in patients with HR+HER2- EBC in clinical remission may impact recommendations for type and duration of adjuvant endocrine therapy. A sensitive technique to identify tumor mutations in plasma is BEAMing digital PCR. The frequency and timing of detectable mutations in plasma of patients in clinical remission from HR+HER2- EBC are unknown. Methods: We screened a prospective institutional repository for patients that met inclusion criteria. Eligible patients must have been enrolled to the repository between 12/1/2008 (repository start) and 12/31/2016, had HR+HER2- EBC, received follow-up at Johns Hopkins with appointment scheduled between 3/1/2017 and 12/31/2017, completed curative surgery at least 6 months prior to this appointment, been recommended or initiated adjuvant endocrine therapy, and been in clinical remission. Appropriate patients were approached for a current blood sample during their follow-up appointment in 2017. Blood was analyzed using a BEAMing digital PCR platform (Sysmex Inostics OncoBEAM™) for AKT1, PIK3CA, and ESR1 mutations. Results: We identified 67 eligible patients and collected blood from 60. Most patients had relatively low risk disease including 40 patients (67%) with stage I disease, and only 21 patients (35%) received chemotherapy. Patients were evenly divided between receiving tamoxifen or an aromatase inhibitor, and some patients switched from one to the other. The majority of patients (68%) had surgery between 1 and 5 years prior to the current blood draw. Detailed patient characteristics are provided in Table 1. Two out of the 60 patients had detectable ptDNA, both with stage IIA disease. One patient had a mutation in the ESR1 ligand-binding domain P535H 9 months after surgery and while taking adjuvant tamoxifen for 7 months. Sanger sequencing of primary tumor tissue did not reveal this mutation. Another patient had a mutation in PIK3CA exon 9 E542K 9.5 years after surgery and after taking adjuvant tamoxifen for at least 7 years. Amplifying this locus in DNA from primary tumor tissue was unsuccessful; further analysis using droplet digital PCR (ddPCR) is planned. Conclusions: Detection of ptDNA was feasible in a relatively low-risk group of patients with HR+HER2- EBC in clinical remission. Sampling a larger number of patients is needed to gain more understanding of the frequency and timing of detectable ptDNA. Next steps should also focus on determining the natural history of detectable ptDNA in patients with HR+HER2 EBC in clinical remission which may impact adjuvant treatment recommendations. Funding sources: Komen SAC110053, P30 CA06973, Breast Cancer Research Foundation Table 1:Characteristics of included patients N (%)Total patients60Age at diagnosis, median(range)57 (30-77)Female59 (98)Caucasian54 (90)Postmenopausal at diagnosis36 (60)Tumor size <2 cm42 (70)Node negative45 (75)Invasive ductal histology44 (73)Received adjuvant chemotherapy21 (35)Type of adjuvant endocrine therapy Tamoxifen25 (42)Aromatase inhibitor26 (43)Tamoxifen and AI7 (12)None2 (3)Time after surgery 6 months to <1 year6 (10)1 year to <5 years41 (68)5 years to <10 years13 (22) Citation Format: Shah M, Hunter N, Ensminger J, Shinn D, Cole AJ, Quinn HE, Edelstein DL, Wang C, Smith KL, Richardson AL, Cimino-Mathews A, Wolff AC, Cravero K, Park BH, Stearns V. Detection of plasma tumor DNA (ptDNA) in patients with hormone receptor-positive HER2-negative (HR+HER2-) early breast cancer (EBC) in clinical remission [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-01-16.

Abstract P4-13-09: Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy

Abstract Background:It is unclear how to define responsiveness to endocrine therapy (ET) during the clinical course of advanced breast cancer (ABC), especially in evaluation of the effect of sequential ET. Objective:The goal of the study was to evaluate the efficacy of second line treatment of physician's choice (2nd-line TPC) for estrogen receptor-positive (ER+) and HER2-negative postmenopausal ABC with very low or low sensitivity to initial ET. Methods:A multicenter prospective observational cohort study was performed for 2nd-line TPCs. ABC with low sensitivity to initial ET was defined as recurrence within 5 years (yrs) during adjuvant ET or progression within 9 months (mo.) of initial ET. Similarly, ABC with very low sensitivity to initial ET was defined as recurrence within 2 yrs during adjuvant ET or progression within 3 mo. of initial ET. The expected clinical benefit rate (CBR: defined as patients who achieved CR, PR or SD for 24 weeks) was 50%. The null hypothesis of a CBR of 30% was tested with a one-sided α of 5%. 90% confidence intervals (CIs) were calculated for hypothesis tests. Results: A total of 56 patients (pts) were enrolled, but 7 were ineligible and one discontinued before starting the protocol treatment. The median age was 66 yrs (range: 41-88) and the median BMI was 23.4 kg/m2 (16.4-31.9). All pts were ER+ and 80% were PgR+. Most of pts had a baseline PS of 0 or 1, 90% had invasive ductal carcinoma, and 10% had invasive lobular carcinoma. Postoperative recurrence was detected in 84% and these pts had a median duration of adjuvant ET of 30.5 mo. (5.3-58.9). De novo stage IV ABC was present in 16%, with a median duration of first-line ET of 5 mo. (2.3-10.8). Adjuvant chemotherapy including anthracycline- and/or a taxane-containing regimen was administered in 58% (29/49). As adjuvant ET before initial recurrence, 34 pts received non-steroidal aromatase inhibitors (AIs) (88.0%), 1 received a steroidal AI (2.3%), and 3 received a selective estrogen receptor modulator (SERM). As first line ET in de novo stage IV, 7 pts (14%) were treated with AIs or a SERM (1 case). 2nd-line TPCs were also used, with 40 pts receiving fulvestrant (82%), 5 receiving SERMs (10%), 3 receiving a mTOR inhibitor plus a steroidal AI (6%), and one patient receiving an AI alone. The overall CBR was 44.9% (90% CI: 34.6-57.6, p=0.009), and CBR was similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2, p=0.0016; very low sensitivity group: n=17, 58.8%, 90% CI: 42.0-78.8, p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175). However, there were not statistically significant CBR in PgR- (n=10, 20.0%, 90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI; 29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6, p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072). The median PFS was 7.1 mo. (95% CI: 5.6-10.6). Conclusion:This study shows that 2nd line ETs was effective and might be a valid option in the sequence of treatments for postmenopausal women with ABC with low sensitivity to initial ET. It was suggested that PgR and visceral metastasis were significant predictive factors for CBR. Citation Format: Araki K, Fujisawa T, Sakamaki K, Kikawa Y, Iwamoto T, Sangai T, Shien T, Takao S, Nishimura R, Takahashi M, Aihara T, Mukai H, Taira N. Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-09.

Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer.

Women with early-stage oestrogen receptor (ER)-positive (ER+) breast cancer who receive standard endocrine therapy for 5 years remain at risk of distant recurrence for at least 15 years after treatment discontinuation. The extension of the duration of adjuvant endocrine therapy to 10 years has been shown to reduce the risk of recurrence only in a subset of women and, to date, predictive biomarkers of benefit from therapy do not exist. In this Review, we briefly explore the epidemiology of late recurrence (>5 years after diagnosis) in patients with ER+ breast cancer. The mechanisms underlying this phenomenon remain poorly understood; we discuss the evidence currently available on processes such as alterations of gene expression or specific genomic aberrations and examine several models used for risk prognostication and for estimating the presence of minimal residual disease, as well as the relevance of these prediction tools for clinicians and patients. Our aim is to enable clinicians to make well-informed decisions on whether to extend endocrine therapy for each individual patient.

Practical consensus recommendations on duration of adjuvant hormonal therapy in breast cancer.

Optimization of adjuvant systemic therapy in women with early-stage hormone receptor-positive breast cancer includes the consideration of chemotherapy and duration of hormone therapy. Adjuvant hormonal therapy significantly improves long-term survival of breast cancer patients with hormone receptor-positive disease. Despite the proven clinical efficacy of tamoxifen and aromatase inhibitors, many breast cancer survivors either fail to take the correct dosage at the prescribed frequency (adherence) or discontinue therapy (persistence). Expert oncologist discussed on the duration of adjuvant hormonal therapy for improvement of OS and quality of life of breast cancer patients by providing reduction in recurrence and mortality. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

Abstract CS1-2: Searching for the optimal duration of adjuvant endocrine therapy in breast cancer

Abstract Endocrine therapy is an integral part of the adjuvant systemic management of women with early stage hormone receptor-positive breast cancer. Adjuvant endocrine therpay is associated with significant improvements in disease-free and overall survival. Several adjuvant endocrine therapy approaches are available to women based on their menopausal status, disease stage, tumor characteristics, co-morbidities, and individual preferences. The optimal duration of adjuvant endocrine therapy established to date is 5 to 10 years. Extended adjuvant endocrine therpay provides only a modest additional benefit compared to a 5-year treatment duration. Studies reported in recent years offer some guidance to help clinicians provide recommendations regarding the type and duration of adjuvant endocrine therpay. Clinicians must weigh treatment benefits and potential adverse events for individual patients. Models to help individualize treatment recommendations are needed. Several opportunities are available to predict personalized risk of recurrence and likelihood of developing bothersome symptoms or serious adverse events. Women should have a close follow up with their physicians during the first year or therapy to identify emerging symptoms and to provide early interventions to optimize adherence to adjuvant endocrine therpay. Clinicians should engage in continuous discussion with each woman regarding the duration of treatment most appropriate for her and revisit recommendations based on evolving clinical trial results or events in the patient's life. In this presentation I will discuss the available data regarding optimal length of adjuvant endocrine therapy. I will review expected benefits and toxicities. I will also discuss emerging biomarkers and approaches that may help individualize treatment duration for women with hormone receptor-positive breast cancer. Citation Format: Stearns V. Searching for the optimal duration of adjuvant endocrine therapy in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr CS1-2.

ER-Positive Breast Cancer Remains a Long-Term Concern

The optimal duration of adjuvant endocrine therapy for early-stage, estrogen receptor–positive (ER+) breast cancer — long believed to be 5 years — is

Optimal duration of adjuvant endocrine therapy: how to apply the newest data.

Background:The benefit of 5 years of adjuvant endocrine therapy for women with hormone receptor-positive (HR+) breast cancer (BC) is beyond discussion. Nevertheless, the risk of recurrence of luminal BC persists for 15 years or more after diagnosis. Consequently, approaches of extended adjuvant therapy have been investigated in large clinical trials, with the ultimate aim of further reducing the risk of recurrence in patients with HR+ BC.Methods:A review of recently published trial data is presented to provide a solid basis for discussion. A discussion of the side effects of long-term endocrine treatment, multigenetic tests aiming to identify patients at particular risk, and an outlook for further promising targets are additional aims of this review.Conclusion:Extended adjuvant therapy seems beneficial in reducing distant relapse and contralateral BC for a selected group of patients with HR+ BC, particularly if aromatase inhibitors (AIs) are used after initial tamoxifen therapy. However, patients with lower risk of recurrence and initial AI therapy may suffer more from side effects than benefit from extended therapy.

Searching for the IDEAL Duration of Adjuvant Endocrine Therapy.

Searching for the IDEAL Duration of Adjuvant Endocrine Therapy.

Standard and Genomic Tools for Decision Support in Breast Cancer Treatment.

Over the past few decades, comprehensive characterization of the cancer genome has elucidated pathways that drive cancer and mechanisms of resistance to therapy and provided important insights for development of new therapies. These advances have resulted in the development of prognostic and predictive tools for use in clinical settings, which can assist clinicians and patients in making informed decisions about the benefits of established therapies. In early-stage breast cancer, multiparameter genomic assays are now available for decision making about the duration of adjuvant endocrine therapy and the use of adjuvant chemotherapy. Similarly, in metastatic disease, there are multiple commercially available next-generation sequencing options for identifying genetic alterations in tumors that may be targeted with a drug. Although these tools hold great promise for providing precision medicine, it can be difficult for the treating physician to evaluate their clinical utility and appropriately select tools for individual clinical situations. This review summarizes the currently available genomic tools in breast cancer, the data underlying their clinical validity and utility, and how they can be used in conjunction with standard clinicopathologic data for making adjuvant and metastatic treatment decisions.