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Endocrine therapy has undergone major changes in the past few years, and is no longer a “one-size-fits-all” prescription. This article discussed some of the new developments and directions.

Locoregional recurrence risk and the role of locoregional radiation therapy (LRRT) in pN0(i+) and pN1mi breast cancer are unclear. This study compares locoregional relapse-free survival (LRRFS) in patients with pN0(i+) and pN1mi relative to pN0 and pN1a disease and evaluates LRRFS according to locoregional treatment.We studied 10,271 patients referred between 2006 and 2011 with newly diagnosed pT1-T2, pN0, pN0(i+), pN1mi, or pN1a, M0 breast cancer. Outcomes were 10-year Kaplan-Meier LRRFS, relapse-free survival (RFS), distant relapse-free survival, and breast cancer-specific survival. Multivariable analysis of LRRFS and RFS was performed in pN0(i+) and pN1mi cohorts.Median follow-up was 9.3 years. In patients with pN0 (n = 7492), pN0(i+) (n = 305), pN1mi (n = 619), and pN1a (n = 1855) disease, LRRT was used in 1.1%, 24.3%, 45.7%, and 71.1%, respectively. Ten-year outcomes were LRRFS 96%, 92%, 97%, and 96% (P.001), distant RFS 94%, 91%, 90%, and 84% (P.001), and breast cancer-specific survival 95%, 90%, 93%, and 87% (P.001), respectively. Ten-year LRRFS for patients treated with breast-conserving surgery alone, with breast RT, and with LRRT were 81%, 93%, and 91% for patients with pN0(i+) (P = .16) and 94%, 96%, and 100% for patients with pN1mi (P = .02), respectively. Among patients treated with mastectomy, 10-year LRRFS with surgery alone and with LRRT were 93% and 100% for patients with pN0(i+) (P = .12) and 95% and 99% for patients with pN1mi (P = .09). On multivariable analysis of patients with pN0(i+) and pN1mi, systemic therapy was associated with improved LRRFS in patients with pN0(i+) (hazard ratio [HR], 0.2; [0.06-0.6]; P = .005) and patients with pN1mi (HR, 0.1; [0.03-0.5]; P = .006). In patients with pN1mi, LRRT was associated with a trend toward increased LRRFS (HR, 0.2; [0.03-1.1]; P = .07). LRRT was not significantly associated with improved RFS in pN0(i+) or pN1mi disease.In the era of sentinel node staging and modern systemic therapy, patients with pN0(i+) and PN1mi treated with LRRT experienced 10-year LRR risks ≤10% after breast-conserving surgery or mastectomy and RT. LRRT was associated with a trend toward increased LRRFS in pN1mi but not pN0(i+) disease.

Table S5: Data from this study have been submitted to the European Genome-Phenome Archive (EGA) (www.ebi.ac.uk/ega/home) under the study accession number EGAS00001001159. This table provides the accession numbers for each dataset included in this study.

Supplementary Figures S1-S5. Supplementary Tables S1-S5. Figure S1. Comparison of SNV mutation signatures across histological and molecular subtypes. Figure S2. Treatment timelines and radiographic outcomes. Figure S3. Mutation signature stability metrics and comparisons to known signatures. Figure S4. Structural variant mutation sigantures. Figure S5. Comparison of mutation burden between aging-driven and non-aging-driven breast tumours. Table S1. Kruskal-Wallis tests. Table S2. HRDetect prediction test metrics. Table S3. Area under the curve of HRD signatures in platinum response prediction. Table S4. Logistic regression model odds ratios of clinical improvement on platinum. Table S5. Accession IDs of genome datasets submitted to the European Genome-Phenome Archive.

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.

Purpose Higher energy (>6 MV) photons reduce dose inhomogeneity with breast tangent beams, thereby reducing late breast toxicity, but skin and superficial tissue sparing by higher energy beams raises concerns about local recurrence (LR) risk. This study aimed to determine whether beam energy and surgical bed-to-skin distance affect LR. Methods and Materials This population-based study included newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with breast-conserving surgery and adjuvant whole breast radiotherapy without bolus or beam spoilers. The primary endpoint was the cumulative incidence of LR (CILR). A multivariable analysis (MVA) included mean beam energy, age, T-stage, nodal status, overall stage, lymphovascular invasion (LVI), grade, margin status, extensive intraductal component (EIC), breast cancer subtype, hormone therapy and chemotherapy. In a subgroup with contoured surgical beds, another MVA included surgical bed-to-skin distance. Results The cohort consisted of 10,083 women treated from 2002 to 2011, 327 with 4MV, 6,006 with 6 MV, 2,083 with >6-10 MV and 1,667 with >10 MV tangents. The median follow-up time was 11.1 years. The 10-year CILR was 3.1% [95% confidence interval 1.6,5.4] with 4 MV, 2.8% [2.4,3.3] with 6 MV, 4.2% [3.4,5.3] with >6-10 MV and 2.6% [1.9,3.5] with >10 MV. On MVA of the entire cohort, LR risk was increased with positive margins, LVI, EIC, and lack of hormone therapy, but was not associated with beam energy (HR = 1.01 [0.96,1.05], p = 0.8). On MVA of 3,359 patients with contoured surgical beds, LR risk was not associated with surgical bed-to-skin distance (HR = 1.00 [0.99,1.02], p = 0.8). Conclusions Use of higher breast tangent beam energies is not associated with increased risk of local recurrence, including in cases with surgical beds that are close to the skin.

Randomized clinical trials have shown that regional nodal irradiation (RNI) in patients with unselected N1 breast cancer improves breast cancer-specific survival. However, the benefit of RNI in women with biologically low-risk N1 breast cancer is uncertain. We conducted a population-based study to determine whether RNI is associated with improved breast cancer recurrence-free interval (BCRFI) in this population.Patients aged 40 to 79 years with pT1-2 pN1 (node-positive) breast cancer diagnosed between 2005 and 2014 were identified. The inclusion criteria were modeled off of the TAILOR RT study, which is a randomized noninferiority clinical trial designed to assess the value of RNI in patients with low-risk N1 disease. Eligible patients had breast-conserving surgery or mastectomy and axillary lymph node dissection with 1 to 3 positive nodes, breast-conserving surgery and sentinel lymph node biopsy with 1 to 2 positive nodes, or mastectomy and sentinel lymph node biopsy with 1 positive node. Additionally, patients had luminal A breast cancers, as approximated by estrogen receptor positive (Allred 6-8/8), progesterone receptor (PR) positive (Allred 6-8/8), human epidermal growth factor receptor 2-negative, and grade 1 to 2 immunohistochemical testing. All patients were prescribed hormonal treatment. The primary endpoint of BCRFI, the time to any breast cancer recurrence or breast cancer-related death, was analyzed using a multivariate competing risks analysis.The cohort included 1169 women with a median follow-up of 9.2 years. Radiation treatments were not performed in 151 women treated with mastectomy alone, were delivered to the breast only in 133 women, and were delivered locoregionally in 885 women. Patients undergoing RNI were younger (median age: 58 vs 62 years), more likely to have 2 to 3 macroscopic lymph nodes involved, and more often received chemotherapy (all P.05). The 10-year estimate of BCRFI was 90% without RNI versus 90% with RNI (P = .5). On multivariable analysis, RNI was not a significant predictor of BCRFI (hazard ratio: 1.0; P = .9).In this retrospective analysis, RNI was not associated with improved BCRFI for women with biologically low-risk N1 breast cancer. We advocate accrual to the ongoing TAILOR RT study.

Background: Chemotherapy (CTx) and hormone therapy may impair fertility in women with breast cancer (BC) by direct gonadotoxicity or delayed childbearing. Inconsistent data regarding the safety and efficacy of ovarian stimulation for fertility preservation (FP) in BC may limit clinician referral and patient uptake of FP. We previously examined the effect of FP on BC recurrence and herein present updated survival and pregnancy outcomes in relation to FP from an expanded BC cohort. Methods: Women aged ≤ 40 years diagnosed with stage I-III BC between 2007-2018 referred to one of six cancer centres and to a reproductive endocrinologist in British Columbia, Canada were identified from a central database. Clinicopathologic, treatment and outcome characteristics were compared using uni/multivariate Cox and logistic regression analyses for survival and pregnancy outcomes, respectively, for patients who did and did not undergo FP prior to systemic cancer treatment. Results: 158 patients were identified. Sixty-four (41%) had lymph node involvement, 119 (75%) had ER-positive and 39 (25%) had HER2-positive BC. The 72 (46%) patients who underwent FP were more likely to be younger (mean age 33 vs 34 y, p=0.030), ECOG 0 (p=0.013), have CTx (p0.05). After a median follow-up of 4.7 years, BC recurrence occurred in 15 (17%) non-FP patients and 9 (13%) FP patients (Table 1). FP did not affect overall survival by univariate (HR 0.9; 95% CI 0.7-1.3) or multivariate analysis controlling for age, BMI, ECOG/ER/HER2 status, tumor stage and receipt of CTx or radiation (HR 1.0, 95% CI 0.7-1.4). Post-diagnosis, 22 (31%) FP patients and 11 (13%) non-FP patients had ≥ 1 pregnancy (Table 2). The use of assisted reproductive technology (ART) was similar in both groups. Patients who had FP were 2.8 times more likely (p=0.013) to conceive at least once. The results remained significant on multivariate analysis controlling for age, BMI, ECOG status and baseline parity (p=0.030). Non-FP patients had a 31% higher miscarriage rate than those who did (p=0.26). Conclusions: FP was not associated with an increased risk of locoregional recurrence, distant recurrence or death over a follow-up period of 3-11 years, supporting its safety in young women with BC. Despite more often receiving CTx, patients who underwent FP were significantly more likely to conceive after BC than those who did not, even when accounting for differences in patient profiles. This may relate to greater use of GnRH agonists during CTx, known to protect ovarian function, and stronger desires for future childbearing in patients who pursued FP. Although there was similar use of ART in both groups, the higher pregnancy rate and more successful reproductive outcomes in FP patients support the value and promotion of pre-oncologic treatment FP in young BC patients early in their disease trajectory, to enhance survivorship family planning. Table 1.Survival outcomes of patients.CharacteristicNo FP (n=86)FP (n=72)p-valueRecurred [n (%)]0.85Locoregional6 (7)4 (6)Distant9 (10)5 (7)Deceased [n (%)]8 (9)4 (6)0.38 Table 2.Characteristics of first pregnancies in patients conceiving after diagnosis.CharacteristicNo FP (n=11)FP (n=21)p-valuePregnancy outcome [n (%)]0.26Completed3 (27)11 (52)Miscarriage7 (64)7 (33)Ongoing1 (9)3 (14)Pregnancy interval from diagnosis [n (%)]0.29≤ 2 y04 (19)2-5 y8 (73)13 (62)> 5 y3 (27)4 (19)Type of conception [n (%)]0.52Natural9 (82)15 (71)Assisted2 (18)6 (29) Citation Format: Megan E Tesch, Ying Wang, Chloe Lim, Ying Hui Xu, Shaina Lee, Kirstin Perdrizet, Dan Yokom, Ellen Warner, Jeffrey Roberts, Caroline Lohrisch. Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes [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 P4-11-08.

INTRODUCTION:. Local and systemic treatments for breast cancer have evolved in the past decades. This study reports the development of a modern population-based nomogram to individualize local recurrence (LR) risk estimates for patients treated with breast conservation surgery (BCS). The magnitude of benefit of adjuvant breast radiotherapy (BRT) depends on individual patient, tumor, and treatment characteristics (1). Nomograms can provide accurate predictions of LR and the absolute LR benefit of BRT that can assist patients in making informed decisions regarding BRT. This nomogram is based on a large cohort of women with prospectively captured biomarker data and modern systemic therapies including anti-human epidermal growth factor receptor 2 (HER2) therapy. METHOD:. Study Population:. The study cohort included women treated curatively for newly diagnosed breast cancer between 1st January 2005 and 31st December 2014. Inclusion criteria were: age >16 years, invasive ductal or lobular carcinoma, stage I-III, and BCS. Patients with metastatic disease, prior or synchronous contralateral breast cancer, unknown tumor or treatment characteristics, or treated with neoadjuvant therapy or mastectomy were excluded. Nomogram Development and Validation:. Age, tumor size, number of positive lymph nodes, grade, margin status, lymphovascular invasion (LVI), extensive intraductal component (EIC), estrogen receptor (ER), progesterone receptor (PR), HER2 status, use of chemotherapy, hormonal therapy, and radiotherapy with or without boost were recorded for each patient. The endpoint was LR as the first event. Fine and Gray’s competing risk model, with distant recurrence and death as competing risks, was used for the multivariable analysis, adjusting for demographics, tumor, and treatment factors. Hazard ratio (HR) and 95% confidence interval (CI) for each variable were calculated. The multivariable model forms the basis for the nomogram, which is being internally validated using the bootstrap and cross-validation. RESULTS:Of 11,310 patients, there were 429 LR (crude risk = 3.8%). The HR and 95% CIs from the Fine and Gray model for each of the variables in the nomogram are presented in the table. Age, number of positive nodes, grade, ER, LVI, margins, hormone therapy, chemotherapy, and radiotherapy were independent prognostic factors for LR. For patients treated with RT, the predicted 10-year cumulative incidence of LR ranged from 2.4% in patients with low-risk disease to 12.5% in patients with high-risk disease. CONCLUSION:A new nomogram for local recurrence, based on patients who had ER/PR/HER2 testing and who received modern systemic therapies is being developed. It will assist clinicians and patients individualize estimates of local recurrence risk and improve shared decision-making regarding the use of BRT in contemporary practice. REFERENCES:. (1)Sanghani, M., et al J Clin Oncol.,2010; 28(5), 718-722. Cox regression hazard ratios and confidence intervals for variablesCharacteristicHR95%CIp-valueAge0.980.970.99 Citation Format: Dylan Narinesingh, Alan Nichol, Pauline Truong, Lovedeep Gondara, Caroline Speers, Laveniya Kugathasan, Caroline Lohrisch, Dave Voduc, Nafisha Lalani. Bc cancer ipsilateral breast tumor recurrence (BCC IBTR) nomogram [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 P4-07-04.

Purpose The use of the 21-gene Recurrence Score (RS) assay is emerging in node-positive estrogen receptor (ER)+ HER2-negative breast cancer (BC), particularly as initial data from the RxPONDER trial are now available. We investigated the impact of the RS result on adjuvant treatment decisions in such patients. Patients and Methods This prospective, multi-center study enrolled patients with ER+, HER2-negative BC and 1 to 3 positive nodes (microscopic [N1mi] or macroscopic [N1]). Treating oncologists documented treatment recommendations/plan before and after knowing the RS result. Sample size was determined assuming an overall treatment change rate (from chemohormonal therapy [CHT] to hormone therapy [HT] and vice-versa) of ≥30%. Results The study included 84 patients across 5 regional cancer centers, of whom 82 underwent 21-gene testing (77%, N1 disease; 63% grade 2 tumors). Of the RS-tested patients, 60%, 33%, and 7% had RS 0 to 17, 18 to 30, and 31 to 100, respectively. In 43 patients (52%), treatment changed post-RS: 40 patients (49%) from CHT to HT and 3 patients (4%) from HT to CHT. The net change was a 45% reduction in chemotherapy use. Treatment recommendation changes were consistent with the RS result. In RS 0 to 17 patients, the only documented change was from CHT to HT (27 patients). In RS 18-30 patients, change was noted in both directions (CHT-to-HT, 13 patients; HT-to-CHT, 3 patients). No treatment change was reported for the RS 31 to 100 patients, all of whom were recommended CHT pre-testing. Conclusion Our results support the clinical utility of the RS assay in ER+ HER2-negative BC with 1 to 3 positive nodes.

Purpose Bolus use during postmastectomy radiation therapy doubles the risk of grade 2 and 3 skin toxicity. Despite its unknown benefit, bolus is often prescribed during postmastectomy radiation therapy for patients without skin involvement. Methods and Materials For women with breast cancer receiving photon 3-dimensional conformal radiation therapy, bolus was used routinely for chest walls but was omitted for breast reconstructions by about half of radiation oncologists from 2007 to 2011. Eligible patients had newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with adjuvant or neoadjuvant radiation therapy. For the bolus and no-bolus groups, we compared the cumulative incidence of local recurrence (LR) and locoregional recurrence (LRR) with distant recurrence and death as competing risks and breast cancer mortality (BCM). Multivariable analysis of LR and BCM included stage, subtype, lymphovascular invasion, grade, margin status, beam energy, bolus use, hormone therapy, chemotherapy, and reconstruction. Results Systemic therapy was used for 98% of the 1887 patients. The bolus group had 1569 patients and the no-bolus group had 318 patients. Bolus was used in 51% (281/550) of patients treated with reconstruction and 96% (1288/1337) of patients treated without reconstruction. The 10-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: LR 1.9% (1.3-2.7) versus 0.9% (0.3-2.6), LRR 3.1% (2.3-4.0) versus 3.2% (1.6-5.5), and BCM 19.4% (17.3-21.6) versus 18.3% (13.9-23.2). On multivariable analysis, bolus use was not associated with better LR (hazard ratio = 1.4 [0.3-6.4]) or BCM (hazard ratio = 0.8 [0.5-1.2]). Conclusions For patients treated with mastectomy, radiation therapy, and modern systemic therapy, the cumulative incidence of LR was low, with or without bolus. Because bolus use increases toxicity and does not reduce LR or BCM, it should no longer be used routinely for patients without skin involvement who receive systemic therapy.

The SSO Choosing Wisely campaign recommended selective sentinel lymph node biopsy (SLNB) in clinically node-negative women aged ≥ 70 years with ER+ breast cancer. We sought to assess the association of SLNB positivity, adjuvant treatment, and survival in a population-based cohort. Women aged ≥ 70 years treated for ER+ HER2− breast cancer between 2010 and 2016 were identified in our prospective provincial database. Overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Kaplan–Meier analysis. Multivariable logistic regression was used to assess the association of SLNB positivity with use of adjuvant treatments and survival outcomes. We identified 2662 patients who met study criteria. SLNB was positive in 25%. Increased use of chemotherapy (ChT), hormone therapy (HT), and radiotherapy (RT) was significantly associated with SLNB positivity. Five-year OS was 86%, and BCSS was 96% with median follow-up of 4.3 years. BCSS was worse with grade 3 disease (HR 4.1, 95% CI 2.1–8.1, p < 0.0001) and better with HT (HR 0.5 95% CI 0.3–0.9, p = 0.01). Patients with a positive SLNB treated without adjuvant therapy had lower BCSS (HR 3.2 95% CI 1.2–8.4, p = 0.017) than those with a negative SLNB, but patients with a positive SLNB treated with any combination of ChT, HT, and/or RT, had similar BCSS to those with a negative SLNB. BCSS in this population was excellent at 96%, and BCSS was similar with negative and positive SLNB when patients received HT. SLNB can be omitted in elderly patients willing to take HT.

Background: Developed with retrospective data, the 21-gene recurrence score assay (RS) reduces adjuvant chemotherapy (CTx) use in hormone-positive (HR+), HER2-negative, node-negative breast cancer, justifying the assay’s cost. The TAILORx trial prospectively confirmed the predictive value of RS and established thresholds for CTx benefit in younger and older patients. We examined CTx use in British Columbia (BC) following TAILORx publication, as a prelude to exploring age-adjusted cost effectiveness of the assay. Methods: We assembled 3 cohorts of patients with HR+, HER2-negative, node-negative breast cancer: diagnosed before RS funding (cohort 1: January 1, 2013-December 31, 2013), after introduction of public funding (cohort 2: July 1, 2015-June 30, 2016), and after TAILORx results (cohort 3: July 1, 2018-June 30, 2019). Patients aged 18-80 years with tumors that were grade 3, grade 2 T1b or larger, or any T size and grade if ≤ 40 years of age were included, matching BC funding criteria. Previous in situ or invasive breast cancer cases were excluded. CTx use by age and RS was compared between cohorts using univariate analyses. Results: 2,066 patients met inclusion criteria (Table 1). CTx use in cohorts 1, 2, and 3 was 21%, 17%, and 13%, respectively. In cohorts 2 plus 3, CTx use was 30% for patients up to 50 years of age and 11% for patients over 50 years of age. Baseline characteristics were balanced, except grade 3 histology (24%, 25%, 17% in cohorts 1, 2, 3, respectively; p=0.01). RS was ≥ 26 in 33% of grade 3 and 34% of PR negative tumors. CTx use declined by 19% after RS funding was introduced and by another 23% after TAILORx publication (p=0.001). Reduction in CTx use was significant for RS 11-20 tumors (cohort 3 vs. 2, p=0.004). A 7.5% nonsignificant increase in CTx was seen for RS 26-30 tumors (cohort 2 vs. 3, p=0.55). There was no significant change in CTx use in patients aged > 50 years (12% in cohort 2 vs. 10% in cohort 3, p=0.22). Among patients aged 70-80 years in cohort 3 with RS, 5% had RS ≥ 26, and of these, 40% had CTx (9% of patients in this age group), compared with 92% CTx use for patients aged ≤ 50 years with RS ≥ 26 (15% of patients in this age group). Conclusions: CTx use decreased after TAILORx publication, particularly for RS 11-20 tumors. CTx use changed less in patients over 50 years old, suggesting that trial results confirmed pre-existing prescribing practices. CTx use increased in patients with RS 26-30 tumors, reflecting acceptance of the new threshold for CTx benefit established by TAILORx. CTx use was low overall in patients aged > 50 years, especially in those aged 70-80 years, in part due to the very low frequency of high RS tumors. Given these findings, we conclude that cost effectiveness modelling for publicly funded RS should take age into consideration. Table 1: Receipt of adjuvant chemotherapy (CTx) by 21-gene recurrence score (RS) result before assay availability (cohort 1), after assay availability (cohort 2), and after TAILORx publication (cohort 3) in patients (pts) aged ≤ 50 (a) and 51-80 years (b).a)Age≤ 50, n = 423Cohort123No. of pts who received CTx / No. of pts in group (%)RS not done51/105 (48.6)28/56 (50)1/6 (16.7)RS ≤ 101/5 (20.0)0/17 (0)1/25 (4.0)RS 11-201/8 (12.5)4/52 (7.7)2/67 (3.0)RS 21-251/3 (33.3)8/17 (47.1)10/20 (50.0)RS 26-300/0 (0)5/5 (100)5/5 (100)RS ≥ 312/2 (100)10/11 (90.9)17/19 (89.5)Entire cohort56/123 (45.5)55/158 (34.8)36/142 (25.4)b)Age51-80, n = 1643Cohort123No. of pts who received CTx / No. of pts in group (%)RS not done72/494 (14.6)25/279 (9.0)2/86 (2.3)RS ≤ 100/6 (0)0/60 (0)0/110 (0)RS 11-202/11 (18.2)5/126 (4.0)0/198 (0)RS 21-252/5 (40.0)6/56 (10.7)2/64 (3.1)RS 26-302/3 (66.7)5/20 (25.0)14/35 (40.0)RS ≥ 312/2 (100)31/40 (77.5)37/48 (77.1)Entire cohort80/521 (15.4)72/581 (12.4)55/541 (10.2) Citation Format: Megan Tesch, Caroline Speers, Rekha Manhas Diocee, Alan Nichol, Caroline Lohrisch. Impact of TAILORx data on chemotherapy prescribing in British Columbia [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-26.

Purpose This study evaluated long-term, population-based, breast cancer–specific outcomes in patients treated with radiation therapy (RT) to the breast/chest wall plus regional nodes using hypofractionated (HF) (40-42.5 Gy/16 fractions) versus conventionally fractionated (CF) regimens (50-50.4 Gy/25-28 fractions). Methods and Materials A prospective provincial database was used to identify patients with lymph node–positive breast cancer treated with curative-intent breast/chest wall + regional nodal RT from 1998 to 2010. The effect of RT fractionation on locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and breast cancer–specific survival (BCSS) was assessed for the entire cohort and for high-risk subgroups: grade 3, ER–/HER2–, HER2+, and ≥4 positive nodes. Multivariable analysis and 2:1 case-match comparison of HF versus CF were also performed. Results A total of 5487 patients met the inclusion criteria (4006 HF and 1481 CF). Median age was 55 years, and median follow-up was 12.7 years. On multivariable analysis, no statistically significant differences were identified in 10-year LRRFS (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.59-1.27; P = .46), DRFS (HR 0.90; 95% CI, 0.76-1.06; P = .19), or BCSS (HR 0.92; 95% CI, 0.76-1.10; P = .36) between the HF and CF cohorts. There was no statistical difference in breast cancer–specific outcomes in the high-risk subgroups. On analysis of 2962 HF cases matched to 1481 CF controls, no statistical difference was observed in LRRFS (HR 0.98; 95% CI, 0.71-1.33; P = .87), DRFS (HR 0.97; 95% CI, 0.85-1.11; P = .68), or BCSS (HR 1.00; 95% CI, 0.87-1.16; P = .92). Conclusions This large, population-based analysis with long-term follow-up after locoregional RT demonstrated that modest HF provides similar breast cancer–specific outcomes compared with CF. HF is an effective option for patients with stage I to III breast cancer receiving nodal RT.

Data guiding radiotherapy (RT) decisions after neoadjuvant chemotherapy (NAC) is largely retrospective, based on older treatment approaches without molecular subtype information. This study evaluated outcomes in breast cancer patients treated with modern NAC by molecular subtype and locoregional treatment.There were 949 patients diagnosed between 2005 and 2016 treated with NAC followed by surgery ± locoregional radiotherapy (LRRT). Outcomes were 7-year locoregional relapse-free survival (LRRFS), breast cancer-specific survival (BCSS), and overall survival (OS).Median follow-up was 6.5 years, 92% had cT2-4 and 72% cN1-3 disease. Subtypes were: 21% Luminal A, 18% Luminal B, 35% Her2+, and 21% triple-negative breast cancer (TNBC). Combined taxane and anthracycline-based NAC was used in 91.7% of cases. All patients with Her2+ disease received anti-Her2 therapy. After NAC, the majority (84.9%) underwent mastectomy, and received LRRT (86.1%). Only 11% had mastectomy without RT. Pathologic complete response (pCR) rates were 2.5% for Luminal A, 14.4% Luminal B, 27% TNBC, and 35.1% Her2+. Overall, adjuvant LRRT was associated with improved outcomes but was most significant for improved LRRFS in TNBC (92.5% vs. 68.5%, P.001; Her2+ 95.4% vs. 93.6%, P = .81; Luminal A 97.4% vs. 100%, P = .49; Luminal B 89.7% vs. 100%, P = .17). On multivariable analysis, factors associated with reduced LRRFS were grade 3 histology (HR 4.96, P = .009) and no pCR (HR 7.0, P = .0008). Predictors of lower BCSS and OS were age50, grade 3, cT3-4, lack of pCR, LRRT omission, and TNBC and Her2+ subtypes.In this analysis of patients treated with modern NAC, pCR rates varied by molecular subtype. Patients who did not receive LRRT, particularly those with TNBC, had lower survival compared to those treated with LRRT. These findings support the need for prospective studies to evaluate the safety of de-escalating RT after NAC.

A breast cancer synoptic operative report was developed using a modified Delphi process METHODS: Data from the British Columbia Cancer Breast Cancer Outcomes Unit (BCOU) was used to analyze the association between the completion of a synoptic operative report and reporting of operative details and The American Society of Breast Surgeons quality indicators.3662 patients had surgery for breast cancer by 185 surgeons. 2281 reports were narrative and 1007 synoptic. Requested surgical details were more commonly reported with synoptic reports for both posterior (96 vs 58%, p 0.0001) and anterior margins (96 vs 5%, p 0.0001). This was true for high and low volume surgeons. Quality Indicators were higher in those cases with an associated synoptic report for high and low volume surgeons.Communication of operative details is improved with synoptic reporting. Investment in platforms to facilitate synoptic reporting could improve patient care through improved multidisciplinary communication.

Background: While it is well recognized that ER positivity is predictive of response to endocrine therapy for patients with early-stage breast cancer (EBC), the method to assess ER level has evolved over time. The applicability of early trial data to clinical practice using contemporary methods of assessment is unclear. Clinical trials of hormone therapy, which inform clinical practice, do not correlate the ER level of positivity to the magnitude of benefit. Given that most newly diagnosed EBCs are ER positive, it is important to determine if the level of ER positivity as determined by current IHC methodology and scoring systems affect the frequency, time and pattern of relapse in patients with low, moderate or high ER positivity. Methods: The BC Cancer Breast Cancer Outcomes Unit (BCOU) database was utilized to identify patients with EBC referred to BC Cancer from 2005-2014. Baseline clinical, pathological and treatment criteria were compiled. Patients were divided into 3 groups, defined as “ER low” (Allred 3-4 OR IHC 1), “ER moderate” (Allred 5-6 OR IHC 2) or “ER high” (Allred 7-8 OR IHC 3). Event-free survival (EFS) was compared across the 3 groups using Kaplan-Meier survival curves in univariate and multivariate models. Key secondary endpoints included breast-cancer specific survival (BCSS) and overall survival (OS). Additional secondary endpoints included local-regional free survival (LRFS) and distant-disease-free survival (DDFS) and sites of relapse. Results: A total of 14,260 patients met the inclusion criteria consisting of 492 (3.5%) ER low, 1,088 (7.7%) ER moderate and 12,613 (88.9%) ER high patients. Median age was 55yrs (24-91) in the ER low, 53yrs (23-92) in the ER moderate and 61yrs (22-99) in the ER high groups (p Citation Format: Nathalie LeVasseur, Kaylie-Anne Willemsma, Caroline Lohrisch, Lovedeep Gondara, Caroline Speers, Christine Simmons, Alan Nichol, Karen Gelmon. Impact of ER-positivity on time and pattern of relapse in early-stage breast cancer patients [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 P3-08-04.

BACKGROUND The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined. METHODS The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx. RESULTS Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed. CONCLUSIONS TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing. LAY SUMMARY The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group.

Purpose Mammographic density is an important breast cancer risk factor, although it is not clear whether the association differs across breast cancer tumor subtypes. We examined the association between indicators of mammographic density and breast cancer risk by tumor subtype among postmenopausal women by investigating heterogeneity across tumor characteristics. Methods Mammographic density measures were determined for 477 breast cancer cases and 588 controls, all postmenopausal, in Vancouver, British Columbia, using digitized screening mammograms and Cumulus software. Mammographic dense (DA), non-dense (NDA), and percent dense (PDA) areas were treated as continuous covariates and categorized into quartiles according to the distribution in controls. For cases only, tests for heterogeneity between tumor subtypes were assessed by multinomial logistic regression. Associations between mammographic density and breast cancer risk were modeled for each subtype separately through unconditional logistic regression. Results Heterogeneity was apparent for the association of PDA with tumor size (p-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (p-heterogeneity values >0.05). Conclusion These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.

Background: Observational studies show that digital breast tomosynthesis (DBT) combined with digital mammography (DM) can reduce recall rates and increases rates of breast cancer detection. The objective of this study was to examine the cost-effectiveness of DBT plus DM versus DM alone in British Columbia and to identify parameters that can improve the efficiency of breast cancer screening programs. Methods: We conducted an economic analysis based on data from a cohort of screening participants in the BC Cancer Breast Screening Program. The decision model simulated lifetime costs and outcomes for participants in breast cancer screening who were aged 40–74 years between 2012 and 2017. We analyzed rates of health care resource utilization, health state costs and estimated incremental cost-effectiveness ratios (ICERs), to measure incremental cost differences per quality-adjusted life years (QALYs) gained from the addition of DBT to DM-based screening, from the government payer’s perspective. Results: The model simulated economic outcomes for 112 249 screening participants. We found that the ICER was highly sensitive to recall rate reductions and insensitive to parameters related to cancer detection. If DBT plus DM can reduce absolute recall rates by more than 2.1%, the base-case scenario had an ICER of $17 149 per QALY. At a willingness-to-pay threshold of $100 000 per QALY, more than 95% of the probabilistic simulations favoured the adoption of DBT plus DM versus DM alone. The ICER depended heavily on the ability of DBT plus DM to reduce recall rates. Interpretation: The addition of DBT to DM would be considered cost-effective owing to the low positive predictive value of screening with DM alone. Reductions in false-positive recall rates should be monitored closely.

Purpose/Objective(s) The benefit of regional nodal irradiation (RNI) for node-positive, low-risk breast cancer is controversial. The ongoing TAILOR RT trial is enrolling breast cancer patients with 1-3 involved macroscopic nodes and a low risk Oncotype DX Recurrence Score ( Materials/Methods We interrogated a population-based database, which included all women treated for breast cancer in the province. Inclusion criteria were: age 40-79, pT1-2 pN1 (macroscopically node-positive) breast cancer, and diagnosis between 2005 and 2014. To reproduce the inclusion criteria of TAILOR RT, patients could have had breast-conserving surgery (BCS) or mastectomy & axillary lymph node dissection (ALND) with 1-3 positive nodes, BCS & sentinel lymph node biopsy (SLNB) with 1-2 positive nodes or mastectomy & SLNB with 1 positive node. To select a cohort of patients likely to have Recurrence Score Results We identified 1,169 eligible women. Median follow-up was 9.2 years. There were 885 patients who received RNI and 284 who did not undergo RNI. The RNI group was younger (median 62 versus 58 years), had a higher rate of nodal involvement, and were more likely to have received chemotherapy (all P 0.05). Conclusion RNI was not associated with improved outcomes in node-positive, low-risk breast cancers. This work underscores the importance of continued accrual onto the ongoing non-inferiority trial of RNI, TAILOR RT.

The SSO Choosing Wisely campaign recommended selective sentinel lymph node biopsy (SLNB) in clinically node-negative women aged ≥ 70 years with ER+ breast cancer. We sought to assess the association of SLNB positivity, adjuvant treatment, and survival in a population-based cohort.Women aged ≥ 70 years treated for ER+ HER2- breast cancer between 2010 and 2016 were identified in our prospective provincial database. Overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Kaplan-Meier analysis. Multivariable logistic regression was used to assess the association of SLNB positivity with use of adjuvant treatments and survival outcomes.We identified 2662 patients who met study criteria. SLNB was positive in 25%. Increased use of chemotherapy (ChT), hormone therapy (HT), and radiotherapy (RT) was significantly associated with SLNB positivity. Five-year OS was 86%, and BCSS was 96% with median follow-up of 4.3 years. BCSS was worse with grade 3 disease (HR 4.1, 95% CI 2.1-8.1, p0.0001) and better with HT (HR 0.5 95% CI 0.3-0.9, p = 0.01). Patients with a positive SLNB treated without adjuvant therapy had lower BCSS (HR 3.2 95% CI 1.2-8.4, p = 0.017) than those with a negative SLNB, but patients with a positive SLNB treated with any combination of ChT, HT, and/or RT, had similar BCSS to those with a negative SLNB.BCSS in this population was excellent at 96%, and BCSS was similar with negative and positive SLNB when patients received HT. SLNB can be omitted in elderly patients willing to take HT.

IMPORTANCE: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. OBJECTIVE: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). DESIGN, SETTING, AND PARTICIPANTS: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. INTERVENTIONS: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m(2), 700 mg/m(2), or 650 mg/m(2) twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. MAIN OUTCOMES AND MEASURES: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). RESULTS: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m(2) in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, −4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. CONCLUSIONS AND RELEVANCE: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01702558

The predictive benefit of breast cancer molecular subtypes for systemic therapy approaches has been well established; yet, there is a paucity of data regarding their use as a predictor of radiation therapy fractionation sensitivity. The purpose of this study was to determine whether rates of local recurrence (LR) for patients treated with hypofractionated (HF) radiation therapy, in comparison to conventional fractionation, differ across breast cancer molecular subtypes in a large, prospectively collected cohort treated with modern systemic therapy.Patients who received a diagnosis of stage I-III breast cancer between 2005 and 2009 were identified. Molecular subtype was determined using the American Joint Committee on Cancer classification system (luminal-A, luminal-B, HER2+, triple negative [TN]). Multivariable Cox regression modeling was used to identify predictors of LR. LR-free-survival (LRFS) was determined using the Kaplan-Meier method and compared using the log-rank test.A total of 5868 cases were identified with a median follow-up of 10.8 years. Patients with luminal-A subtype composed 45% of the cohort (n = 2628), compared with 30% luminal-B (n = 1734), 15% HER2+ (n = 903), and 10% TN (n = 603). A total of 76% (n = 4429) of patients were treated with HF. The 10-year LRFS was 97.1% (95% confidence interval [CI], 96.6-97.6) for the whole cohort. The 10-year LRFS based on molecular subtypes was 98.3% (95% CI, 97.6-98.7) luminal-A, 96.6% (95% CI, 95.5-97.4) luminal-B, 97.0% (95% CI, 95.5-98.0) HER2+, and 93.5% (95% CI, 91.1-95.3) TN (P.001). There was no difference in the 10-year LRFS between patients treated with HF versus conventional fractionation among those with luminal-A (98.2% vs 98.4%; P = .42), luminal-B (96.6% vs 96.8%; P = .90), HER2+ (97.5% vs 95.8%; P = .12), or TN (93.9% vs 92.2%; P = .47). There was no significant interaction between subtype and fractionation regimen.These data support the routine use of hypofractionated radiation therapy regimens across all breast cancer subtypes.

Background The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). Methods Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. Results We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34–86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1–20) with associated progression-free survival of 3.2 months (95% CI 1.61–4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. Conclusions The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0836-3) contains supplementary material, which is available to authorized users.

Background The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time. Methods Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts. Results Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years). Conclusions Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade.

543 Background: We sought to explore the impact of locoregional recurrence (LRR) on survival in breast cancer (BC) patients in British Columbia treated in the modern era. Methods: A retrospective cohort study design identified patients diagnosed with stage I-III BC from 04/2005-12/2013 treated with surgery and who had a subsequent LRR. Exclusions were death or distant metastasis within 120 days of LRR, bilateral previous/synchronous BC, and other invasive cancers. After LRR, overall survival (OS) and factors associated with OS, including clinical subtype and adjuvant therapy (AdTx), were examined. We defined clinical subtypes as: Luminal (Lum) A-estrogen receptor (ER) and progesterone receptor (PR) positive, HER2 negative, and grade 1 or 2; Lum B-as Lum A but grade 3, or as Lum A but only one of ER or PR positive; triple negative (TNBC)-ER and PR and HER2 negative; and HER2 positive (with any ER, PR). In the absence of earlier LRR, we defined adequate AdTx as: (a) TNBC: >=50% of planned chemotherapy (Chx), (b) HER2 positive: >=50% of planned Chx and >=8 cycles of anti-HER2 therapy, (c) Lum A, B: >=4 years of endocrine therapy and (d) after partial mastectomy or positive final margins: >=50% of radiation therapy dosage. Results: The final cohort had 492 patients with a median follow-up of 7.2 years from LRR and 11.8 years from diagnosis. LRR was local in 69.3% (n=341) and regional +/- local in 30.7% (n=151). Compared with local only, regional recurrences were associated with higher T and N stage, grade, and Lum status (p

e18791 Background: Patients with HER2 positive early-stage breast cancer (ESBC) with residual disease (RD) following neoadjuvant therapy derive benefit from treatment escalation. However, treatment modifications for patients who achieve a complete pathologic response (pCR) remains controversial. The Neo-Bioscore is a validated prognostic tool used for patients with ESBC treated neoadjuvantly. To understand the impact of pCR on outcomes in a real-world setting, and better refine patient selection for treatment escalation or de-escalation, we investigated the use of the Neo-Bioscore and/or other prognostic variables. Methods: Patients diagnosed from 2005 to 2014 with stage I-III HER2 positive breast cancer and treated with neoadjuvant systemic therapy were identified from the BC Cancer Breast Cancer Outcomes Unit database. Outcomes of interest included breast cancer specific survival (BCSS), overall survival (OS), distant disease- free survival (DRFS), and locoregional recurrence free survival (LRFS), and were assessed using the Kaplan-Meier method, comparing the pCR and RD groups. Multivariate analysis was used to assess clinical and pathologic prognostic factors beyond pCR. Results: Of the 417 patients meeting inclusion criteria, median age was 50, including 38.1% with clinical stage 2 and 58.3% with clinical stage 3 disease and 59.5% with hormone receptor (HR) positive tumors. 98.1% received chemotherapy and 92.6% received trastuzumab. Median follow-up was 9.6 years (9.2, 10.0). Overall, 193 patients (46.3%) achieved a pCR. Those with RD had higher clinical T stage (p < 0.01) and more HR positive disease (p < 0.01). Patients who achieved a pCR had significantly better 5-year BCSS (91.2% vs. 74.8%, p< 0.0001), OS (90.7% vs. 69.9%, p< 0.0001), DRFS (87.9% vs. 66.3%, p< 0.0001) and LRFS (98.9% vs. 92.5%, p= 0.007) in univariate analyses. In multivariate analyses, the neo-bioscore (1 vs 5: HR 0.05, 95% CI 0.003,0.666, p = 0.02), higher pathological T stage (ypT3 vs ypT0: HR 7.2, 95% CI 1.3, 40.9, p = 0.03) and pathological N stage (ypN1 vs ypN0: HR 2.2, 95% CI 1.1, 4.5, p = 0.03) were associated with BCSS, whereas patients’ age, ER status and baseline clinical T and N stage were not. Conclusions: In a real-world population, ESBC patients with HER2 positive tumors treated with neoadjuvant systemic therapy who achieved pCR derived significant improvements across all survival parameters compared to those with RD. However, distant relapses still occurred in 12% of patients who achieved pCR. Further analyses to identify patients with pCR who relapsed are underway to determine who may benefit from treatment escalation. The final pathological stage and neo-bioscore for patients with RD were prognostic in a real-world cohort and should be considered for adjuvant treatment decisions. Validation of these results in an independent cohort are also ongoing to better understand predictive and prognostic variables.

Background:Based on randomized controlled trials demonstrating no survival benefit of axillary dissection in elderly breast cancer patients, the SSO/Choosing Wisely campaign recommended against the routine use of sentinel lymph node biopsy (SLNB) in clinically node negative patients aged ≥70 with estrogen receptor (ER) positive breast cancer in 2016. SLNB is still performed in >80% of such patients and we have previously shown that at our institution, SLNB positivity influences adjuvant therapy decisions in this population. In this study, we sought to validate the association of SLNB positivity and adjuvant treatment in a larger population-based cohort, and to evaluate the impact of this finding on oncologic outcomes. Methods:The Breast Cancer Outcome Unit (BCOU) prospectively collects demographic, pathologic, treatment and outcomes data on all patients referred to BC Cancer with breast cancer in British Columbia, Canada. Female patients aged ≥70 with newly diagnosed estrogen receptor-positive invasive breast cancer who underwent SLNB from 2010-2016 were included. Patients with HER2-positive disease or those treated with neoadjuvant therapy were excluded. Multivariable analysis was used to assess the effect of SLNB positivity on adjuvant treatment. Overall survival (OS) and breast cancer specific survival (BCSS) were assessed using Kaplan-Meier analysis and Cox regression was used to assess contribution of SLNB positivity and adjuvant treatment. A nomogram was created to model the effect of nodal positivity and adjuvant treatment on BCSS. Results:We identified 2580 patients who met study criteria with a median age of 75 and a median tumor size of 15 mm. SLNB was positive in 23%. Sixty-seven percent of patients had breast conserving surgery (BCS) and 62% of patients had RT (BCS 79%, mastectomy 25%). As systemic therapy 5% of patients had chemotherapy (CT) and 78% of patients had hormone therapy (HT). Use of adjuvant therapies was associated with SLNB positivity: Systemic therapy (HR = 2.4, 95% CI: 1.84-3.14, p Conclusions:In this modern, population-based cohort of patients over 70 with ER-positive breast cancer, 5-year BCSS was excellent at 96%. Although the use of adjuvant treatment was associated with a positive SLNB, BCSS was not changed based on nodal status when patients received HT. Our results support the Choosing Wisely recommendations; SLNB can be safely omitted in elderly patients willing to take HT, and we advocate that SLNB can be omitted in low-risk patients aged ≥75 even in the absence of planned HT. Citation Format: Elaine McKevitt, Rona Cheifetz, Kimberly DeVries, Alison Laws, Rebecca Warburton, Lovedeep Gondara, Caroline Lohrisch, Alan Nichol. Sentinel node biopsy should not be routine in older patients with ER positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-02.