Hormone Receptor-positive Early Breast Research Articles

Abstract P1-13-03: Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence

Abstract Purpose/Objective(s):. Several trials have compared endocrine therapy (ET) alone vs. ET and radiotherapy (RT) in low risk early stage estrogen receptor (ER)-positive breast cancer and have shown that the addition of RT to ET modestly reduces the rate of loco-regional recurrence (LRR) without altering survival. ET may also yield modest reductions in contralateral breast events. ET alone has thus become a standard strategy in select patients. Data evaluating the efficacy of RT alone are scarce. However, the toxicity of ET is not trivial and its effectiveness is dependent upon treatment adherence. As RT courses become ever shorter and safer, a re-evaluation of the strategy of RT alone is warranted. This analysis reports on the treatment outcomes of ER-positive early stage breast cancer treated with adjuvant RT or ET alone at a multi-hospital health system. We hypothesized that adjuvant RT alone would yield loco-regional control comparable to that of ET alone and that ET adherence would influence outcomes. Materials/Methods:. The shared electronic health record of multiple facilities within a university health system was queried to identify women with pathologic T1-2 N0 breast cancer treated with breast-conserving surgery between 2007 and 2016. Data collection included demographic features, tumor characteristics, treatment type, and evidence of LRR. Analysis was restricted to those patients with ER positive disease who underwent either RT alone or ET alone. Five-year LRR were compared across groups using the Kaplan-Meier method. Results:. 240 patients met inclusion criteria. Of these, 86 were treated with RT alone and 154 with ET alone. Patient, tumor and ET variables are listed in the table below. ET adherence and duration information were available for 135 out of 154 patients who received ET alone. Patients who completed 5 years of ET or whose ET was discontinued due to the disease recurrence or death were categorized as ET-adherence (ET-A). Patients who discontinued ET before reaching 5 years due to other reasons were categorized as ET-non adherence (ET-NA). Median ET duration in ET-A was 60 months (range, 15-101 months) and in ET-NA was 13 months (range, 1-54 months). The 5-year rates of LRR for RT alone vs. ET alone were 4.1 % (95% CI 0-8.8) vs. 5.0 % (95% CI 1.1-8.9). The 5-year rates of LRR for ET-A vs. ET-NA were 2.0 % (95% CI 0-4.7) vs. 16.4 % (95% CI 1.1-31.7). While the difference in the LRR rates between RT alone vs. ET-A was not statistically significant (p= .481), ET-NA was associated with significantly higher LRR rate compared to RT alone or ET-A (p<.05). The rate of ET non-adherent rate was 21.4%. Conclusion:. RT yielded LRR equivalent to overall ET and superior to ET non-adherence. For patients with early stage ER+ breast cancer, a prospective randomized trial comparing RT to ET and evaluating quality of life (QoL) is needed. In light of emerging data, a five-day course of RT can be considered as an alternative to five years of ET, and RT should be strongly considered if ET adherence is in doubt. Table 1.Patient, tumor and treatment characteristicsRT alone (n=86)ET alone (n=154)Median follow-up (months)50.6 (1-135)48 (3-114)Age (median)63 (39-91)74 (50-87)StageT176 (88.4%)142 (92.2%)T210 (11.6%)12 (7.8%)HistologyGrade 38 (9.3%)9 (5.8%)+LVI5 (5.8%)3 (2.0%)Endocrine Therapy (ET)ET duration (median, months)-57 (1-101)ET-Adherent-102 (66.2%)ET-Non adherent-33 (21.4%)ET duration not available-19 (12.3%) Citation Format: Seung Won Seol, Travis Pflederer, Lauren Weller, Chelain Goodman, Eric D Donnelly, John P Hayes, Jonathan B Strauss. Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence [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 P1-13-03.

Abstract PD14-08: Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status

Abstract Background: In post-menopausal women with hormone receptor (HR) positive early breast cancer, aromatase inhibitors (AIs) are more effective than tamoxifen as endocrine therapy. However, some trial reports indicate greater benefit from AIs in lobular than ductal cancers. Invasive lobular cancer can be identified using conventional microscopy and/or immunohistochemistry for e-Cadherin status. We performed an individual patient data meta-analysis to explore possible differential treatment benefits for AI vs tamoxifen in women with lobular vs ductal hormone receptor positive breast cancer. Methods: Individual patient data were collected from three randomised controlled trials (BIG 01-98, TEAM and ATAC) of AI vs tamoxifen for postmenopausal women with estrogen receptor positive breast cancer, as well as results of central pathology review and e-Cadherin expression. Central pathology and e-Cadherin data were available on 9328 and 7654 women. Local pathology data was available for TEAM, BIG 01-98. Data were analysed using the same methodology as the previous EBCTCG meta-analysis of AI vs tamoxifen: results of different methods of diagnosing ductal vs lobular cancer were cross tabulated, and outcomes analysed using log-rank methods, yielding event rate ratios (RR) and confidence intervals. Interactions were evaluated using standard tests for heterogeneity; the primary outcomes were time to any invasive breast cancer recurrence, and time to distant recurrence. Results: Rates of lobular cancer were higher when assessed by central pathology (BIG 01-98 16%; ATAC 16%; TEAM 12%) than e-Cadherin (15% vs 14% vs 9%). Methods agreed in over 80% of cases classified as ductal using either pathology or e-Cadherin, while the agreement rate for lobular cancers was only about 50%. A similar pattern was seen comparing local pathology with either central pathology or e-Cadherin. Consequently, analyses were stratified by pathology and e-Cadherin both separately and together. Consistent with the previous meta-analysis there was a significant reduction in recurrence for AI compared to tamoxifen (RR 0.73 (0.61-0.87) p=0.0004). Exploration of interaction found no evidence of heterogeneity of treatment effect on recurrence by pathology (ductal HR 0.76 (0.64-0.89); lobular HR 0.76 (0.50-1.15) interaction p&gt0.99; nor by e-Cadherin status (interaction p=0.9). No significant interactions were seen on other endpoints. Conclusion: Analyses of three large trials of adjuvant AI vs tamoxifen found discordance in identifying patients with lobular carcinoma by local or central pathology or e-Cadherin status, indicating variability in the consistency of diagnosis. The trials included showed a benefit for AI over tamoxifen in line with the previous meta-analysis, but with no evidence of differential efficacy in lobular compared to ductal carcinomas, however measured. These data cannot rule out smaller quantitative interactions or differences in site of recurrence: however, in contrast to earlier reports, this meta-analysis of the totality of the data does not identify ductal/lobular cancer as a predictive marker for differential endocrine treatment benefit. Citation Format: Robert K Hills, Steffi Oesterreich, Otto Metzger, David Dabbs, Hongchao Pan, Jeremy Braybrooke, Richard Gray, Richard Peto, Rosie Bradley, Ewan Straiton, Richard Berry, Daniel Rea, David Cameron, Jack Cuzick, Meredith Regan, Mitch Dowsett, Ivana Sestak, Jonas Bergh, Sandra M Swain, John Bartlett, Early Breast Cancer Trialists' Collaborative Group. Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status [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 PD14-08.

Survival outcome and treatment tolerability for postmenopausal females with early stage hormone receptor positive breast cancer treated with different adjuvant hormonal lines (TAM vs. AI vs. switching strategy) for 5 years

Abstract Background The standard adjuvant endocrine treatment for postmenopausal female patients with hormone receptor positive early breast cancer was 5 years of tamoxifen, but recurrence and side effects restrict its usefulness. The aromatase inhibitor (anastrozole or exemestane or letrozole) was compared with tamoxifen for 5 years or started after completing 2-3 years of tamoxifen in postmenopausal female patients diagnosed with early breast cancer at "Ain Shams University Hospitals" Objective The aim of the study was to measure survival outcome and treatment tolerability for postmenopausal females with Hormone Receptor Positive early breast cancer who received adjuvant hormonal treatment with tamoxifen [TAM] only for 5 years versus those who received adjuvant hormonal treatment with tamoxifen [TAM] for 2 years switching to aromatase inhibitors [AI] in the sequential 3 years versus those who received adjuvant hormonal treatment with aromatase inhibitors [AI] solely for 5 years. Patients and methods This study included 100 postmenopausal women with early breast cancer who presented at the Clinical Oncology Department, Ain Shams University, in the interval from January 2010 until December 2015. Conclusion Similar disease free survival and overall survival were observed among the three studied groups. Switching tamoxifen to aromatase inhibitors provides better tolerability in terms of endometrial thickness when compared to 5 years of tamoxifen monotherapy. Patients who administer aromatase inhibitor included in the switching strategy experience less osteoporosis and less generalized bone pain compared to upfront aromatase inhibitor to 5 years. There was a significant improvement of disease free survival (DFS) in human epidermal growth factor receptor 2 (HER 2) negative patients receiving any adjuvant hormonal treatment line for five years in comparison to HER 2 positive patients receiving the same adjuvant hormonal treatment for five years.

The impact of tumor detection method on genomic and clinical risk and chemotherapy recommendation in early hormone receptor positive breast cancer

BackgroundSymptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendations. Patients and methodsPatients with early hormone receptor positive (HR+) HER2neu-negative (HER2-) breast cancer, and known OncotypeDX Breast Recurrence Score test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared. ResultsThe NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX recurrence score (RS) varied between the groups. In the symptomatic group there were lower proportions of low RS (13% vs 23%) and higher proportions of high RS (24% vs. 13%) compared to the screen-detected group. Symptomatic tumors were significantly more likely to have a high clinical risk (59% vs 40%). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with a symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (60% vs. 37%). ConclusionsWe demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans.

Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer

BackgroundRecent data suggest that human epidermal growth factor receptor 2 (HER2)-low breast cancer may represent a distinct entity. We aimed to compare disease characteristics and outcomes between HER2-low and HER2-0 in estrogen receptor (ER) positive, early-stage breast cancer. MethodsA single center retrospective study comprising all women with ER positive, HER2 negative early breast cancer, for whom an Oncotype DX test was performed between 2005 and 2012. Women were grouped to HER2-low (immunohistochemistry +1 or +2 and in situ hybridization not amplified) or HER2-0. Clinico-pathological features and Oncotype recurrence score (RS) were collected. Data on overall-survival (OS), disease-free survival (DFS) and distant disease-free survival (DDFS) were evaluated according to HER2 expression status. Results608 women were included, of which 304 women had HER2-0 and 304 had HER2-low disease. Lobular subtype was significantly more common in HER-0 compared to HER2-low disease (17% vs. 8%, p = 0.005). The prevalence of other clinic-pathological characteristics and long-term prognosis were comparable between both groups. For women with high genomic risk (RS > 25), HER2-low expression was associated with significantly favorable OS (HR = 0.31, 95% CI 0.11–0.78, p = 0.01), DFS (HR = 0.40, 95% CI 0.20–0.82, p = 0.01) and DDFS (HR = 0.26, 95% CI 0.11–0.63, P = 0.002) compared to women with HER2-0. For women with low genomic risk (RS ≤ 25), long-term prognosis was unrelated to HER2 expression. ConclusionThe prognostic impact of HER2-low expression in early-stage luminal disease varies across the genomic risk, with significant favorable outcomes of HER2-low expression compared to HER2-0 in women with high genomic risk.

The Cost-Effectiveness of Adjuvant Tamoxifen Treatment of Hormone Receptor–Positive Early Breast Cancer Among Premenopausal and Perimenopausal Ghanaian Women

ObjectivesMost breast cancer cases in Ghana occur in premenopausal and perimenopausal (PPM) women. This study evaluated the cost-effectiveness of tamoxifen compared with no tamoxifen for the adjuvant treatment of hormone receptor–positive (HR+) early breast cancer (EBC) among PPM Ghanaian women. MethodsA Markov model was constructed to synthesize data on the effectiveness, costs, and health benefits of tamoxifen. Effectiveness and utility data were sourced from a literature review. Resource use and healthcare costs were estimated from Ghanaian sources. The evaluation was conducted in 2017 from the perspective of the health system over a 15-year time horizon. The financial impact of funding tamoxifen on Ghana’s National Health Insurance Scheme (NHIS) was also estimated. ResultsAdjuvant tamoxifen treatment for women with HR+ EBC was more effective and more costly than no-tamoxifen therapy. The incremental benefit and costs were estimated to be 1.38 quality-adjusted life-years gained and Ghana cedis (GHC) 2338 ($520), respectively. The incremental cost-effectiveness ratio was estimated to be GHC 1694 ($376). The model was sensitive to the cost of tamoxifen and utility values. The cost of tamoxifen for the treatment of HR+ EBC represents less than 0.01% GHC 96 960 ($21 547) of the current NHIS total claims expenditure. ConclusionsTamoxifen provides additional benefits to PPM Ghanaian women with HR+ EBC and is cost-effective compared with no tamoxifen. These results support the public funding of tamoxifen under the NHIS and provide Ghanaian policy makers with vital information for future budgetary planning.

Thromboembolism (TE) and adjuvant endocrine therapy (AET) in hormone receptor positive (HR+) early breast cancer (EBC): Did the evolution of treatment change the incidence of the adverse event? A metanalysis.

e12516 Background: The AET of HR+ EBC has been changing in the recent years. Aromatase inhibitors (AI) as upfront, or in a planned switch strategy after Tamoxifen (T), have been added to the choice of T alone. An increased risk of TE is well known in the T treated patients while AIs have showed a reduced rate of TE. Recently, adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) abemaciclib to AIs, has showed a positive impact in the high risk HR+ EBC subgroups, but we are seeing an increase of the TE rate. We conducted this meta-analysis to evaluate the impact of the new AETs on the incidence of TE if compared to the standard monotherapy. Methods: We performed a meta-analysis of the randomized phase III trials comparing the experimental AETs and the endocrine standard therapy. A random-effect model to find differences in the rate of TE events between the experimental treatments and the standard therapy has been used. Results: Twelve phase III trials were included. Five trials evaluated the upfront strategy, 6 studies the switch and one the combination with a CDK4/6inhibitor (i.e. abemaciclib). Overall, the new AETs did not significantly modify or affect the rate of TE events (OR 0.708, 0.444-1.130, p = 0.148) with high heterogeneity among studies (I2 87, p < 0.0001). Excluding the abemaciclib trial, the incidence of TE is reduced (OR 0.609, 0.462-0.802, p < 0.0001) with a moderate heterogeneity among the studies (I2 59, p < 0.006). Considering the upfront strategies with AIs, the TE events are reduced (OR 0.507, 0.394-0.651, p < 0.0001) but they are not if we consider the trials in which T is used upfront before AIs (OR 0.762, 0.546-1.065, p = 0.112). Conclusions: Overall, the new treatments (AIs alone or plus CDK4/6 inhibitors) did not affect the rate in TE events. AIs as upfront strategy is the safest AETs of HR+ EBC, being associated to the lowest incidence of TE. The switch strategy increases the TE rate whereas the addition of abemaciclib to the standard AET showed to significantly increase the TE events. The results of the currently ongoing trials with the CDK4/6 inhibitors will help to obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and to clarify the weight of the TE adverse events in the balance of benefit/risk of this new adjuvant strategy.

56P The impact of tumour detection method on genomic and clinical risk and chemotherapy recommendation in early hormone receptor positive breast cancer

Symptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. The decision to administer adjuvant chemotherapy for early hormone receptor positive (HR+) HER-2 negative (HER2-) breast cancer patients, is guided by both the genomic and the clinical risk of disease recurrence. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendation. Patients with early HR+ HER2- breast cancer, and known OncotypeDX Breast Recurrence Score (RS) test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared. The NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX RS varied between the groups. In the symptomatic group there were lower proportions of low RS (13 vs 23%) and higher proportions of high RS (24 vs. 13%) compared to the screen-detected group (p=.03). Symptomatic tumors were significantly more likely to have a high clinical risk (59 vs 40%; p<.0001). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (57 vs. 35%; p=.03). We demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans.

Abstract PS12-27: From theory to practice: Impact of aromatase inhibitors in the bone health of women with early breast cancer

Abstract Background: Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. They decrease bone mineral density, accelerate osteoporosis and lead to increased risk of fractures, thus impairing quality of life. Identification of patients at higher risk would be helpful for best treatment decisions. Recommendations have been published for bone health preservation but real-world data regarding implementation and adherence to these recommendations is scarce. This work aimed to assess bone loss, fracture incidence and risk factors associated with these events, as well as the prognostic influence of fractures in women undertaking adjuvant AI. Materials and Methods: In this retrospective cohort study, we have evaluated women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. A minimum of 3 months under AI and 3 years of follow-up after AI start were necessary for inclusion. Statistical analysis of collected data was performed using R 3.5.2, R-Studio 1.1.456 and Stata 15.1 software. Results: 451 eligible women were reviewed (median age 68 years, 30-98 min-max). Median time under AI was 40 months (3-114). Baseline bone densitometry, carried out in only 69% patients, showed abnormal results in 75%, but only 69% and 16% started calcium/vitD supplementation and bisphosphonates therapy, respectively. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in women with higher age (p=0.006). This group also showed lower T-scores at lumbar spine and femoral neck (p=0.067). On multivariate analysis, age (OR 1.04, 95% CI 1.01-1.07, p=0.016) and time under AI (OR 1.02, 95% CI 1.00-1.03, p=0.045) were independent predictors of fracture events, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups disfavouring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6-92.4 vs. 95.6%, 95% CI, 91.2-97.8, p=0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted-HR of 3.17, 95% CI 1.10-9.11; p=0.032). Conclusion: Bone health is often forgotten, despite its great impact in survivorship. Our results suggest a pathophysiologic link between EBC and bone metabolism, potentially estrogen-mediated, which translates into EBC recurrence. Further research in this area may help refining these findings. Moreover, early identification of women at higher risk with individualized treatment plans comprising shorter duration of AI is warranted. Poor adherence to existing guidelines is a crucial barrier to effective approaches to bone health. Citation Format: Leonor Vasconcelos Matos, Maria Teresa Neves, Fatima Alves, Mafalda Baleiras, André Ferreira, Pedro Cotovio, Tiago Dias Domingues, Mariana Malheiro, Joana Graça, Leonor Fernandes, Ana Plácido, Helena Miranda, Ana Martins. From theory to practice: Impact of aromatase inhibitors in the bone health of women with early 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 PS12-27.

The variant T allele of PvuII in ESR1 gene is a prognostic marker in early breast cancer survival

The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480–0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411–0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380–0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.

Effects of systemic inflammation on relapse in early breast cancer

Chronic inflammation has been a proposed mechanism of resistance to aromatase inhibitors in breast cancer. Stratifying by HER2 status, a matched case-control study from the Wellness After Breast Cancer-II cohort was performed to assess whether or not elevated serum inflammatory biomarkers (C-Reactive protein [CRP], interleukin-6 [IL-6], and serum amyloid A [SAA]) and/or the presence of a high-risk IL-6 promoter genotype were associated with recurrence of hormone receptor positive (HR+) early breast cancer. Estrogen levels were also measured and correlated with biomarkers and disease outcomes. CRP and SAA were significantly associated with an increased risk of recurrence in the HR+/HER2− group, but not the HR+/HER2+ group. Mean serum estrogen levels were non-significantly elevated in patients who relapsed vs. non-relapsed patients. Surprisingly, high-risk IL-6 promoter polymorphisms were strongly associated with HER2+ breast cancer relapse, which has potential therapeutic implications, as elevated intracellular IL-6 has been associated with trastuzumab resistance in pre-clinical models.

Development of a Prognostic Tool to Guide the Decision to Extend Adjuvant Aromatase Inhibitors for up to Ten Years in Postmenopausal Early Breast Cancer Patients

Simple SummaryPostmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitors (AIs) for five years. However, recurrences still occur at a steady rate over at least twenty years, and extending adjuvant AIs for up to ten years is an option. Our work focuses on a specific population of postmenopausal patients who have already received five years of adjuvant AIs. This population is at high risk of osteoporosis and extending AIs must be carefully decided in line with the potential benefit. In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AI treatment. The score it provides is available free of charge upon diagnosis and divides patients into two prognostic groups. Combining that score with comorbidities, bone mineral density, and patient motivation may help the decision-making process to recommend extending adjuvant AIs.Background: The selection of women with hormone receptor-positive (HR+) early breast cancer (EBC) at high risk of relapse after five years (yrs.) of adjuvant aromatase inhibitors (AIs) is crucial, as the benefit of extending AIs is counterbalanced by toxicity. We developed a clinicopathological tool to estimate the residual risk of relapse after five years of adjuvant AIs. Methods: The Institut de Cancérologie de l’Ouest (ICO) database was used to determine a prognostic score of post-five-year AI relapse. Cox regression models estimated our score’s prognostic performance. Results: In total, 1105 women were included. Median follow-up was 44 months (IQR = 21–70) post-AI treatment. From the Cox models, we designed a dichotomous prognostic score including the number of macrometastases, age (>70 yrs. vs. ≤70 yrs.), tumor size (≥T2 vs. not), and mitotic activity (≥2 vs. not). Overall, 77.5% of patients were classified as being at low risk and 22.5% at high risk of late recurrence. Low-risk patients had a five- to ten-year local or distant recurrence risk of 7.6% (95% CI, 5.4% to 10.6%) as compared with 26.9% (95% CI, 19.9% to 35.7%) for the high-risk roup. Conclusion: In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AIs.

Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.

Abstract P3-08-46: Correlation of prognostic indicators based on clinical and pathological features in hormone receptor positive and HER2 receptor negative early breast cancer with the 21 gene assay recurrence score

Abstract Background: With the advent of genomic testing in routine practice to predict the benefit of adjuvant chemotherapy, in a resource limited health service, many multi-disciplinary breast cancer teams are relying on known clinical and pathological factors to determine which patients undergo testing or to avoid/receive chemotherapy in hormone receptor positive, HER2 negative (HR+, HER2 -ve) breast cancer. These factors are manipulated in formulae or in online prognostic calculators to determine "risk". Oncotype DX Recurrence Score® is routinely used in the UK to determine benefit of adjuvant chemotherapy in early breast cancer according to National guidelines (NICE) which determines risk using the Nottingham Prognostic Index (NPI) and Predict. Methods: With the kind permission of surgical and oncology colleagues within the Wales Cancer Network Breast Clinical Site Group, all patients with HR+, HER2-ve invasive breast cancer who had undergone Oncotype DX Recurrence Score® testing between 31/10/15 and 1/11/18 were matched to the prospectively held national cancer database. Post- operative tumour size, grade, nodal status, age of patient and route of diagnosis were then utilized to calculate the NPI for each case and the PREDICT! on line calculator for chemotherapy benefit in addition to endocrine therapy. A correlation co-efficient was then calculated for NPI, PREDICT 5 and PREDICT 10 to the recurrence score®. Ki 67 is not routinely calculated. Results: There were 734 cases with a RS® available matched to the cancer registry database, 96 of which had missing data items preventing calculation of NPI or PREDICT! values. Demographics of patients tested – n= 734MeanMedianRangeAge (years)585927-97Referral RouteBreast Cancer Screening296GP Referral/ Symptomatic438RS®Low - &amp;lt;18381Intermediate: 18-25202Intermediate: 26-3051High - ≥31100 GradeG143G2457G3225Grade unknown4Tumour Size T1244T2402T346T45Size unknown36Nodal StatusN0528N1mic58N1 (1_3)110Nodal status unknown38 all RS® (n= 638)r co-efficient of correlationNPI0.07Predict 5 year0.09Predict 10 year0.08LN0 (n= 481)NPI0.12Predict 5 year0.11Predict 10 year0.10LN mic (n= 52)NPI0.29Predict 5 year0.40Predict 10 year0.35LN1 (1_3) (n=105)NPI0.02Predict 5 year0.05Predict 10 year0.05 Conclusions: This is the largest cohort analysis in the UK of recurrence score testing published to date and covers a wider range of node negative, micro metastatic and node positive patients. We have demonstrated a weak correlation between the RS® and the NPI or PREDICT outcome in predicting benefit of chemotherapy and we do not believe these clinic-pathological surrogates should be relied upon to determine indications for adjuvant chemotherapy in HR+, HER2-ve early breast cancer patients or in determining if Oncotype DX Recurrence Score® testing should be performed in order to reduce over treatment with chemotherapy. Citation Format: Marianne Dillon, Adam Yarwood, Daniel Thomas, Wales Cancer Network Breast Clinical Steering Group. Correlation of prognostic indicators based on clinical and pathological features in hormone receptor positive and HER2 receptor negative early breast cancer with the 21 gene assay recurrence score [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 P3-08-46.

Abstract P3-08-17: Clinical factors of late recurrence of HR+ early breast cancer after completion of 5 years of aromatase inhibitor and development of a prognostic tool. A study of 1496 women of the ICO database

Abstract INTRODUCTION: Post-menopausal women with hormone receptor positive (HR+) early breast cancer receive generally 5 years of adjuvant aromatase inhibitor (AI). However, more than half of recurrences occur after that period and the identification of patients who could derive benefit from the prolongation of AI above 5 years is a critical task. We aimed to develop a simple prognostic tool to estimate the risk of late recurrence of patients with HR+ EBC who had completed 5 years of AI, in order to help the decision making process of extending AI. METHODS: We conducted a monocentric, retrospective study based on a local database (BERENIS), which included all patients treated for EBC at the Institut de Cancerologie de L’Ouest (ICO). We identified all post-menopausal women diagnosed with HR+ EBC and who had completed at least 54 months of adjuvant AI. We analysed the outcome after stopping AI, including HR+ metastatic, contralateral and ipsilateral relapses. RESULTS: Between January 2003 and December 2011, 1107 post-menopausal women were retrieved. Median follow-up after completion of 5y AI was 32.6 months [1-132]. The recurrence rate of HR+ disease was 8% (n=89) including 60 metastatic relapses, and 8 and 21 ipsilateral and contralateral local relapses respectively. Multivariate analysis showed that the pathological tumour size (continuous variable) (HR = 1.02; p = 0.035), the number of macro-metastases (continuous variable) (HR = 1.17; p = 0.001) and age (HR = 1.04; p = 0.012) were independent factors of HR+ invasive disease free survival. We then designed a score estimating the risk of late relapse. This was designed as follow: 10*(tumour size (mm)) +79*(number of macro metastases) +14*(years old). Patients were classified as low risk (78.8% of patients) or high risk (21.2%) with a threshold at 1200 points. Low risk patients had a mean 5- to 10-year risk of invasive HR+ local or distant recurrence of 9.8% (95% CI, 7.1% to 13.5%) as compared with 38.3% (95% CI, 27.6% to 50.9%) for high-risk groups. CONCLUSION: Our study is one of the first estimating the risk of late relapse in a population of post-menopausal women who have completed 5y of adjuvant AI for EBC. Our simple score identify accurately patients at high risk of relapse despite 5 years of treatment. This tool may help oncologist to select patients who could derive the most benefit of extending adjuvant AI above 5 years. A validation of this score in an independent population is necessary. Citation Format: Jean-Sebastien Frenel, Loïc Campion, Marie Robert, Classe Jean-Marc, Campone Mario, Camille Moreau-Bachelard. Clinical factors of late recurrence of HR+ early breast cancer after completion of 5 years of aromatase inhibitor and development of a prognostic tool. A study of 1496 women of the ICO database [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 P3-08-17.

Satisfaction with care and adherence to treatment when using patient reported outcomes to individualize follow-up care for women with early breast cancer – a pilot randomized controlled trial

Background: The population of breast cancer survivors is increasing as a positive consequence of early detection and enhanced treatment. The disease and treatment associated side-effects or late-effects often impact on quality of life and daily life functions during survivorship. This calls for optimization of follow-up care. We aimed to evaluate the patients’ satisfaction with the care provided, when using electronic patient reported outcomes (ePROs) to individualize follow-up care in women with early breast cancer receiving adjuvant endocrine therapy.Material and methods: Postmenopausal women treated for hormone receptor positive early breast cancer were included in a pilot randomized controlled trial and randomized to receive standard follow-up care with prescheduled consultations every six months or individualized follow-up care with the active use of ePROs to screen for the need of consultations. ePROs were distributed every third month over a two-year period. Primary outcomes were satisfaction with the assigned follow-up care and unmet needs. Secondary outcomes were use of consultations, adherence to treatment and quality of life.Results: Of the 207 consecutive patients who were potentially eligible for the study, 134 women were enrolled (65%). In total 64 women in standard care and 60 women in individualized care were analyzed. No statistically significant differences were reported in relation to satisfaction, unmet needs, adherence to treatment or quality of life. Women in standard care attended twice as many consultations during the two year follow-up period as women in individualized care; 4.3 (95% CI 3.9–4.7) versus 2.1 (95% CI: 1.6–2.6), p < .001.Conclusion: A significant reduction in consultations was observed for the group attending individualized care without compromising the patients’ satisfaction, quality of life or adherence to treatment. For the majority of postmenopausal women treated for early breast cancer, implementation of ePROs to individualize follow-up care was feasible.

Particularités de l’hormonothérapie adjuvante de la femme jeune

For young patients with hormone receptor–positive early breast cancer, tamoxifen for at least 5 years is the standard endocrine treatment. Prolonged endocrine treatment over 5 years is recommended for patients with high risk of late relapse.When adjuvant chemotherapy is indicated, prolonged iatrogenic amenorrhea is a strong pronostic factor. WIthout persistant amenorrhea after chemotherapy, it is indicated to associate ovarian suppression to the endocrine treatment. Optimal duration of this induced amenorrhea is unknown.

246P - Triple blinded prospective study assessing the impact of genomics & artificial intelligence Watson for oncology (WFO) on MDT’s decision of adjuvant systemic therapy for hormone receptor positive early breast carcinoma

BackgroundDecision on adjuvant systemic therapy in hormone positive early breast carcinoma is the only grey area in breast carcinoma management. This study was done to investigate the concordance between the results of genomic test(Endopredict), artificial intelligence(Watson For Oncology,WFO) and tumor board decision and implications of the same in clinical practice. MethodsThis was a triple blinded, prospective study. Decision regarding the adjuvant systemic therapy was done by the multidisciplinary tumor board (MDT)after reviewing the pathology reports & the results correlated with Endopredict test reports & artificial intelligence(Watson for Oncology). ResultsTotal of 42 patients included. Mean age was 58.3 years, 71.4% were post-menopausal. Breast conservation was done in 47.6%. 64.2% were T1-2N0 stage. Infiltrating ductal carcinoma was major type (83.3%). Decision by MDT to give adjuvant chemotherapy was for 25 patients (59.5%) & hormonal therapy for rest. Recommendation by Watson for oncology was to give adjuvant chemotherapy in 50%. Endopredict score (EPclin) resulted in a low-risk group of 22 patients (52.3%), while 15(47.6%) had a high risk EPclin score. Discordance between the endopredict test, Watson & tumor board was for 11 patients (26.1%): 3 patients had high risk score, but the tumor board decision was to give hormonal therapy due to the age factor. 8 patients had low risk score, but tumor board decision was to give adjuvant chemotherapy. Extremes of age, premenopausal status, intermediate grade & high Ki 67% values were the factors associated with discordance. The treatment decision changed for 4 patients (4/11, 36%) after reviewing the endopredict test and Watson recommendation. ConclusionsTumor board decision can be more scientific & evidence based with the help of genomics & a learnt colleague in the form of Watson for Oncology. Even though the clinical experience is the important determinant of adjuvant therapy, genomic test with artificial intelligence, which includes the scientific evidence, will guide in decision making. Long term follow up is needed for the validation in our clinical setting. Legal entity responsible for the studyManipal Hospital Ethical Committee. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

242P - Clinical validation of CanAssist breast in a Spanish cohort

BackgroundCanAssist-Breast (CAB) is a prognostic test for predicting risk of distant recurrence within five years in hormone receptor positive early stage breast cancer patients. It is unique in that the test uses immunohistochemistry coupled with a support vector machine learning based algorithm to predict risk score and category (High or Low). It has been developed and validated on a mix of Asian and Caucasian patients. The test has been clinically validated in over 1000 retrospective patient samples. In this study, we present for the first time data on the performance of CAB in a single center study from Spain (Vall D’Hebron Institute of Oncology, Barcelona). MethodsPost-surgical FFPE tumor blocks along with patient demographics and clinical follow up data up to a mínimum of five years were obtained from the hospital. CAB was performed on the tumor samples at the CAP and ISO 15189 accredited OncoStem reference laboratory in India. Distant Metastasis Free Survival (DMFS) and Hazard Ratio were used were computed using survival analysis. MedCalc software (Version 18.10.2) was used for all statistical analysis. The negative predictive value (NPV) was computed for establish the accuracy of prediction in the low risk group. ResultsSixty-two percent of this cohort had stage II disease. Sixty-nine percent and 61% had node negative and Grade 2 disease respectively. The median at onset was 61 years. The DMFS in the low risk category was 98% and 85% for the high risk (P=0.0032). The Hazard Ratio was 7.04 (95% CI: 1.93-25.73). The NPV was calculated to be 98%. To exclude any confounding effect of chemotherapy, survival analysis was done in the chemotherapy naïve sub-group. In the chemotherapy naïve sub-group, the DMFS for the low risk group was 100% and 85% for the high risk (P=0.02). These are results of the interim analysis of the study at half way mark and complete study data will be presented at the time ESMO meeting. ConclusionsCAB performs well in stratifying risk of recurrence in this Spanish cohort with the data matching performance shown earlier with the mix of Asian and Caucasian patients. In the absence of any inter-mediate risk category in CAB, it offers a cost effective alternative to existing prognostic tests providing definitive results to plan treatment of early stage breast cancer patients. Legal entity responsible for the studyManjiri M. Bakre. FundingHas not received any funding. DisclosureM. Bakre: Leadership role, Full / Part-time employment, Officer / Board of Directors, CEO and Founder: OncoStem Diagnostics Pvt Limted.

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor–Positive Early Breast Cancer

IntroductionA 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor–positive, lymph node–negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries. Patients and MethodsHormone receptor–positive, lymph node–negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period. ResultsThe median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets. ConclusionA nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.