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Background: The combination of cyclin-dependent kinases 4/6 inhibitors (CDK4/6is) and endocrine therapy (ET) is standard of care for patients with hormone receptor-positive (HRþ), HER2-negative (HER2À) advanced breast cancer (BC). However, studies evaluating adjuvant CDK4/6is provided contradictory results thus far. Materials and methods: We conducted a systematic review and meta-analysis to assess if the addition of CDK4/6is to adjuvant ET impacts on survival's outcomes and safety of patients with HRþ/HER2À early BC (EBC). This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and was registered in the PROSPERO database (ID: CRD42020218597). A systematic review of PubMed, Cochrane and EMBASE databases and major conference proceedings was performed up to 15 December 2020. All randomized controlled trials including patients with HRþ/HER2À EBC treated with CDK4/6is plus ET versus ET alone in the adjuvant setting were included. Pooled hazard ratios (HRs) and odds ratios (ORs) for survival and safety outcomes, respectively, were calculated with 95% confidence intervals (95% CIs) using random effect models. Results: With data available from three studies (N ¼ 12 647), the addition of CDK4/6is to adjuvant ET showed a trend for a benefit in terms of invasive disease-free survival (IDFS; HR 0.85, 95% CI 0.71-1.01; P ¼ 0.071). No significant improvement in distant relapse-free survival was observed (HR 0.83, 95% CI 0.58-1.19; P ¼ 0.311). The risk of allgrade toxicities and early treatment discontinuation increased significantly with the addition of CDK4/6is to ET (OR 9.36, 95% CI 3.46-25.33, P < 0.001, and OR 22.11, 95% CI 9.45-51.69, P < 0.001, respectively). Conclusion: The administration of adjuvant CDK4/6is to patients with HRþ/HER2À EBC showed a trend for an IDFS benefit and an increase in the risk of toxicities and treatment discontinuation. The role of adjuvant CDK4/6is remains controversial and a longer follow-up of these randomized controlled trials is needed before supporting a straightforward change in clinical practice.

Background: Breast cancer (BC) is the most commonly diagnosed cancer worldwide, 91% diagnosed in early stages and 80% of them expressing estrogen receptor (ER +). It is known that distant late recurrence (DLR) represents about 50% of all relapses. Thus, identifying patients with a higher risk of DLR is a essential need in ER + BC, leading to a potential personalized management. Within this scope, CTS 5 (Clinical Treatment Score after 5 years) was developed as a simple clinical-pathological tool that aims to estimate the residual risk of distance recurrence after 5 years of endocrine therapy (ET). Methodology: The validity of CTS5 was tested in a retrospective cohort. Patients diagnosed between 2005 and 2011 with early BC, ER+/HER2- tumors, alive and without recurrence within the first 5 years were selected. The primary endpoint was the time for distant late recurrence (DLR). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated risks of DLR. Results: A total of 797 women were included with a median follow-up of 105 months. According to the CTS5, 424 (53.2%), 239 (30.0%), and 134 (16.8%) patients were classified into the low-, intermediate-, and high-risk of DLR, respectively (table 1). CTS5 results were prognostic for DLR: patients with CTS5-high showed a fivefold relative risk of developing an DLR compared to patients with CTS5-low (HR, 5.1 IC95% [2.24-11.47], p &lt;0.0001) (table 2). When assessing continuously, an one-point increase in CTS5 increased the relative risk of DLR by 87% (HR, 1,87 95% CI [1,324 - 2,632] p &lt;0.0001). These results were confirmed when we stratified by age (age≤50 years vs. age&gt;50 years). Conclusion: Our results support its use in clinical practice as a predictor for patients with early-stage BC, ER +, and HER2- in real life. Besides, our study serves as a hypothesis generator for future confirmations through prospective studies. Thus, we will be able to assess, through prospective studies, whether the CTS5 can be used to personalize the patient's follow-up or even evaluate its usefulness in the decision to prolong or not ET. Such results would be extremely important, given the known difficulty in accessing genomic assays, especially in developing countries. Table 1 Risk groups classifed according to the CTS5 and the clinicopathological characteristicsFactorsNo. (%)P valueTotalLowIntermediateHigh424 (53.2)239 (30.0)134 (16.8)Age, years&lt;50175 (41.3)100 (41.8)47 (35.1).383322 (40.4)&gt;50249 (58.7)139 (58.2)87 (64.9)475 (59.6)Number of the positive nodes0389 (91.7)133 (55.6)12 (9.0)&lt;.0001534 (67.0)131 (7.3)81 (33.5)28 (20.9)139 (17.4)2-32 (0.5)21 (8.8)41 (30.6)64 (8.0)4-92 (0.5)3 (1.7)32 (23.9)38 (4.8)9+0 (0.0)1 (0.4)21 (15.7)22 (2.8)Histological grade188 (20.7)25 (10.4)7 (5.2)&lt;.0001120 (15.0)2196 (46.2)129 (48.5)38 (28.4)363 (45.6)3140 (33.1)85 (35.6)89 (66.4)314 (39.4)Tumor size, mm&lt;10193 (45.5)9 (3.8)3 (2.2)&lt;.0001205 (25.7)10-20199 (47.0)94 (39.3)29 (21.6)322 (40.4)20-3022 (5.2)82 (34.3)41 (30.6)145 (18.2)&gt; 3010 (2.3)54 (22.6)61 (45.5)125 (15.7)Histological TypeDuctal342 (80.7)207 (86.6)112 (83.6)&lt;.0001661 (82.9)Tubular57 (13.4)21 (8.8)17 (12.7)95 (11.9)Others25 (5.9)11 (4.6)5 (3.7)41 (5.1)ChemotherapyNeoadjuvant10 (2.4)22 (9.2)25 (18.7)&lt;.000157 (7.2)Adjuvant153 (36.1)146 (61.1)92 (68.7)391 (49.1)RadiotherapyYes271 (63.9)184 (77.0)119 (88.8)&lt;.0001574 (72.0)No153 (36.1)55 (23)15(11.2)223 (28)Administered endocrine therapy5 years tamoxifen183 (43.2)66 (27.6)29 (21.6)&lt;.0001278 (34.9)5 years used aromatase inhibitor210 (49.5)146 (61.1)78 (58.2)434 (54.4)&gt; 5 years tamoxifen20 (4.7)18 (7.5)19 (14.2)57 (7.2)&gt; 5 years used aromatase inhibitor11 (2.6)9 (3.8)8 (6.0)28 (3.5)ET time, years5393 (92.7)212 (88.7)107 (79.9)&lt;.0001712 (89.3)7 - 1031 (7.3)27 (11.3)27 (20.1)85 (10.7)Vital statusAlive420 (99.1)236 (98.7)128 (95.5).016784 (98.3)Dead4 (0.9)3 (1.3)6 (4.5)13 (1.7)Distant recurrenceNo415 (97.9)222 (92.9)118 (88.1)&lt;.0001755 (94.7)Yes9 (2.1)17 (7.1)16 (11.9)42 (5.3) Table 2. Survival analyses for DLR and Overall Survival in diferent subgroups (CTS5 as categorical)Distance Late RecurrenceLow riskIntermediate risk HR (95% CI)pHigh risk HR (95% CI)pAll patientsReference3.155 (1.406 - 7.080).0055.067 (2.239 - 11.467)&lt; .0001&gt;50 years oldReference2.889 (1.049 - 7.952).0404.701 (1.737 - 12.723).002&lt;50 years oldReference3.730 (.964 - 14.435).0575.494 (1.311 - 23.029).02Overall SurvivalLow riskIntermediate risk HR (95% CI)pHigh risk HR (95% CI)pAll patientsReference1.152 (.258 - 5.150).8533.948 (1.113 - 14.00).034 Citation Format: Lucas Vian, Ronaldo Souza, Vladmir C. C. Lima, Daniella Y. T. Honda, Samara T. Pacheco, Caio D. Liz, Luciana B.M. Gomes, Bruno C. M. U. Júnior, Paula T. Guimarães, Celso S. S. Filho, Andréa P. Guimarães, Mauro D. S. Donadio, Angelo B.S. Fêde, Augusto O. Saito, Adriana R.G. Ribeiro, Joyce M. L. Maia, Iara K. F. Lustosa, Fabricio S. Castro, Monique C. Tavares, Marcelle G. Cesca, Marcelo Corassa, Noam F. Pondé, Solange Sanches. Validation of CTS5 as a predictor of distant late recurrence risk in HER2 negative luminal breast cancer: Latin American experience [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 PS6-63.

Background: Breast cancer (BC) accounts for 30% of female cancer, is the most commonly diagnosed cancer worldwide and the second most common cause of cancer-related deaths among females. The majority (79%) of breast cancers express the estrogen receptor (ER+) and 91% of them are diagnosed at an early stage. But it is also known that late recurrence (5 years or more after diagnosis) represents about 50% of all recurrences of ER+ BC. Identify those patients who are at greatest risk for late recurrence and develop strategies to prevent it has emerged as a major unmet need in ER+ BC. In an attempt to reduce late recurrences, several studies have recently proposed that endocrine therapy (ET) prolonged beyond five years would achieve this goal. Conversely, extended ET increases the rates of side-effects, compared to conventional ET. Therefore, selecting patients who would really benefit from extended ET is crucial, as this would spare low-risk patients from potentially greater side effects and impacts in quality of life, restricting the treatment only for those who really could take advantage of this approach. That is why, currently, the subject late recurrence is being studied so much. CTS 5 (Clinical Treatment Score after 5 years) is a simple clinical-pathological tool developed to estimate the residual risk of distant recurrence after 5 years of ET. Objective: To assess the prognostic and predictive impact of CTS5 in overall survival (OS) of ER+BC patients treated with conventional or extended ET in a Brazilian Cancer Center. Study design and statistical analysis: A retrospective cohort study was conducted, selecting, through administrative databases of AC Camargo Cancer Center, 1085 ER+ BC patients with at least 5 years of adjuvant ET. Patients who missed follow-up before completing ET were excluded, but we kept those who presented any event related to illness or treatment. Statistical analysis includes a Kaplan-Meier analysis and the Log Rank test. Prognostic factors were assessed using univariate and multivariate Cox analysis. Results: The demographic and clinical characteristics of patients are described in table 1. In this cohort, continuous CTS5 was a significant predictor for OS (HR = 4,49 [3.12-6.46], p&lt;0.001). In addition, in the high CTS5 group a significant benefit was observed with prolongation of adjuvant ET beyond 5 years (HR = 4,91 [3.41-7.06], p&lt;0.001), not observed for low and intermediate risks. Conclusion: In this cohort, composed of real-life Brazilian women with ER+/ HER2- BC, irrespective of menopausal status, CTS5 proved to be an excellent predictor of OS. In addition, it was shown to be a predictor of response to extended ET. CTS5 score can identify a group of high-risk patients who benefits from extended ET. We consider that it would be of great value to expand the study population and follow-up, especially to analyze whether this tool also has a predictive value in contraindicating extended ET in low- risk and intermediate-risk patients. Table 1. Demographic and Clinical CharacteristicsCharacteristicNo. (%)Age, yearsMedian53IQR26-91&lt; 50 years446 (41.1)&gt;50 years639 (58.9)Tumor size, mm≤ 10285 (24.1)10-20458 (38.7)20-50378 (31.9)&gt;5060 (5.1)GradeWell142 (11,9)Intermediate385 (32,5)Poor654 (55,2)Nodal status (No. of positive nodes)0756 (64.0)1 -3305 (25.8)≥4120 (10.2)ChemotherapyAdjuvant592 (50.1)Neoadjuvant118 (10.0)Endocrine TerapyET 5 years1060 (89,7)ET extendend100 (8.4)ET for less than 5 years.21 (1,8)CTS5Low587 (49.6)Intermediate344 (29.1)High250 (21.1)RecurrenceDistant147 (12,4)Local 39 (3,3) Citation Format: Lucas Vian, Ronaldo Souza, Vladmir Claudio Cordeiro de Lima, Daniella Yumi Tsuji Honda, Samara Theodoro Pacheco, Caio Dabbous de Liz, Luciana Beatriz Mendes Gomes, Bruno Cezar Mendonça Uchôa Júnior, Paula Tavares Guimarães, Celso Silva e Souza Filho, Andréa Paiva Guimarães, Maria Fernanda Evangelista Simões, Mauro Daniel Spina Donadio, Angelo Bezerra de Souza Fêde, Augusto Obuti Saito, Adriana Regina Gonçalves Ribeiro, Joyce Maria Lisboa Maia, Iara Karoline Freire Lustosa, Fabricio de Souza Castro, Monique Celeste Tavares, Marcelle Goldner Cesca, Marcelo Corassa, Noam Falbel Pondé, Solange Sanches. Cts5 tested in a Brazilian population: A tool that can predict global survival in early breast cancer ER+/HER2-, as well as the response to extended endocrine therapy [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 PS6-25.