Purpose: Increased insight in tumor biology has revealed that not all young women are at high risk of disease recurrence. Therefore, in some patients extent of treatment could probably be safely scaled down. We aimed to evaluate the risk of breast cancer (BC) relapse according to the 70-gene signature (70-GS) result in relation to young age, in early-stage BC patients enrolled in the MINDACT trial. Patients and Methods: The analyzed population consisted of enrolled BC patients in the MINDACT trial with available clinical (C), as per a modified version of Adjuvant!Online, and genomic (G), according to the 70-GS, risk assessments and known age (n=6693). Patients were categorized in three age groups; <45 (young), 45-55 (peri-menopausal) and >55 years (post-menopausal). Clinicopathological and treatment characteristics as well as gene expression were compared for the different age groups further split by corrected risk groups (C-low/G-low, C-low/G-high, C-high/G-low, C-high/G-high). Subsequently, the 5-year distant metastasis-free survival according to risk category was calculated. Results: The study included 1100 patients <45 (16%), 2272 aged 45-55 (34%) and 3321 patients >55 years of age (50%). Median age of the young group was 41 (25.8-45.0) years. The young age group had a higher frequency of lymph node involvement (25% vs. 22% and 19%), poorly differentiated tumors (42% vs. 26% and 27%), ER-negative tumors (20% vs. 11% and 11%) and triple negative molecular IHC subtype (16% vs. 9% ad 8%). Median tumor size was the same across the 3 age groups (17mm). Of the 1100 young patients, 61% were C-high while the 70-GS assessed 48% as G-high. Overall, 31% were CL/GL (vs. 43% in other age groups), 9% CL/GH, 21% CH/GL and 40% CH/GH (vs. 24% and 25%). In the discordant risk groups, chemotherapy (CT) allocation when randomized to no chemo occurred in 5% of young women as compared to 3% and 1% in the older age groups. Reason for non-compliance was 50/50 between patient refusal and PI decision. Overall, the 5-year DMFS was 94.1% (95% CI 92.4-95.4) in <45 age group, 95.3% (95% CI 94.2-96.1) in 45-55 and 94.9% (95% CI 94.0-95.6) in >55. For the young patients, 5-year DMFS was 98.3% for the CL/GL (96.0-99.3), 97.4% in CL/GH (90.0-99.4), 95.5% in CH/GL (91.6-97.7) and 89.2% in CH/GH (85.6-92.0). In the older two age groups (45-55 and >55), the 5-year DMFS rates were 97.8% (96.5.98.6) and 97.2% (96.2-98.0) for CL/GL, 93.9% (88.8-96.7) and 94.5% (91.0-96.7) for CL/GH, 94.5% (92.0-96.3) and 95.4% (93.5-96.8) for CH/GL and 92.0% (89.2-94.1) and 90.4% (88.0-92.4) for CH/GH, respectively. With 9 events in the <45 group at a CH/GL risk, numbers were too small to evaluate chemotherapy effect in this population. Conclusion: The use of the 70-GS reduces the proportion of patients characterized as high risk as compared to traditional clinical risk assessment (48% vs. 61%). Outcome was comparable for the 3 age categories with a very good 5-year DMFS of 95-98% in all GL groups. Performing the 70-GS provides clinically relevant information concerning the prognosis for young early-stage BC patients categorized as CH. These results add important new data to the limited available evidence on genomic expression in young BC patients. Citation Format: Aalders K, Genbrugge E, Poncet C, Kuijer A, Pistilli B, Piccart M, Tryfonidis K, van Dalen T, Cardoso F, van 't Veer L, Rutgers E. Young age and the risk of disease recurrence as assessed by the 70-gene signature – an analysis from the EORTC 10041/BIG 03-04 MINDACT trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-08.
Introduction: Historically, young breast cancer patients proved to have a poorer prognosis regarding survival and locoregional recurrence. Over the last two decades, the survival of breast cancer patients has improved substantially, while at the same time locoregional recurrence rates decreased. The diminishing recurrence rates in the overall breast cancer population and acknowledgement of tumor biology and intrinsic subtypes in relation to age, raise the question whether the historically high locoregional recurrence risk in young women has decreased over a time where systemic treatment has evolved, particularly for the aggressive tumor types that occur frequently in young women. The aim of this study was to evaluate contemporary local and regional recurrence rates in very young breast cancer patients in relation to tumor biology in the shape of intrinsic subtypes. Methods: Women <35 years of age who were operated for primary unilateral invasive breast cancer between 2003-2008 were selected from the Netherlands Cancer Registry. Patients were categorized according to intrinsic subtypes using hormone receptor and HER2 status. The 5-year risks of developing local recurrence (LR) and regional lymph node recurrence (RR) were estimated using Kaplan Meier statistics. The prognostic influence of different clinicopathological and treatment factors was assessed. Results: A total of 1,000 patients were identified. The overall 5-year LR and RR rates were 3.5% and 3.7% respectively and a decreasing trend for both rates was observed over time. Overall 5-year local, regional and distant recurrence rates over time in breast cancer patients <35 years (n=1,000) Local recurrence*Regional recurrenceDistant metastases NRateNRateNRate2003n=21384.2%116.1%3617.8%2004n=212105.6%105.1%3819.2%2005n=18232.0%53.1%2514.6%2006n=17053.2%21.2%138.2%2007•n=11722.1%10.9%98.1%2008•n=10633.2%44.4%1010.0%Totaln=1,000313.5%333.7%13113.9%*Local recurrence (ipsilateral in-breast recurrence + new primary) •Fewer patients were included in the years 2007-2008 compared to earlier years due to the fact that some hospitals did not provide data for those years. Rates represent Kaplan Meier estimates Intrinsic subtype proved to be a prognostic factor for both LR and RR (P=0.0556 and P=0.0141, respectively). Particularly HR-/HER2+ tumors were associated with high LR and RR rates. Patients with lymph node metastases at time of diagnosis had a higher RR-risk in both the total population (P=0.0349) as well as within the different intrinsic subtypes, although only significantly in the triple negative group (P=0.0401). Type of surgery did not influence the rate of LR and RR in this study. Conclusions: Overall, the LR and RR rates in very young breast cancer patients were relatively low and decreased over time. The higher recurrence rates in this population were associated with the presence of more aggressive intrinsic subtypes. We emphasize that tumor biology should guide decision-making towards optimal treatment in this specific population. Although longer follow-up is needed, especially for this very young patient population, the results of this study provide important insight in the locoregional recurrence risks for this historically high-risk population. Citation Format: Aalders KC, Postma EL, Strobbe LJ, van der Heiden-van der Loo M, Sonke GS, Boersma LJ, van Diest PJ, Siesling S, van Dalen T. Contemporary local and regional recurrence rates in very young breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-01.
Introduction Neo-adjuvant chemotherapy (NAC) is increasingly used in breast cancer to enable less extensive surgery and monitor the response to systemic therapy. Little is known about local recurrence (LR) in patients who received NAC. However, this information is important when deciding on optimal local treatment in these patients, especially since NAC is increasingly being offered to patients with smaller tumors. The aim of this study is to assess the contemporary rates of local breast cancer recurrence in patients that received NAC. Methods All women treated with NAC for primary invasive breast cancer in the years 2003-2008 were selected from the Netherlands Cancer Registry. The first event within five years after NAC was included for analyses. The 5-year local (LR) recurrence rate was calculated using Kaplan Meier estimates and the prognostic value of various clinicopathological and treatment factors was evaluated. Results A total of 2,457 patients were identified of whom 43% had cT1-2, 25% cT3 and 29% cT4 tumors. Two-thirds of the patients had metastatic lymph node involvement and 85% received adjuvant radiotherapy. The overall 5-year risk of LR was 6.7% and decreased from 2003-2008. Table 1. Overall 5-year rate of local breast cancer recurrence in 2,457 breast cancer patients that received neo-adjuvant chemotherapy in the period 2003-2008. Local recurrencea NRate2003N=412309.6%2004N=429288.0%2005N=549398.1%2006N=604234.7%2007N=406164.7%2008N=489245.5%TotalN=2,4571606.7%aLocal recurrence defined as ipsilateral in-breast recurrence or new primary Rates represent Kaplan Meier estimates The LR-rate was lower in hormone receptor positive (HR+) than HR-negative (HR-) tumors (3.3% vs. 12.9%) and increased with larger residual tumor size (from 1.2% in ypT0 to 13.0% in ypT3 and 16.1% in ypT4 tumors). The LR-rate also increased with the ypN-stage (4.1% in ypN0, 5.7% in ypN1 and 11.3% in ypN>1 patients) and was lower following breast-conserving surgery (BCS) than after mastectomy (4.8% vs. 7.2%). Currently, we are working on the multivariate analyses, which will be available at the San Antonio Breast Cancer Symposium. Conclusions The rate of LR in patients treated with NAC has decreased over time. This will most likely be caused by enhanced imaging and radiotherapy techniques, as well as by increased insight in tumor biology resulting in improvements in both the development and application of systemic treatment modalities. Multivariate analyses will have to provide further insight into the risk of developing LR in patients treated with NAC, as well as into the prognostic value of different clinicopathological factors. Citation Format: Aalders KC, Sonke GS, van der Heiden-van der Loo M, Boersma LJ, van Diest PJ, Siesling S, van Dalen T. Contemporary risk of local breast cancer recurrence after neo-adjuvant chemotherapy: Results of a population-based cohort study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-36.
Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at higher risk of chemotherapy-induced toxicity raising high interest in a less toxic backbone such as metronomic chemotherapy and in chemo-free dual HER2 blockade (TP). Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed.T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6 months seeking a difference of ≥ 10% between the two arms. Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 71% and/or to short physical performance battery (<10) 81%, Charlson comorbidity score > 0 in 40%. With 20.7 months of median follow-up, 6-month and median PFS were 46.2% (95% CI 30.2-60.7) and 5.6 months (95% CI 3.6-16.8) versus 73.4% (95% CI 56.6-84.6) and 12.7 months (95% CI 6.7-24.8) for TP and TPM, respectively. Four patients in TPM and 2 in TP developed brain metastases only as progression event. OS and breast cancer specific survival were comparable between the two arms; 9/29 deaths were not breast cancer-related. Response rate was 44% in TP arm and 53% in TPM arm. In 29 patients who received T-DM1 second line, 6-month PFS, median PFS and response rate were 49.5% (95% CI 29.2-66.9), 5 months (95% CI 2.5-12.5) and 13.5%. In patients who discontinued TP(M), 37, 9 and 14 stopped because of progression, toxicity or other reasons, respectively. During TPM treatment, 1 patient died of heart failure and 1 developed grade 3 heart failure; 1 patient in each arm developed a ≥ 10% asymptomatic left ventricular ejection fraction decrease below 50%. Diarrhea any grade and grade ≥ 3 were observed in 56% and 8% versus 71% and 12% patients in TP and TPM arms, respectively. No grade 3 or febrile neutropenia was reported. There was no relevant difference in functional evolution between both groups. In the whole population, several geriatric items were of prognostic value by multivariate analysis: e.g. for OS, G8 >14 vs ≤ 14 HR=0.12 (95% CI 0.03-0.55, p 0.006). In 29 patients receiving T-DM1, grade 3 toxicity was rare: fatigue (2 patients), thrombocytopenia and epistaxis (1 patient). Conclusions: Metronomic chemotherapy-based dual blockade (TPM) seems to be superior to dual blockade alone (TP) in an elderly/frail HER2+ MBC population, with an attractive safety profile. TPM, followed by T-DM1 after progression, may delay or supersede taxane chemotherapy in this population. Citation Format: Wildiers H, Tryfonidis K, dal Lago L, Vuylsteke P, Curigliano G, Waters S, Brouwers B, Aalders K, Meulemans B, Litiere S, Touati N, Cardoso F, Brain E. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-09.
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