Assessment of 25-Year Survival of Women With Estrogen Receptor–Positive/<i>ERBB2</i>-Negative Breast Cancer Treated With and Without Tamoxifen Therapy

Dar, Huma; Johansson, Annelie; Nordenskjöld, Anna; Iftimi, Adina; Yau, Christina; Pérez-Tenorio, Gizeh; Benz, Christopher C.; Nordenskjöld, Bo; Stål, Olle; Esserman, Laura J.; Fornander, Tommy; Lindström, Linda S.

doi:10.1001/jamanetworkopen.2021.14904

Cited by 16 publications

(34 citation statements)

References 31 publications

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“…This effect was substantially mitigated in the group without hormone treatment. This finding is in line with a recent study by Dar et al (2021) , which found a significant tamoxifen treatment benefit only among patients suffering from lower grade tumors, while no benefit was observed for grade 3 tumors. In summary, we observed strong hints that hormone treatment alleviates the negative effect of menopause, and increases the negative effect of high tumor grade on patient survival.…”

Section: Resultssupporting

confidence: 92%

BITES: balanced individual treatment effect for survival data

et al. 2022

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Motivation Estimating the effects of interventions on patient outcome is one of the key aspects of personalized medicine. Their inference is often challenged by the fact that the training data comprises only the outcome for the administered treatment, and not for alternative treatments (the so-called counterfactual outcomes). Several methods were suggested for this scenario based on observational data, i.e. data where the intervention was not applied randomly, for both continuous and binary outcome variables. However, patient outcome is often recorded in terms of time-to-event data, comprising right-censored event times if an event does not occur within the observation period. Albeit their enormous importance, time-to-event data are rarely used for treatment optimization. We suggest an approach named BITES (Balanced Individual Treatment Effect for Survival data), which combines a treatment-specific semi-parametric Cox loss with a treatment-balanced deep neural network; i.e. we regularize differences between treated and non-treated patients using Integral Probability Metrics (IPM). Results We show in simulation studies that this approach outperforms the state of the art. Furthermore, we demonstrate in an application to a cohort of breast cancer patients that hormone treatment can be optimized based on six routine parameters. We successfully validated this finding in an independent cohort. Availability and implementation We provide BITES as an easy-to-use python implementation including scheduled hyper-parameter optimization (https://github.com/sschrod/BITES). The data underlying this article are available in the CRAN repository at https://rdrr.io/cran/survival/man/gbsg.html and https://rdrr.io/cran/survival/man/rotterdam.html. Supplementary information Supplementary data are available at Bioinformatics online.

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Section: Resultssupporting

confidence: 92%

BITES: balanced individual treatment effect for survival data

et al. 2022

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“…Shorter recurrence-free survival was also recorded in patients with larger tumor size, patients with regional lymph node metastasis, metastatic cancer and more advanced stage of disease. These findings are in accordance with substantial published evidence supporting the conclusion that an advanced disease stage and its components (higher tumor size, presence of lymph node metastasis and presence of distant organ metastases) are strongly associated with shorter recurrence-free survival in breast cancer [ 57 , 58 , 59 , 60 ]. In univariate survival analysis, patients with higher EORTC-QLQ-C30 scores and better physical activity had a longer time to recurrence than those with lower HRQOL and worse physical activity; however, these associations did not remain significant after adjustment for several confounding factors.…”

Section: Discussionsupporting

confidence: 92%

“…By increasing the sample of our study, the proportion of metastatic breast cancer may be reduced, becoming more representative in accordance with the existing literature [ 57 , 58 , 59 , 60 ]. Lastly, the short-term recurrence rate of our study population is quite high compared to the existing studies [ 57 , 58 , 59 , 60 ]. Accordingly, by increasing the sample of our study, the short-term recurrence rate may be lowered, also becoming more representative and in accordance with the existing literature [ 57 , 58 , 59 , 60 ].…”

Section: Discussionsupporting

confidence: 80%

“…Moreover, in our study population, a rather high proportion of metastatic breast cancer compared to the existing literature was recorded, which may be ascribed by chance to the small number of patients [ 57 , 58 , 59 , 60 ]. By increasing the sample of our study, the proportion of metastatic breast cancer may be reduced, becoming more representative in accordance with the existing literature [ 57 , 58 , 59 , 60 ]. Lastly, the short-term recurrence rate of our study population is quite high compared to the existing studies [ 57 , 58 , 59 , 60 ].…”

Section: Discussionmentioning

confidence: 82%

“…In the meantime, the cumulative risk of recurrence at the 5th and the 20th year after treatment is 6,8% and 21%, respectively [ 57 ]. Stage of cancer [ 58 ], tumor size and tumor differentiation grade can impact disease prognosis [ 59 ]. Even at the early stage of Τ1Ν0, there is a long-term risk of recurrence [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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Adherence to Mediterranean Diet and Nutritional Status in Women with Breast Cancer: What Is Their Impact on Disease Progression and Recurrence-Free Patients’ Survival?

et al. 2022

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Introduction: Nutritional status impacts the survival of patients with cancer. There are few studies that investigate the role of nutritional status on breast cancer survival in women with breast cancer, and even fewer regarding the impact of adhering to the Mediterranean diet (MD). The present study aims to assess the nutritional status, MD adherence, physical activity levels and health-related quality of life (HRQOL) in women diagnosed with breast cancer and evaluate these parameters regarding recurrence-free survival. Methods: A total of 114 women, aged 35–87 years old, diagnosed with breast cancer in Larissa, Greece, participated in the study. Tumor histopathology was reported, and anthropometric indices were measured by a trained nurse, while questionnaires regarding nutritional status (via mini nutritional assessment), HRQOL via EORTC QLQ-C30, physical activity levels via IPAQ and Mediterranean diet adherence via MedDietScore were administered. The participants were followed-up for a maximum time interval of 42 months or until recurrence occurred. Results: A total of 74% of patients were overweight or obese, while 4% of women were undernourished, and 28% were at risk of malnutrition. After 42 months of follow-up, 22 patients (19.3%) had relapsed. The median time to recurrence was 38 months (IQR: 33–40 months) and ranged between 23 to 42 months. Higher levels of MD adherence were significantly associated with lower body mass index (BMI) values, earlier disease stage, smaller tumor size, absence of lymph node metastases and better physical activity levels (p < 0.05). Normal nutritional status was significantly associated with higher BMI values and better health-related quality of life (p ≤ 0.05). In univariate analysis, patients with higher levels of MD adherence and well-nourished patients had significantly longer recurrence-free survival (p < 0.05). In multivariate analysis, MD adherence and nutritional status were independently associated with recurrence-free patients’ survival after adjustment for several confounding factors (p < 0.05). Conclusions: The impact of MD on time to recurrence is still under investigation, and future interventional studies need to focus on the role of adhering to the MD before and after therapy in survival and breast cancer progression. Furthermore, the present study also highlights the importance of an adequate nutritional status on disease progression, and the need for nutritional assessment, education and intervention in women with breast cancer.

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Molecular Genetic Characterization of a Subset of Women With Early Breast Cancer Followed Up for 25 Years in the Stockholm Tamoxifen Clinical Trial

Burton

2021

JAMA Netw Open

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The Dar et al 1 secondary analysis of data from the Stockholm tamoxifen randomized clinical trial published in this issue of JAMA Network Open was conducted in the context of life-long follow-up of women with early breast cancer who received treatment with surgery and adjunct biological therapy, endocrine therapy, and/or chemotherapy. Dar and colleagues 1 performed an immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), ERBB2 (formerly HER2), and cellular proliferation marker Ki-67 status using archival formalin-fixed paraffin-embedded tissue samples from the primary breast cancer tumor; these tissue samples were available for 808 of the 1780 women randomized in the Stockholm tamoxifen clinical trial, which was conducted from 1976 to 1990. Among 808 women, 565 were diagnosed with ER-positive and ERBB2-negative (ER-positive/ ERBB2-negative) breast cancer and were included in the secondary analysis. 1 In this selected subgroup, the outcome measure, distant recurrence-free interval at 25 years, was reported as significantly better among women who received tamoxifen therapy for 5 years compared with women who did not. 1 The authors compared this selected subgroup of women with the total clinical trial cohort and concluded that, although highly selected, the patients in the subgroup were representative of all women with respect to primary tumor size and ER status. Nevertheless, the reported conclusions can only directly apply to this subpopulation of women with ER-positive/ ERBB2-negative breast cancer, which was subsequently recategorized by the immunohistochemical analysis performed in 2014. 1 Lifelong follow-up of breast cancer treatment in randomized clinical trials began with the International Breast Cancer Study Group (IBCSG) clinical trials I to V, which have included lifetime follow-up of all participants since 1978. 2 The IBCSG reported in 2016 that the duration of breast cancer-free interval, the primary outcome measure, from diagnosis and attempted curative treatment for women with ER-positive operable breast cancer remained significantly higher than that of women with ER-negative breast cancer for a median follow-up of 24 years. 2 In the IBCSG clinical trials I to IV, participants received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil for 6 months and adjuvant endocrine therapy with tamoxifen for 12 months; in clinical trial V, participants also received prednisolone for 6 months. 2 The only breast cancer molecular markers measured were the hormone receptors for estrogen and progesterone. 2 The current long-term follow-up report from Dar and colleagues 1 is in the context of adjuvant tamoxifen administered for 5 years to all participants who survived for 2 or more years, 1 which would be expected to improve on the long-term outcome findings reported in the IBCSG clinical trials.The Dar et al 1 study was also performed in the context of increasing recognition that breast cancer is a very complex cancer and that mammographic screening, which is b...

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Assessment of 25-Year Survival of Women With Estrogen Receptor–Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy

Cited by 16 publications

References 31 publications

BITES: balanced individual treatment effect for survival data

BITES: balanced individual treatment effect for survival data

Adherence to Mediterranean Diet and Nutritional Status in Women with Breast Cancer: What Is Their Impact on Disease Progression and Recurrence-Free Patients’ Survival?

Molecular Genetic Characterization of a Subset of Women With Early Breast Cancer Followed Up for 25 Years in the Stockholm Tamoxifen Clinical Trial

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