Annemieke Witteveen

Survival after Locoregional Recurrence or Second Primary Breast Cancer: Impact of the Disease-Free Interval

The association between the disease-free interval (DFI) and survival after a locoregional recurrence (LRR) or second primary (SP) breast cancer remains uncertain. The objective of this study is to clarify this association to obtain more information on expected prognosis. Women first diagnosed with early breast cancer between 2003–2006 were selected from the Netherlands Cancer Registry. LRRs and SP tumours within five years of first diagnosis were examined. The five-year period was subsequently divided into three equal intervals. Prognostic significance of the DFI on survival after a LRR or SP tumour was determined using Kaplan-Meier estimates and multivariable Cox regression analysis. Follow-up was complete until January 1, 2014. A total of 37,278 women was included in the analysis. LRRs or SP tumours were diagnosed in 890 (2,4%) and 897 (2,4%) respectively. Longer DFI was strongly and independently related to an improved survival after a LRR (long versus short: HR 0.65, 95% CI 0.48–0.88; medium versus short HR 0.81, 95% CI 0.65–1.01). Other factors related to improved survival after LRR were younger age (<70 years) and surgical removal of the recurrence. No significant association was found between DFI and survival after SP tumours. This is the first study to explore the association between the DFI and survival after recurrence in a nationwide population-based cancer registry. The DFI before a LRR is an independent prognostic factor for survival, with a longer DFI predicting better prognosis.

Stratified breast cancer follow-up using a partially observable Markov decision process

Frequency and duration of follow-up for patients with breast cancer is still under discussion. Current follow-up consists of annual mammography for the first five years after treatment and does not depend on the personal risk of developing a locoregional recurrence (LRR) or second primary tumor. Aim of this study is to gain insight in how to allocate resources for optimal and personal follow-up. We formulate a discrete-time Partially Observable Markov Decision Process (POMDP) with a finite horzion in which we aim to maximize the total expected number of quality-adjusted life years (QALYs). Transition probabilities were obtained from data from the Netherlands Cancer Registry (NCR). Twice a year the decision is made whether or not a mammography will be performed. Recurrent disease can be detected by both mammography or women themselves (self-detection). The optimal policies were determined for three risk categories based on differentiation of the primary tumor. Our results suggest a slightly more intensive follow-up for patients with a high risk and poorly differentiated tumor, and a less intensive schedule for the other risk groups.

Validation of the online prediction tool PREDICT v. 2.0 in the Dutch breast cancer population.

BACKGROUND PREDICT version 2.0 is increasingly used to estimate prognosis in breast cancer. This study aimed to validate this tool in specific prognostic subgroups in the Netherlands. METHODS All operated women with non-metastatic primary invasive breast cancer, diagnosed in 2005, were selected from the nationwide Netherlands Cancer Registry (NCR). Predicted and observed 5- and 10-year overall survival (OS) were compared for the overall cohort, separated by oestrogen receptor (ER) status, and predefined subgroups. A >5% difference was considered as clinically relevant. Discriminatory accuracy and goodness-of-fit were determined using the area under the receiver operating characteristic curve (AUC) and the Chi-squared-test. RESULTS We included 8834 patients. Discriminatory accuracy for 5-year OS was good (AUC 0.80). For ER-positive and ER-negative patients, AUCs were 0.79 and 0.75, respectively. Predicted 5-year OS differed from observed by -1.4% in the entire cohort, -0.7% in ER-positive and -4.9% in ER-negative patients. Five-year OS was accurately predicted in all subgroups. Discriminatory accuracy for 10-year OS was good (AUC 0.78). For ER-positive and ER-negative patients AUCs were 0.78 and 0.76, respectively. Predicted 10-year OS differed from observed by -1.0% in the entire cohort, -0.1% in ER-positive and -5.3 in ER-negative patients. Ten-year OS was overestimated (6.3%) in patients ≥75 years and underestimated (-13.%) in T3 tumours and patients treated with both endocrine therapy and chemotherapy (-6.6%). CONCLUSIONS PREDICT predicts OS reliably in most Dutch breast cancer patients, although results for both 5-year and 10-year OS should be interpreted carefully in ER-negative patients. Furthermore, 10-year OS should be interpreted cautiously in patients ≥75 years, T3 tumours and in patients considering endocrine therapy and chemotherapy.

Risk-based breast cancer follow-up stratified by age

Although personalization of cancer care is recommended, current follow‐up after the curative treatment of breast cancer is consensus‐based and not differentiated for base‐line risk. Every patient receives annual follow‐up for 5 years without taking into account the individual risk of recurrence. The aim of this study was to introduce personalized follow‐up schemes by stratifying for age. Using data from the Netherlands Cancer Registry of 37 230 patients with early breast cancer between 2003 and 2006, the risk of recurrence was determined for four age groups (<50, 50‐59, 60‐69, >70). Follow‐up was modeled with a discrete‐time partially observable Markov decision process. The decision to test for recurrences was made two times per year. Recurrences could be detected by mammography as well as by self‐detection. For all age groups, it was optimal to have more intensive follow‐up around the peak in recurrence risk in the second year after diagnosis. For the first age group (<50) with the highest risk, a slightly more intensive follow‐up with one extra visit was proposed compared to the current guideline recommendation. The other age groups were recommended less visits: four for ages 50‐59, three for 60‐69, and three for ≥70. With this model for risk‐based follow‐up, clinicians can make informed decisions and focus resources on patients with higher risk, while avoiding unnecessary and potentially harmful follow‐up visits for women with very low risks. The model can easily be extended to take into account more risk factors and provide even more personalized follow‐up schedules.

Abstract P6-09-03: Time-dependent nomogram for risk of locoregional recurrence in early breast cancer patients: 10 year extension

Background The objective of this study was to extent the recently developed and validated time-dependent logistic regression model and web-based nomogram. This nomogram is suitable for the annual long term risk prediction of locoregional recurrence (LRR) in individual breast cancer patients and clinical decision support with regard to the follow-up. Methods Women first diagnosed with early breast cancer between 2003-2006 in all Dutch hospitals were selected from the Netherlands Cancer Registry with five year of recurrence follow-up (n=37,230). Of the year 2003 follow-up was retrieved for ten years. In the first five years following primary breast cancer treatment 3.7% of the selected patients developed a LRR as a first event, in ten years 6.2%. Risk factors were determined using logistic regression and the risks were calculated per year, conditional on not being diagnosed with recurrence in the previous year. Discrimination and calibration were assessed. Bootstrapping was used for internal validation. Data on primary tumors diagnosed between 2007-2008 in 43 Dutch hospitals was used for external validation of the performance of the nomogram (n=12,308). Results The final model included the variables grade, size, multifocality, and nodal involvement of the primary tumor, and whether patients were treated with radio-, chemo- or hormone therapy. Model predictions were well calibrated. Estimates in the validation cohort did not differ significantly from the index cohort. The results were incorporated in a web-based nomogram. In 0.7% of the patients, the risk of LRR between year 5-10 was higher than the average risk of all patients in the first five years. All of these patients were aged below 50, had a tumour size larger than 2 cm, non-negative hormone status, received radiotherapy, but no hormone therapy and 19% developed a recurrence during ten years. Conclusion/discussion This validated and time-dependent nomogram for the prediction of annual LRR risks over ten years is simple to use and shows a good predictive ability in the Dutch population. It can be used as an instrument to identify patients with a low or high risk of LRR who might benefit from a less or more intensive and longer follow-up after breast cancer and to aid clinical decision-making for personalized follow-up. Citation Format: Witteveen A, Vliegen IMH, Sonke GS, Klaase JM, IJzerman MJ, Siesling S. Time-dependent nomogram for risk of locoregional recurrence in early breast cancer patients: 10 year extension. [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 P6-09-03.

Survival After Locoregional Recurrence or Second Primary Breast Cancer: Impact of the Disease-Free Interval

The association between the disease-free interval (DFI) and survival after a locoregional recurrence (LRR) or second primary (SP) breast cancer remains uncertain. The objective of this study is to clarify this association to obtain more information on expected prognosis. Women first diagnosed with early breast cancer between 2003–2006 were selected from the Netherlands Cancer Registry. LRRs and SP tumours within five years of first diagnosis were examined. The five-year period was subsequently divided into three equal intervals. Prognostic significance of the DFI on survival after a LRR or SP tumour was determined using Kaplan-Meier estimates and multivariable Cox regression analysis. Follow-up was complete until January 1, 2014. A total of 37,278 women was included in the analysis. LRRs or SP tumours were diagnosed in 890 (2,4%) and 897 (2,4%) respectively. Longer DFI was strongly and independently related to an improved survival after a LRR (long versus short: HR 0.65, 95% CI 0.48–0.88; medium versus short HR 0.81, 95% CI 0.65–1.01). Other factors related to improved survival after LRR were younger age (<70 years) and surgical removal of the recurrence. No significant association was found between DFI and survival after SP tumours. This is the first study to explore the association between the DFI and survival after recurrence in a nationwide population-based cancer registry. The DFI before a LRR is an independent prognostic factor for survival, with a longer DFI predicting better prognosis