Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: A matched cohort study

Abstract

Introduction

Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking.

Methods

We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls.

Results

The median follow-up was 4.4 years (range 0.1–30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74–1.04) and BRCA2 (HR 0.58, 95% CI 0.41–0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58–0.84) and BRCA2 (HR 0.41, 95% CI 0.29–0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients.

Conclusion

For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.

Introduction

Despite a relatively low cumulative life-time risk–~1.6% for women in the western world–ovarian cancer is the fifth most common cause of cancer death in women, with worldwide over 150,000 deaths each year [1, 2]. The high mortality rate is largely due to the tendency to early spreading in the abdominal cavity, and most ovarian cancers being diagnosed at advanced stages (FIGO stage III/IV) [3–5]. Despite a high response rate to platinum-based chemotherapy, the overall survival (OS) remains poor with a 5-year overall survival of only 30–40% [3, 4].

Approximately 11–15% of all epithelial ovarian cancer (EOC) patients carry a BRCA1 or BRCA2 germline pathogenic variant (gPV) [6–10]. Women with a BRCA gPV have a high cumulative life-time risk of developing EOC, being 40–60% for BRCA1 and 10–25% for BRCA2 gPV carriers [11–15]. In general, EOC in BRCA gPV carriers is diagnosed at a younger age than in sporadic patients, and younger in BRCA1 gPV carriers than in BRCA2 gPV carriers [11–16]. In view of the absence of effective screening for EOC, women with a proven BRCA gPV are advised to opt for premenopausal risk-reducing salpingo-oophorectomy at the age of 35 to 40 years for BRCA1 gPV carriers and 40 to 45 years for BRCA2 gPV carriers.

BRCA-deficiency is associated with an impaired ability to repair double-strand DNA breaks by the DNA repair mechanism homologous recombination [17–21]. This may lead to higher response rates to first-line platinum-based chemotherapy–which causes double-strand DNA breaks–and thus to improved survival [22–24]. Indeed, some studies have reported better survival for BRCA-associated EOC patients than for sporadic patients [10, 22–26], although the reported results are not consistent [27–29]. Survival benefit may be limited to BRCA2 gPV carriers [30], or only applicable to the first five to ten years [31–33]. A few studies showed also higher response rates to platinum-based chemotherapy after recurrent EOC in BRCA gPV carriers than in sporadic EOC patients, but the numbers of included patients are small [10, 24, 34]. Further, the sensitivity to platinum-based chemotherapy might depend on the associated gene and/or the specific pathogenic variant [28, 30].

Altogether, definitive evidence of better prognosis for BRCA-associated EOC patients is still unavailable. Moreover, while BRCA1 and BRCA2 tumors might represent different entities, most studies did not investigate prognosis and survival after EOC separately for BRCA1 and BRCA2. In the current retrospective cohort study we compare progression-free survival (PFS) and overall survival (OS) between either germline BRCA1-associated EOC patients or germline BRCA2-associated EOC patients and matched sporadic EOC patients treated with first-line chemotherapy.

Participants and methods

Study population

For this retrospective matched cohort study, we selected BRCA1 and BRCA2 gPV carriers with a history of EOC from the national Hereditary Breast and Ovarian Cancer Netherlands (HEBON) database. In the context of the HEBON study, members of breast and/or ovarian cancer families are being identified through the departments of Clinical Genetics/Family Cancer Clinics at eight Dutch academic centers and the Netherlands Cancer Institute [35]. The study was approved by the Medical Ethical Committees of all participating centers. Written informed consent was obtained from each participant or from a close relative in case of deceased individuals. Relevant data on participants including data on preventive strategies, the occurrence of cancer, and vital status were retrieved and updated through medical files and questionnaires, and through linkages to the Netherlands Cancer Registry, the Dutch Pathology Database, and the municipal registry database. The latest follow-up date was December 31, 2017.

From this national cohort, we selected 389 BRCA1 gPV carriers and 123 BRCA2 gPV carriers with EOC. Patients were eligible for the study if they were diagnosed with EOC after 1988, had a proven BRCA gPV (with DNA test result either before or after EOC diagnosis), and received chemotherapy after diagnosis of primary EOC (in case of surgery, either before or after).

The selected BRCA gPV carriers were matched 1:1 to sporadic EOC patients from the National Cancer Registry on year of birth (+/– 5 years), year of EOC diagnosis (+/- 5 years), and FIGO stage (≤IIA/≥IIB/unknown). Sporadic patients were defined as patients who were either not DNA tested due to a negative family history of breast cancer or ovarian cancer or because DNA testing was not available yet, or DNA tested and without a proven BRCA gPV. Notably, about 5% of EOCs have a somatic BRCA pathogenic variant, but somatic testing has only been widely implied since 2020 in the Netherlands and data hereon is therefore not available for the current cohort.

Data collection

We retrieved data on the associated gene (i.e. BRCA1 or BRCA2) and date of DNA test result, dates of birth and death, and dates of diagnosis of EOC, first recurrent disease, and other cancers. We also collected data on tumor characteristics (FIGO stage, histology, and differentiation grade), CA125 at EOC diagnosis, and treatment details after primary EOC diagnosis and in the recurrent setting (surgery, type of chemotherapy, and maintenance treatment with poly(ADP-ribose) polymerase inhibitors (PARPi)).

Statistical analyses

We evaluated clinical characteristics by comparing EOC patients with (BRCA1 and BRCA2 groups) and without a proven BRCA gPV (sporadic groups). We used Pearson’s chi-squared test for differences between the BRCA groups and the sporadic groups for categorical variables, and Wilcoxon rank-sum to test the equality of the medians for continuous variables.

The outcomes PFS and OS were measured in person-years of observation. The observation period started at the date of EOC diagnosis, and ended at the date of a censoring event or the date of first recurrence for the PFS analyses or death for the OS analyses. Censoring events included diagnosis of a new primary malignant tumor, date of last follow-up, and date of death (for PFS only).

To estimate the associations between gPV status (BRCA1 or BRCA2 versus sporadic) and survival endpoints, we used Cox proportional hazards models with the sporadic groups as the references to obtain hazard ratios (HR) with corresponding 95% confidence intervals (CI). We considered age at EOC diagnosis, grade, CA125 at diagnosis, type of chemotherapy, debulking surgery (yes/no), and complete debulking surgery (yes/no, i.e. the absence/presence of any residual disease) as potential confounders. The matching variables year of birth, year of EOC diagnosis, and FIGO stage were by definition not confounding factors. We generated Kaplan-Meier survival curves, and used the log-rank test for equality of survivor functions to test whether the curves were significantly different from each other. We performed all analyses separately for BRCA1 and BRCA2 gPV carriers.

Further, BRCA gPV carriers who underwent DNA testing after EOC diagnosis survived at least until this DNA test, which was in some cases many years after EOC diagnosis. To investigate whether this resulted in survival bias in favor of the BRCA gPV carriers, we also performed prospective analyses limited to BRCA-associated EOC patients with a DNA test result before EOC diagnosis and their matched sporadic controls.

Furthermore, as previous studies reported different short-term and long-term survival rates for gPV carriers [31–33], the proportional hazards assumption may be violated. Therefore we used Schoenfeld residuals to test whether the proportional hazards assumption is violated. If that was the case, we stratified the Cox models by a specified time-of-observation, i.e. the moment t where the HR switched from under 1 to above 1 (or vice versa). We calculated this exact moment using the formula(1)where x is the variable of interest (i.e. BRCA1/BRCA2 or sporadic), β is the β coefficient, and δ is the time-varying coefficient. When the proportional hazards assumption is valid, δ equals zero. Otherwise, we can calculate t using

1. HR(t) = 1

2. ⇨ ln(HR(t)) = 0

3. ⇨ ln(exp(βx + δxt)) = 0

4. ⇨ βx + δxt = 0

5. ⇨ t = -β / δ

where β and δ are derived from the Cox model including both the variable for gPV status and the interaction term of this variable with time.

All p-values were two-sided, and a significance level α = 0.05 was used. Analyses were performed using Stata/SE (version 16.0, StataCorp, Collegestation, TX).

Results

Study population

As shown in Table 1, the 389 BRCA1 gPV carriers and the 123 BRCA2 gPV carriers had longer follow-up than their matched sporadic EOC patients (median years 4.8 versus 3.5 for the BRCA1 comparison, p<0.001; 5.7 versus 3.5 for the BRCA2 comparison, p<0.001). The vast majority of the patients received platinum-based chemotherapy. After recurrence of disease, BRCA1-associated EOC patients were treated more often with chemotherapy than the sporadic patients (90% versus 79%, p<0.001), which did not apply for the BRCA2 comparison (Table 1). The characteristics for the dataset used for the prospective analyses (in total n = 82 matched pairs) are shown in S1 Table.

[Figure omitted. See PDF.]

Potential confounders

No differences between the groups were observed for the matching variables year of birth, year of EOC diagnosis, and FIGO stage, nor for age at EOC diagnosis and type of chemotherapy (Table 1). Due to the large proportion of missing data for CA125 at diagnosis, EOC grade, and completeness of debulking surgery, no adjustment was possible for these variables. We performed Cox models adjusted for debulking surgery (yes/no), with the sporadic groups as the references.

Survival analyses

We observed no differences between the BRCA-associated groups and their matched sporadic patients in the percentage of patients with recurrent disease. The time between diagnoses of EOC and first recurrence, though, was longer for BRCA-associated patients than for the sporadic patients (BRCA1 comparison: 18.3 versus 15.9 months, p<0.005; BRCA2 comparison: 22.3 versus 15.7 months, p<0.001; Table 1). Likewise, the percentages of deceased patients were similar in all comparison groups, while the time between diagnosis of first recurrence and death is longer for EOC patients with a BRCA gPV (BRCA1 comparison: 25.9 versus 13.9 months, p<0.001; BRCA2 comparison: 25 versus 15.3 months, p<0.001; Table 1).

As shown in Table 2, while BRCA1 gPV status was not associated with significant differences in PFS, the Cox model for OS yielded an HR of 0.82 (95% CI 0.7–0.97) in favor of BRCA1 gPV carriers. In addition, the prospective analyses–limited to BRCA1-associated EOC patients with a DNA test result before EOC diagnosis and their matched sporadic controls–showed better PFS (HR 0.65, 95% CI 0.43–0.97), but no significant OS benefit for BRCA1 gPV carriers (HR 0.86, 95% CI 0.56–1.3; Table 2). Accompanying survival curves are depicted in Fig 1. As the proportional hazards assumption was violated for all models, the analyses were stratified for the moment in time t where the HR equals 1. The stratified analyses revealed HRs under 1 when the observation time was shorter than t (varying from 3.1 to 6 years), and above 1 for longer observation time (Table 2).

[Figure omitted. See PDF.]

(A) progression-free survival and (B) overall survival for the complete dataset; (C) progression-free survival and (D) overall survival for the prospective dataset.

[Figure omitted. See PDF.]

Overall, as shown in Table 3, BRCA2 gPV carriers showed better PFS (HR 0.67, 95% CI 0.5–0.91) and OS (HR 0.61, 95% CI 0.44–0.83) than their matched sporadic patients, which can also be seen in Fig 2. The stratified analyses revealed a significant risk-reduction in favor of BRCA2 gPV carriers for PFS (HR 0.58, 95% CI 0.41–0.81; Table 3) and OS (HR 0.41, 95% CI 0.29–0.59) for the observation period under t (being 3 and 6 years, respectively), but a higher risk for death after t (HR 3.14, 95% CI 1.34–7.34). The numbers of patients in the prospective analyses were too small to draw meaningful conclusions (Table 3 and Fig 2).

[Figure omitted. See PDF.]

(A) progression-free survival and (B) overall survival for the complete dataset; (C) progression-free survival and (D) overall survival for the prospective dataset.

[Figure omitted. See PDF.]

Discussion

In this retrospective matched cohort study, we confirmed better PFS during the first three years after EOC diagnosis and OS benefit during the first six years for patients with a BRCA1 or BRCA2 germline PV. After surviving this period, the benefit disappears, and might even turn into a higher risk of dying for gPV carriers. The observed survival benefit was slightly stronger for BRCA2 than for BRCA1.

Our results are in line with a number of previous studies. Studies with limited follow-up periods showed improved PFS and OS–with comparable periods without progression and time till death as seen in our study–for BRCA1-associated EOC patients [23], BRCA2-associated patients [23, 30], or combined BRCA1/2 cohorts [10, 22, 24–26]. Studies with long-term periods of follow-up showed that improved overall survival seems to be mainly driven by the first five years after diagnosis, with no benefit for those surviving that first period [31, 33, 36], or even worse OS afterwards [32], as observed in the current study.

Previously observed survival benefit could have been an age-effect. Recently, Mallen et al. observed worse survival for older patients, although the authors noted this may merely be the result of tumor biology rather than comorbidities [37]. As we currently matched–indirectly by matching on year of birth and year of diagnosis–on age at diagnosis, in contrast to most of the previous studies, our results support the suggestion that the observed difference is not related to age.

Our results support the hypothesis regarding BRCA1/2-associated EOC patients being more sensitive to platinum-based chemotherapy, especially since none of the patients in the current cohort received first-line maintenance treatment with a PARPi. Primary systemic treatment was not different for EOC patients with and without a BRCA1/2 germline gPV. Therefore, differences in PFS cannot be attributed to differences in received chemotherapy treatment, leaving gPV status as the most likely explanation. Although debulking surgery was performed in the vast majority of the patients (~95%), sporadic patients underwent less often debulking surgery, possibly due to a very poor prognosis of disease at diagnosis, or due to the presence of comorbidities. As this may indicate a higher baseline risk for death in the sporadic EOC groups, we adjusted the analyses for this variable.

In the recurrent setting BRCA-associated EOC patients were more often treated with chemotherapy, which may have influenced survival. The rationale for omitting systemic treatment may have been a worse clinical situation at presentation of recurrent disease, potentially resulting in a higher baseline risk of dying after recurrent EOC in the sporadic group. Further, in the BRCA groups more patients received PARPi after recurrent disease as a maintenance therapy. However, since PARPi has only been administered since 2015, the majority of the patients in the current cohort (approximately 95%) did not receive PARPi. For the sake of completeness, we performed subgroup analyses for OS excluding patients who were treated with PARPi in the recurrent setting and their matched counterparts. As none of the patients were treated with PARPi in the first-line, such subgroup analyses were not necessary for PFS. The subgroup analyses for OS revealed similar results as the original analyses (HR 0.81, 95% CI 0.68–0.97 for BRCA1 and HR 0.65, 95% CI 0.47–0.9 for BRCA2). Thus, the influence of PARPi in the recurrent setting is very limited in this study. This will increase, though, in future studies due to current clinical practice [38].

As previously described, including prevalent cases in studies involving BRCA gPV carriers can introduce seriously biased results [39, 40]. The majority of the gPV carriers in our cohort had their DNA tested after EOC diagnosis, with survival times up to 20 years until DNA test. Reassuringly, for the BRCA1 comparison, the additional prospective analyses showed comparable overall survival as for the complete analyses, suggesting minimal bias as a result from delayed DNA testing. Unfortunately, due to the small number of BRCA2 gPV carriers with a DNA test before cancer diagnosis, we were unable to draw meaningful conclusions from the prospective analyses among BRCA2 gPV carriers and matched sporadic patients. Alternatively, we performed left-truncated analyses with the observation for the BRCA groups starting at the date of either DNA test result or EOC diagnosis, whichever came last, thus excluding patients with recurrent disease, LFU or death before DNA test result. As shown in S2 Table, the results were comparable to those for the complete and prospective analyses, confirming minimal bias due to delayed DNA testing.

Other strengths of the current design include the separate BRCA1 and BRCA2 analyses, and the fact that we matched–indirectly by matching on year of birth and year of diagnosis–on age at diagnosis. The advantage of the latter is that also the sporadic EOC patients were relatively young at diagnosis. Therefore, we can reasonably assume that the leading cause of death is ovarian cancer in both groups, and that the mortality in the sporadic group is not distorted by competing causes of death due to older age.

One of the limitations of the study may be that not all sporadic patients were tested for a BRCA germline gPV. As mentioned before, the majority of the BRCA-associated EOC patients were tested after cancer diagnosis. Theoretically, the sporadic group may contain patients who were actually gPV carriers but never had the opportunity to get tested because they had died before DNA testing was performed or was even implemented in clinical practice. Unintentional misclassification of deceased patients in the sporadic groups may simultaneously overestimate the risk of dying in the sporadic groups and underestimate that risk in the BRCA groups, thus potentially overestimating the benefit for BRCA gPV carriers. Oppositely, the sporadic group may also include untested gPV carriers without recurrent disease or death, oppositely leading to an underestimation of the benefit. With regard to potential misclassification, we would like to emphasize that with the introduction of PARPi in 2015, more and more EOC patients undergo DNA testing sooner after diagnosis in order to receive the optimal treatment, at first only in the recurrent setting but nowadays also at primary disease.

In addition, data on somatic testing is not available for the current cohort. As a result, the sporadic group may contain a number of BRCA positive specimens, which may have influenced the results. However, as about only 5% of EOCs have a somatic BRCA pathogenic variant, we think this influence will be limited. Moreover, under the assumption that survival benefit will also apply to EOCs with a somatic BRCA pathogenic variant, potential misclassification of these EOCs in the sporadic group would led to an underestimation of the observed survival benefit on the short-term rather than an overestimation. Therefore, although the lack of data on somatic testing may be a deficiency in the study, in our opinion this may play a minor role.

Another limitation is the limited availability of data regarding complete debulking or residual disease after primary surgery in our study. In a previous study the only independent prognostic factor for survival in BRCA1/2 gPV carriers was the extent of debulking at primary surgery, with better survival for patients without macroscopic disease [10]. Recently, Ataseven et al. confirmed that complete macroscopic tumor resection is a strong prognostic factor in patients with EOC, regardless of BRCA status [26]. In the current study we did adjust for debulking surgery (yes/no), but the amount of residual disease may be more important in this respect. However, we found no differences between the comparison groups in the percentages of patients with residual disease for those patients with available data. Therefore, we expect no influence on the estimated HRs by adjusting for the amount of residual disease.

In conclusion, in this large case-matched cohort study we confirmed survival benefit for BRCA1/2-associated EOC patients treated with mainly platinum-based chemotherapy. This may indicate higher sensitivity to chemotherapy, both in the first-line and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after EOC diagnosis. Future research is warranted to assess in more detail the added value of PARPi on both PFS and OS, especially on the long-term, where the benefit of classic systemic treatment seems to diminish and even disappear.

Supporting information

S1 Table. Patient and tumor characteristics–dataset for prospective analyses.

https://doi.org/10.1371/journal.pone.0275015.s001

(DOCX)

S2 Table. Association of BRCA1 and BRCA2 germline pathogenic variant status with progression-free survival and overall survival for the left-truncated analyses.

https://doi.org/10.1371/journal.pone.0275015.s002

(DOCX)

Acknowledgments

The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, University of Amsterdam, NL: I. van de Beek; Amsterdam UMC, Vrije Universiteit Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez García, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): E.C. van den Broek. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. The authors thank Dr. M. Kriege and Dr. C. Seynaeve for their intellectual contribution to the design of the study.

Citation: Heemskerk-Gerritsen BAM, Hollestelle A, van Asperen CJ, van den Beek I, van Driel WJ, van Engelen K, et al. (2022) Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: A matched cohort study. PLoS ONE 17(9): e0275015. https://doi.org/10.1371/journal.pone.0275015

About the Authors:

Bernadette A. M. Heemskerk-Gerritsen

Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft

E-mail: [email protected]

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

https://orcid.org/0000-0002-9724-6693

Antoinette Hollestelle

Roles: Conceptualization, Writing – review & editing

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

https://orcid.org/0000-0003-1166-1966

Christi J. van Asperen

Roles: Resources, Writing – review & editing

Affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands

Irma van den Beek

Roles: Writing – review & editing

Affiliation: Department of Human Genetics, Amsterdam University Medical Center (University of Amsterdam), Amsterdam, the Netherlands

Willemien J. van Driel

Roles: Writing – review & editing

Affiliation: Department of Gynecology, Netherlands Cancer Institute, Amsterdam, the Netherlands

Klaartje van Engelen

Roles: Resources, Writing – review & editing

Affiliation: Department of Clinical Genetics, Amsterdam University Medical Center (VUmc), Amsterdam, the Netherlands

Encarna B. Gómez Garcia

Roles: Resources, Writing – review & editing

Affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands

Joanne A. de Hullu

Roles: Resources, Writing – review & editing

Affiliation: Department of Obstetrics & Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands

Marco J. Koudijs

Roles: Writing – review & editing

Affiliation: Department of Biomedical Genetics, Utrecht University Medical Center, Utrecht, the Netherlands

Marian J. E. Mourits

Roles: Resources, Writing – review & editing

Affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, Groningen, the Netherlands

Maartje J. Hooning

Contributed equally to this work with: Maartje J. Hooning, Ingrid A. Boere

Roles: Conceptualization, Resources, Supervision, Writing – review & editing

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

Ingrid A. Boere

Contributed equally to this work with: Maartje J. Hooning, Ingrid A. Boere

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

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