Exclusion of Male Patients in Breast Cancer Clinical Trials

Exclusion of Male Patients in Breast Cancer Clinical Trials JNCI J Natl Cancer Inst (2018) 0(0): pky018 doi: 10.1093/jncics/pky018 Brief Communication BR I E F C OMM U N I CA T I ON Exclusion of Male Patients in Breast Cancer Clinical Trials Narjust Duma, Katherine P. Hoversten, Kathryn J. Ruddy See the Notes section for the full list of authors’ affiliations. Correspondence to: Narjust Duma, MD, 200 First Street SW, Rochester, MN 55905 (e-mail: duma.narjust@mayo.edu). Men make up an estimated 1% of patients diagnosed with included. Only five studies designed to include men were com- breast cancer in the United States each year (1). This analysis pleted; two of these were observational studies (NCT00773669 examined the inclusion and representation of men in breast and NCT00666731). To our knowledge, none of these studies cancer trials between January 1, 2000, and April 31, 2017. On have been peer-reviewed and published in manuscript form ClinicalTrials.gov, 426 trials were identified and evaluated for (3,4). Table 1 summarizes trial characteristics. During the study inclusion and recruitment of male breast cancer patients. Of period, 31 clinical trials in male breast cancer were early termi- these, 277 trials (65%) excluded male breast cancer patients in nated and 11 were withdrawn; none of these were included in their enrollment criteria. Overall, 0.42% of trial participants our analysis. were men, with the lowest enrollment rates in hormonal and A total of 106 353 patients were enrolled. Out of 426 breast targeted therapy trials (0.1% and 0.1%, respectively). No men cancer trials, 277 trials (65%) excluded male breast cancer were included in the 70 trials studying neoadjuvant therapies. patients and 28 trials (7%) did not address male patients’ inclu- Future trials should take extra measures to recruit male partici- sion/exclusion in their criteria. pants to adequately understand the efficacy and safety of new Men represented 0.42% of the trial participants (n ¼ 452). regimens in this subset of patients. Hormonal and targeted therapy trials had the lowest male en- In 2018, 2550 new cases of invasive breast cancer will be diag- rollment rates (0.1% and 0.1%, respectively). Despite chemother- nosed in men (1). Recent studies have identified differences in apy trials having the highest proportion of male enrollment clinical and biological features between male and female breast (0.2%), the number of male participants was only 234 (Table 1). cancer, highlighting the importance of inclusion of both sexes in Further, 70 trials (16%) studied neoadjuvant therapies, and no clinical trials (2).The goal of our analysis was to methodically de- men were recruited into any of these trials. After dividing trials fine the representation of men in breast cancer trials. by phase, 67% of phase I trials included male patients compared ClinicalTrials.gov was queried on May 1, 2017, for all therapeu- with 22% of phase III trials. tic breast cancer trials from January 1, 2000, to April 31, 2017. In univariate analyses, hormonal trials and trials designed Search terms included breast cancer and studies with results and for metastatic disease had higher odds of excluding men (odds interventional trials (n ¼ 721 trials). Trials with unknown recruit- ratio [OR] ¼ 4.17, 95% CI ¼ 1.14 to 15.23, P < .03; OR ¼ 2.28, 95% CI ment status or without status verification in 12 months were ex- ¼ 1.08 to 4.81, P < .03, respectively). University cooperative cluded. As the registry does not include personal identifiers, this group–sponsored trials had lower odds of excluding men than analysis received a waiver for the informed consent requirement. those sponsored by the pharmaceutical industry and National For the analysis, exclusion of male patients was classified as Cancer Institute (NCI)–sponsored trials (OR ¼ 0.55, 95% CI ¼ 0.27 “strict exclusion” vs “allowed” and treated as a binary variable. to 0.98, P < .05). However, none of these associations remained We used logistic regression models to test the association be- statistically significant in multivariable analysis. tween male patients’ exclusion and trial characteristics. All sta- Most of the trials included in our analysis were completed tistical tests were two-tailed, and a P value of less than .05 was between 2011 and 2016 (83%). No changes were seen in the rep- considered statistically significant. Data analysis was per- resentation of male breast cancer patients over time. formed using SPSS statistical software. Multiple efforts have been spearheaded by the NCI and other Our initial search yielded 721 trials, 295 of which were later institutions to improve the recruitment of men in breast cancer excluded (Figure 1). In the final analysis, 426 trials were trials. Despite these efforts, we observed that the recruitment of Received: October 11, 2017; Revised: March 26, 2018; Accepted: April 6, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 1of 3 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 3 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. Trial characteristics* Trial characteristics No. (%) Phase Phase 1 18 (4) Phase 1b–2 87 (20) Phase 2 270 (63) Phase 3 51 (12) Sponsor University-Cooperative group 158 (37) Industry 209 (49) NCI 59 (14) Location Asia 43 (10) Europe only 64 (15) United States only 187 (44) International 95 (22) Other 37 (9) Treatment Chemotherapy 184 (43) Chemotherapy and targeted therapy 50 (12) Hormonal therapy 117 (27) Targeted therapy 33 (8) Other 42 (10) Line of therapy Figure 1. Consort diagram depicting the criteria used to identify trials used in the analysis. First 162 (38) Second 72 (17) Third 21 (5) male patients remains low. Out of 106 353 trial participants, Various lines of therapy 171 (40) only 452 were men. Recruitment sites In our analysis, the extent of exclusion varied by certain clin- Single 177 (42) ical trial characteristics. Hormonal trials were more likely to Multiple sites 249 (58) exclude men; this may be due to the fact that gonadotropin-re- Other Neoadjuvant trials 70 (16) leasing hormone agonists appear to be needed to safely treat Metastatic/recurrent cancer 288 (68) men with aromatase inhibitors (5,6), increasing trial complexity and cost. Also, multiple trials designed to study hormonal ther- *NCI ¼ National Cancer Institute. apy in men have been prematurely closed due to poor accrual (eg, S0611, Goserelin and anastrozole in men with recurrent/ metastatic breast cancer; NCT 00217659). Cardoso et al. (5) have demonstrated the importance of in- The lowest recruitment of men was seen in neoadjuvant tri- ternational collaborations with the creation of an international als. One possible explanation is a perceived lesser benefit of registry, allowing further characterization of male breast can- neoadjuvant therapy in men, who usually opt for mastectomy cer. Hence, the German Breast Group is also leading efforts to (7). However, the CREATE-X trial (8) demonstrated that response improve the understanding of endocrine treatment options for to neoadjuvant therapy can guide adjuvant treatment decisions; male breast cancer patients, with preliminary data reporting improving accrual of men to neoadjuvant trials will allow that all three treatment strategies were well tolerated. We await investigators and regulatory agencies understand the safety the final results for this trial as an opportunity to learn from and efficacy of experimental regimens in this unique group of their recruitment strategies (4). patients. Randomized trials including female and male breast cancer There are several limitations to our analysis. First, frequent patients should be designed carefully, with recruitment targets, amendments to protocols occur, and these can result in tailored inclusion/exclusion criteria, and individual analyses by changes to inclusion/exclusion criteria that may not have been sex. Understanding of the requirements and limitations of male captured. Next, the trials we evaluated were weighted heavily breast cancer trials is necessary to avoid early termination and toward those from the United States and may not be generaliz- withdrawal of future clinical trials. able to the rest of the world. Finally, additional factors likely In conclusion, we found that most clinical trials excluded played into the recruitment of male breast cancer patients be- male breast cancer patients from participating. Future trials yond those we observed. should aim to increase male patient participation, especially in In the absence of a clear rationale for exclusion, male breast neoadjuvant and hormonal therapy trials where most of the cancer patients should be included in all breast cancer clinical data is lacking. trials. Longer accrual periods and adequate budgets to support community outreach are necessary to improve recruitment. Patient navigation and educational programs that target both patients and medical providers on the availability and benefits Notes of clinical trials have been proven to be effective in improving the recruitment of underrepresented groups and could be uti- Affiliations of authors: Medical Oncology (ND, KJR) and Internal lized in breast cancer trials (9). Medicine (KPH), Mayo Clinic, Rochester, MN. Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 by Ed 'DeepDyve' Gillespie user on 21 June 2018 N. Duma et al. | 3 of 3 treatment with either tamoxifen þ/- gonadotropin releasing hormone ana- The authors have no conflicts of interest to declare. This re- logue (GnRHa) or an aromatase inhibitor þ GnRHa in male breast cancer search did not receive external funding. patients. Cancer Res. 2018;78(4 Supplement):PD7-10-PD7-10. 5. Giordano SH, Hortobagyi GN. Leuprolide acetate plus aromatase inhibition for male breast cancer. J Clin Oncol. 2006;24(21):e42–e43. References 6. Zagouri F, Sergentanis TN, Koutoulidis V, et al. Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; cancer: A case series. Br J Cancer. 2013;108:2259. 68(1):7–30. 7. Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of partial mastectomy 2. Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: in male breast cancer patients: Analysis of SEER, 1983–2009. Ann Surg Oncol. Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast 2013;20(5):1545–1550. Cancer Program. Ann Oncol. 2018;29(2):405–417. 8. Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer af- 3. Strauss LC, O’Shaughnessy J, Jackson J, et al. Three parallel randomized phase ter preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–2159. II trials of dasatinib plus hormone therapy (HT) in advanced ERþ breast cancer 9. Treweek S, Mitchell E, Pitkethly M, et al. Strategies to improve (ERþ ABC). J Clin Oncol. 2010;28(15_suppl):TPS133–TPS133. recruitment to randomised controlled trials. Cochrane Database Syst Rev. 2010; 4. Reinisch M, Seiler S, Hauzenberger T, et al. Abstract PD7-10: Male-GBG54: A (1):MR000013. prospective, randomised multi-centre phase II study evaluating endocrine Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 by Ed 'DeepDyve' Gillespie user on 21 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Cancer Spectrum Oxford University Press

Exclusion of Male Patients in Breast Cancer Clinical Trials

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Abstract

JNCI J Natl Cancer Inst (2018) 0(0): pky018 doi: 10.1093/jncics/pky018 Brief Communication BR I E F C OMM U N I CA T I ON Exclusion of Male Patients in Breast Cancer Clinical Trials Narjust Duma, Katherine P. Hoversten, Kathryn J. Ruddy See the Notes section for the full list of authors’ affiliations. Correspondence to: Narjust Duma, MD, 200 First Street SW, Rochester, MN 55905 (e-mail: duma.narjust@mayo.edu). Men make up an estimated 1% of patients diagnosed with included. Only five studies designed to include men were com- breast cancer in the United States each year (1). This analysis pleted; two of these were observational studies (NCT00773669 examined the inclusion and representation of men in breast and NCT00666731). To our knowledge, none of these studies cancer trials between January 1, 2000, and April 31, 2017. On have been peer-reviewed and published in manuscript form ClinicalTrials.gov, 426 trials were identified and evaluated for (3,4). Table 1 summarizes trial characteristics. During the study inclusion and recruitment of male breast cancer patients. Of period, 31 clinical trials in male breast cancer were early termi- these, 277 trials (65%) excluded male breast cancer patients in nated and 11 were withdrawn; none of these were included in their enrollment criteria. Overall, 0.42% of trial participants our analysis. were men, with the lowest enrollment rates in hormonal and A total of 106 353 patients were enrolled. Out of 426 breast targeted therapy trials (0.1% and 0.1%, respectively). No men cancer trials, 277 trials (65%) excluded male breast cancer were included in the 70 trials studying neoadjuvant therapies. patients and 28 trials (7%) did not address male patients’ inclu- Future trials should take extra measures to recruit male partici- sion/exclusion in their criteria. pants to adequately understand the efficacy and safety of new Men represented 0.42% of the trial participants (n ¼ 452). regimens in this subset of patients. Hormonal and targeted therapy trials had the lowest male en- In 2018, 2550 new cases of invasive breast cancer will be diag- rollment rates (0.1% and 0.1%, respectively). Despite chemother- nosed in men (1). Recent studies have identified differences in apy trials having the highest proportion of male enrollment clinical and biological features between male and female breast (0.2%), the number of male participants was only 234 (Table 1). cancer, highlighting the importance of inclusion of both sexes in Further, 70 trials (16%) studied neoadjuvant therapies, and no clinical trials (2).The goal of our analysis was to methodically de- men were recruited into any of these trials. After dividing trials fine the representation of men in breast cancer trials. by phase, 67% of phase I trials included male patients compared ClinicalTrials.gov was queried on May 1, 2017, for all therapeu- with 22% of phase III trials. tic breast cancer trials from January 1, 2000, to April 31, 2017. In univariate analyses, hormonal trials and trials designed Search terms included breast cancer and studies with results and for metastatic disease had higher odds of excluding men (odds interventional trials (n ¼ 721 trials). Trials with unknown recruit- ratio [OR] ¼ 4.17, 95% CI ¼ 1.14 to 15.23, P < .03; OR ¼ 2.28, 95% CI ment status or without status verification in 12 months were ex- ¼ 1.08 to 4.81, P < .03, respectively). University cooperative cluded. As the registry does not include personal identifiers, this group–sponsored trials had lower odds of excluding men than analysis received a waiver for the informed consent requirement. those sponsored by the pharmaceutical industry and National For the analysis, exclusion of male patients was classified as Cancer Institute (NCI)–sponsored trials (OR ¼ 0.55, 95% CI ¼ 0.27 “strict exclusion” vs “allowed” and treated as a binary variable. to 0.98, P < .05). However, none of these associations remained We used logistic regression models to test the association be- statistically significant in multivariable analysis. tween male patients’ exclusion and trial characteristics. All sta- Most of the trials included in our analysis were completed tistical tests were two-tailed, and a P value of less than .05 was between 2011 and 2016 (83%). No changes were seen in the rep- considered statistically significant. Data analysis was per- resentation of male breast cancer patients over time. formed using SPSS statistical software. Multiple efforts have been spearheaded by the NCI and other Our initial search yielded 721 trials, 295 of which were later institutions to improve the recruitment of men in breast cancer excluded (Figure 1). In the final analysis, 426 trials were trials. Despite these efforts, we observed that the recruitment of Received: October 11, 2017; Revised: March 26, 2018; Accepted: April 6, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 1of 3 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 3 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. Trial characteristics* Trial characteristics No. (%) Phase Phase 1 18 (4) Phase 1b–2 87 (20) Phase 2 270 (63) Phase 3 51 (12) Sponsor University-Cooperative group 158 (37) Industry 209 (49) NCI 59 (14) Location Asia 43 (10) Europe only 64 (15) United States only 187 (44) International 95 (22) Other 37 (9) Treatment Chemotherapy 184 (43) Chemotherapy and targeted therapy 50 (12) Hormonal therapy 117 (27) Targeted therapy 33 (8) Other 42 (10) Line of therapy Figure 1. Consort diagram depicting the criteria used to identify trials used in the analysis. First 162 (38) Second 72 (17) Third 21 (5) male patients remains low. Out of 106 353 trial participants, Various lines of therapy 171 (40) only 452 were men. Recruitment sites In our analysis, the extent of exclusion varied by certain clin- Single 177 (42) ical trial characteristics. Hormonal trials were more likely to Multiple sites 249 (58) exclude men; this may be due to the fact that gonadotropin-re- Other Neoadjuvant trials 70 (16) leasing hormone agonists appear to be needed to safely treat Metastatic/recurrent cancer 288 (68) men with aromatase inhibitors (5,6), increasing trial complexity and cost. Also, multiple trials designed to study hormonal ther- *NCI ¼ National Cancer Institute. apy in men have been prematurely closed due to poor accrual (eg, S0611, Goserelin and anastrozole in men with recurrent/ metastatic breast cancer; NCT 00217659). Cardoso et al. (5) have demonstrated the importance of in- The lowest recruitment of men was seen in neoadjuvant tri- ternational collaborations with the creation of an international als. One possible explanation is a perceived lesser benefit of registry, allowing further characterization of male breast can- neoadjuvant therapy in men, who usually opt for mastectomy cer. Hence, the German Breast Group is also leading efforts to (7). However, the CREATE-X trial (8) demonstrated that response improve the understanding of endocrine treatment options for to neoadjuvant therapy can guide adjuvant treatment decisions; male breast cancer patients, with preliminary data reporting improving accrual of men to neoadjuvant trials will allow that all three treatment strategies were well tolerated. We await investigators and regulatory agencies understand the safety the final results for this trial as an opportunity to learn from and efficacy of experimental regimens in this unique group of their recruitment strategies (4). patients. Randomized trials including female and male breast cancer There are several limitations to our analysis. First, frequent patients should be designed carefully, with recruitment targets, amendments to protocols occur, and these can result in tailored inclusion/exclusion criteria, and individual analyses by changes to inclusion/exclusion criteria that may not have been sex. Understanding of the requirements and limitations of male captured. Next, the trials we evaluated were weighted heavily breast cancer trials is necessary to avoid early termination and toward those from the United States and may not be generaliz- withdrawal of future clinical trials. able to the rest of the world. Finally, additional factors likely In conclusion, we found that most clinical trials excluded played into the recruitment of male breast cancer patients be- male breast cancer patients from participating. Future trials yond those we observed. should aim to increase male patient participation, especially in In the absence of a clear rationale for exclusion, male breast neoadjuvant and hormonal therapy trials where most of the cancer patients should be included in all breast cancer clinical data is lacking. trials. Longer accrual periods and adequate budgets to support community outreach are necessary to improve recruitment. Patient navigation and educational programs that target both patients and medical providers on the availability and benefits Notes of clinical trials have been proven to be effective in improving the recruitment of underrepresented groups and could be uti- Affiliations of authors: Medical Oncology (ND, KJR) and Internal lized in breast cancer trials (9). Medicine (KPH), Mayo Clinic, Rochester, MN. Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 by Ed 'DeepDyve' Gillespie user on 21 June 2018 N. Duma et al. | 3 of 3 treatment with either tamoxifen þ/- gonadotropin releasing hormone ana- The authors have no conflicts of interest to declare. This re- logue (GnRHa) or an aromatase inhibitor þ GnRHa in male breast cancer search did not receive external funding. patients. Cancer Res. 2018;78(4 Supplement):PD7-10-PD7-10. 5. Giordano SH, Hortobagyi GN. Leuprolide acetate plus aromatase inhibition for male breast cancer. J Clin Oncol. 2006;24(21):e42–e43. References 6. Zagouri F, Sergentanis TN, Koutoulidis V, et al. Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; cancer: A case series. Br J Cancer. 2013;108:2259. 68(1):7–30. 7. Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of partial mastectomy 2. Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: in male breast cancer patients: Analysis of SEER, 1983–2009. Ann Surg Oncol. Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast 2013;20(5):1545–1550. Cancer Program. Ann Oncol. 2018;29(2):405–417. 8. Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer af- 3. Strauss LC, O’Shaughnessy J, Jackson J, et al. Three parallel randomized phase ter preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–2159. II trials of dasatinib plus hormone therapy (HT) in advanced ERþ breast cancer 9. Treweek S, Mitchell E, Pitkethly M, et al. Strategies to improve (ERþ ABC). J Clin Oncol. 2010;28(15_suppl):TPS133–TPS133. recruitment to randomised controlled trials. Cochrane Database Syst Rev. 2010; 4. Reinisch M, Seiler S, Hauzenberger T, et al. Abstract PD7-10: Male-GBG54: A (1):MR000013. prospective, randomised multi-centre phase II study evaluating endocrine Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky018/5026707 by Ed 'DeepDyve' Gillespie user on 21 June 2018

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