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Attitudes of patients with metastatic breast cancer toward research biopsies
original articles
Annals of Oncology
Annals of Oncology 24: 1853–1859, 2013 doi:10.1093/annonc/mdt067 Published online 13 March 2013
Attitudes of patients with metastatic breast cancer toward research biopsies D. S. Seah1, S. M. Scott2,†, J. Najita3, T. Openshaw4, K. Krag5, E. Frank1, J. Sohl1, Z. K. Stadler6, M. Garrett4, S. G. Silverman7, J. Peppercorn8, E. P. Winer1, S. E. Come2 & Nancy U. Lin1* 1
Deparment of Medical Oncology, Dana-Farber Cancer Institute, Boston; 2Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston; Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston; 4Department of Medical Oncology, Cancer Care of Maine, Bangor; 5 Department of Medical Oncology, North Short Cancer Center, Danvers; 6Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York; 7 Department of Radiology, Brigham and Women’s Hospital, Boston; 8Department of Medicine, Duke University Medical Center, Durham, USA 3
Background: Research studies involving human tissue are increasingly common. However, patients’ attitudes toward research biopsies are not well characterized, particularly when the biopsies are carried out outside the context of therapeutic trials. Patients and methods: One hundred sixty patients with metastatic breast cancer (MBC) from two academic (n = 80) and two community (n = 80) hospitals completed a 29-item self-administered survey to evaluate their willingness to consider providing research purposes only biopsies (RPOBs) (as a stand-alone procedure) and additional biopsies (ABs) (additional needle passes at the time of a clinically indicated biopsy). Results: Eighty-two (51%) of 160 patients would consider having RPOBs, of which 42 (53%) and 40 (50%) patients were from academic and community hospitals, respectively. Patients who had more prior biopsies were less likely to consider RPOBs (RR = 0.6, 95% CI: 0.4–1.0, P = 0.03). Of 160 patients, 115 (72%) patients would consider having ABs. Of these, 64 (80%) and 51 (64%) patients from academic and community hospitals, respectively, would consider ABs (RR = 1.2, 95% CI: 1.0–1.5, P = 0.03). Conclusions: Many patients with MBC in both academic and community settings report willingness to consider undergoing biopsies for research. Further research is needed to understand ethical, logistical and provider-based barriers to broader participation in such studies. Key words: metastatic breast cancer, patient’s preferences, research biopsies
introduction In the era of molecularly targeted therapy, the inclusion of pharmacodynamic and tissue-based correlative end points in clinical trials is increasingly common. Although preclinical models provide insights about tumor biology, the direct evaluation of patients’ tumor tissue is required to determine whether a target is present in humans to validate whether novel therapeutics ‘hit the target’ when administered at doses that are tolerable in humans and whether postulated resistance mechanisms are operative in the clinical setting. Research biopsies are procedures through which tissue is collected for correlative studies, with no intent to use the information for the clinical management of the patient [1]. The biopsy may either be performed as a stand-alone procedure [research purposes only biopsy (RPOB)] or involve *Correspondence to: Prof Nancy U. Lin, Department of Medical Oncology, Division of Women’s Cancers, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Tel: +1-617-632-2335; Fax: +1-617-632-1930; E-mail: [email protected]
additional needle passes at the time of a clinically indicated biopsy [additional biopsy (AB)]. In the context of clinical trials, research biopsies may be either mandatory, where the patient can receive the investigational drug only if the patient agrees to the biopsies, or optional, where the patient can refuse the biopsies but receive the drug. A retrospective review from MD Anderson found that 86.6% of patients who had consented to mandatory biopsies subsequently had the biopsies performed. In contrast, only 4.4% of patients who were offered a biopsy on an optional basis had a biopsy performed [2]. The rate of optional biopsies in clinical trials has been higher in other institutions [3]. Previous survey-based studies have also reported that 18%–36% of patients felt that mandatory research biopsies would deter them from the trial participation [4,5]. Collectively, these data suggest that patients’ willingness to undergo research biopsies are likely influenced by the linkage to clinical trials and extrapolating these data to understand patient perceptions toward research biopsies divorced from the therapeutic trial participation may not be valid.
†
Co-first authors.
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Received 23 October 2012; revised 18 January 2013; accepted 22 January 2013
original articles
methods This study was conducted in accordance with the Declaration of Helsinki and the Dana-Farber/Harvard Cancer Center Institutional Review Board (IRB). The IRB of all participating sites approved the study protocol before patient recruitment.
participants From September 2010 to October 2011, we conducted a cross-sectional self-administered paper survey in the breast oncology practices of two community [Cancer Care of Maine (MCC) and North Shore Cancer Center (Danvers, MA) (NSCC)] and two academic centers [Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) and Beth Israel Deaconess Medical Center (BIDMC)]. Eligibility criteria included a diagnosis of MBC, being above 18 years old, and an ability to understand written English. Patients were identified from oncologists providing a list of MBC patients or through pharmacy records of patients on metastatic regimens. Consecutive patients were approached and the purpose of the study explained. Patients either completed the questionnaire onsite or returned home to complete it. Patients were informed that a $5 gift certificate would be given upon returning the questionnaire.
questionnaire The questionnaire was developed based on the authors’ experience with the recruitment of patients into clinical trials and a literature review. Inputs from doctors, patients and a patient advocate were sought. The questionnaire was piloted in 38 patients with MBC to ensure the clarity of content and acceptability to patients. The final questionnaire was a 29-item survey (supplementary Figure S1, available at Annals of Oncology online). The primary outcome was patients’ attitudes toward undergoing an RPOB or an AB. Patients were asked to rate if they would consider undergoing an RPOB or an AB on a 5-point Likert scale (Definitely, Probably, Maybe, Probably Not, Definitely Not). Patients were counted as willing to undergo an RPOB or an AB if they gave a rating of Definitely or Probably. The questionnaire also collected information on age, education, marital status, prior trial participation, number of prior biopsies and transportation time to the clinic to evaluate the associations with sociodemographic factors, prior experience with biopsies, prior experience with research studies and travel time to the clinic as potential barriers of research participation.
| Seah et al.
statistical methods The primary analysis treated willingness to consider an RPOB as a dichotomous variable, collapsing categories (Definitely or Probably versus Maybe, Probably Not or Definitely Not). The sample size of 160 was chosen to provide at least 80% power to detect a difference of 25% among groups in terms of the proportion of patients who would consider an RPOB. Groups were defined by the practice type (academic versus community). To describe the relationship among patient characteristics and willingness to consider an RPOB, univariate and multivariate analyses were carried out. In addition to the group, independent variables included demographic factors, prior clinical trial participation, number of prior biopsies and transportation time to the clinic. Relative risks (RRs) were determined using the Poisson regression and 95% CI’ based on robust variance estimates [14,15]. Variables were included in multivariate analyses if they were statistically significant at the 0.05 level in univariate analyses. Willingness to consider an AB was analyzed similarly. Comparisons of categorical variables were made using a Fisher’s exact test or a Chi-square test where appropriate. All tests were two-sided at the 0.05 significance level.
results Of 165 women who were invited to complete the questionnaire, 161 (98%) agreed to participate. Four people declined participation; three cited lack of interest and one cited too much paperwork. One patient did not return the questionnaire. Fifty-six (35%), 24 (15%), 32 (20%) and 48 (30%) patients were recruited from DFCI/BWH, BIDMC, NSCC and MCC respectively. The median age was 57 years (range: 28–87). Patient characteristics are reported in Table 1.
research purpose only biopsies Fifty-three percent and 50% of patients from academic and community sites, respectively, would consider an RPOB (P = 0.75) (Table 2). The only univariate variable that was statistically significant among patients who would and would not consider an RPOB was the number of previous biopsies (P = 0.03). Patients who had more prior biopsies were less likely to consider an RPOB. With the exception of the number of previous biopsies, multivariate analysis revealed no significant association with any other variable.
additional biopsies In contrast, 80% and 64% of patients from academic and community sites, respectively, would consider undergoing an AB (P = 0.03; Table 3). In the univariate analysis, the only variable associated with patients’ willingness to undergo an AB was the practice type (P = 0.03). With the exception of the type of practice, multivariate analysis again revealed no significant association with any other variable.
research biopsies of different organs Patients in both academic and community sites responded that they were less likely to consider an RPOB in the organs involved that are considered more invasive such as bone marrow or liver biopsies. A statistically significant difference between the two practice types was not observed (Table 4).
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Although there have been numerous studies evaluating barriers to patient enrollment in therapeutic trials [6–9], there are limited data examining patients’ willingness and barriers to undergo research biopsies [10], especially outside the context of a therapeutic trial [11–13]. We believe that insights into patients’ perceptions associated with correlative research tumor biopsies that are unlinked to clinical trials would provide a more accurate assessment of patient perceptions about research biopsies. Our study reports the results of a survey of the attitudes of metastatic breast cancer (MBC) patients toward undergoing research biopsies. Our research aims to assess whether patients would consider RPOBs and/or ABs outside the context of a clinical trial and to evaluate the factors that are associated with consideration of both RPOBs and ABs. Understanding patients’ attitudes may help us improve strategies to further increase patients’ willingness to consent to research biopsies.
Annals of Oncology
original articles
Annals of Oncology Table 1. Patient characteristics Characteristic
Academic (N = 80)
Community (N = 80)
0.01
reasons for not participating in research biopsies 0.17
0.002
0.95
discussion 0.01
<0.0001
1.00
0.88
N/A
<0.0001
When patients were asked to consider an RPOB of the breast, 82 (51%) of 160 patients would not consider it. When these same patients were asked to consider undergoing an AB,
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Patients were asked to list a few reasons why they would not consider participating in RPOBs. For patients in academic sites (n = 14), reasons included; pain or discomfort (n = 9), risk of biopsy (n = 4), no direct benefit (n = 4), anxiety related to biopsy (n = 4) and inconvenience of the procedure (n = 4). Among 23 patients in community sites who responded, their reasons included; pain or discomfort (n = 14), risk of biopsy (n = 11), inconvenience of the procedure (n = 9), anxiety related to biopsy (n = 8) and no direct benefit (n = 4). Among patients from academic sites who listed reasons for not participating in ABs (n = 5), their reasons included; risk of biopsy (n = 3), pain or discomfort (n = 2), no direct benefit (n = 1) and anxiety related to biopsy (n = 1). Among patients from community sites (n = 8), their reasons included; pain or discomfort (n = 6), anxiety related to biopsy (n = 5), risk of biopsy (n = 5), inconvenience (n = 1) and no direct benefit (n = 1).
Tissue from research biopsies are essential to our understanding of tumor biology, and understanding patients’ attitudes toward research biopsies may improve our strategies to increase their willingness to consent to research biopsies, leading to more access to tumor tissue. We carried out a crosssectional survey of patients with MBC treated in academic and community hospital clinics to ascertain their willingness to undergo research biopsies either in the setting of having additional needle passes in clinically indicated biopsies (AB) or as a stand-alone procedure (RPOB). We found that 51% of patients would consider RPOBs outside the context of a clinical trial. This is a substantial proportion of patients who would potentially contribute to research purely for altruistic reasons. In addition, patients’ consideration of an RPOB did not vary by setting. We also found that most patients (72%) would consider an AB, though the likelihood was higher among patients at academic hospitals (80% versus 64%, P = 0.03). Several groups have evaluated factors associated with participation in clinical trials, showing that practice type, age, education, race, insurance type and employment status are important factors [6,8,9,13]. In our study, the practice type was associated with a patient’s willingness to undergo an AB but was not associated with the likelihood of considering an RPOB. It is conceivable that patients who are treated at academic centers are more exposed to the research environment and feel inclined toward contributing to research, especially if they perceive that the cost in terms of time or risk is low, as in the case of ABs. In addition, it is possible that physicians’ attitudes toward ABs may differ between academic
doi:10.1093/annonc/mdt067 |
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Age Mean (SD) 54.7 (10.0) 59.1 (12.4) Median (Min–Max) 55 (33–87) 59 (28–85) Unknown 2 0 Race [n (%)] Black/African American 3 (4) 1 (1) White 71 (89) 79 (99) Other 2 (3) 0 (0) Unknown 4 (5) 0 (0) Highest level of education [n (%)] No high school 0 (0) 1 (1) Some high school 2 (3) 0 (0) High school graduate 8 (10) 26 (33) Some college 9 (11) 14 (18) 2-year college 6 (8) 6 (8) 4-year college 28 (35) 21 (26) Postgraduate school 25 (31) 12 (15) Unknown 2 (3) 0 (0) Marital status [n (%)] Single 8 (10) 8 (10) Married/long-term 58 (73) 60 (75) partner Divorced 9 (11) 7 (9) Separated 0 (0) 1 (1) Widowed 3 (4) 4 (5) Unknown 2 (3) 0 (0) Employment status [n (%)] Not employed 37 (46) 54 (68) Employed 42 (53) 26 (33) Unknown 1 (1) 0 (0) Prior clinical trial participation [n (%)] No 27 (34) 57 (71) Yes 51 (64) 22 (28) Unknown 2 (3) 1 (1) Prior breast biopsy? [n (%)] No 2 (3) 2 (3) Yes 78 (98) 78 (98) Number of prior biopsies [n (%)] 0 biopsies 2 (3) 2 (3) 1–2 biopsies 57 (71) 56 (70) ≥3 biopsies 18 (23) 14 (18) Unknown 3 (4) 8 (10) Biopsy other than breast? [n (%)] Skin 7 (9) 8 (10) Liver 12 (15) 8 (10) Lung 10 (13) 5 (6) Bone 19 (24) 8 (10) Bone marrow 4 (5) 4 (5) Other 24 (30) 11 (14) Transportation time to appointment [n (%)] <45 min 23 (29) 51 (64) ≥45 min 55 (69) 28 (35) Unknown 2 (3) 1 (1)
P-value
49 (60%) of 82 patients replied differently and would consider a research biopsy in this setting (Table 5). When considering an RPOB of the liver, 121 (76%) of 160 patients would not consider it. However, of this group, 74 (62%) of 121 patients would consider having an AB of the liver (Table 6).
original articles
Annals of Oncology
Table 2. Univariate analysis of patients’ willingness to undergo a research biopsy for research purposes alone Variable
N
Consider [n (%)]
Would not consider [n (%)]
Unknown [n (%)]
RR (95% CI)
P-value
80 80
42 (53) 40 (50)
36 (45) 39 (49)
2 (3) 1 (1)
1.1 (0.8–1.4) Ref
0.75
53 55 50 2
25 (47) 31 (56) 25 (50) 1 (50)
28 (53) 22 (40) 24 (48) 1 (50)
0 (0) 2 (4) 1 (2) 0 (0)
Ref 1.2 (0.9–1.8) 1.1 (0.7–1.6)
0.53
37 35 86
18 (49) 19 (54) 44 (51)
18 (49) 16 (46) 40 (47)
1 (3) 0 (0) 2 (2)
Ref 1.0 (0.7–1.5) 1.1 (0.7–1.7)
0.95
16 118 24 2
8 (50) 61 (52) 12 (50) 1 (50)
8 (50) 55 (47) 11 (46) 1 (50)
0 (0) 2 (2) 1 (4) 0 (0)
Ref 1.1 (0.6–1.8) 1.0 (0.6–1.9)
1.00
68 91 1
37 (54) 45 (49) 0 (0)
29 (43) 45 (49) 1 (100)
2 (3) 1 (1) 0 (0)
1.12 (0.83–1.51) Ref
0.52
73 84 3
35 (48) 45 (54) 2 (67)
37 (51) 37 (44) 1 (33)
1 (1) 2 (2) 0 (0)
0.9 (0.7–1.2) Ref
0.52
117 32 11
67 (57) 11 (34) 4 (36)
48 (41) 20 (63) 7 (64)
2 (2) 1 (3) 0 (0)
Ref 0.6 (0.4–1.0)
0.03
74 83 3
40 (54) 41 (49) 1 (33)
32 (43) 41 (49) 2 (67)
2 (3) 1 (1) 0 (0)
1.1 (0.8–1.5) Ref
0.52
and community sites and may influence patients’ perceptions. However, this question has not been studied previously. Another interesting finding is that patients who had more prior biopsies were less likely to consider an RPOB (P = 0.03). This suggests that prior biopsy experiences may have been negative and further research into patients’ experience may be required. However, this variable was not associated with willingness to consider an AB. Ethical concerns about including mandatory research biopsies in therapeutic trials have been raised because of the potential for coercion or the lack of patient understanding about the intent of the biopsy [1,12,16,17]. Others have endorsed the inclusion of required biopsies provided that participants are fully informed and the study is designed to address the scientific questions at hand [18,19]. Most of the literature on patients’ perspectives on research biopsies has been in the context of phase 1 trials [2,12] with little data outside of the context of a clinical trial (e.g. without potential for confounding based on a desire to receive an experimental agent) to inform the debate [2,12]. One study interviewed 40 phase 1 trial patients, with 70% of participants indicating that they would undergo optional
| Seah et al.
non-therapeutic biopsies within a clinical trial, suggesting that non-therapeutic biopsies are not barriers to research participation [4]. In a follow-up study, Pentz et al. reported that two-thirds of patients misunderstood the lack of benefit of a research biopsy in the context of a phase 1 trial, raising concerns that patients would not agree to biopsies outside of a trial if they had a true understanding of the lack of personal benefit. Although cross-study comparisons are limited given major differences in the study populations, it is notable that 72% and 51% of MBC patients in our study indicated a willingness to undergo an AB and an RPOB, respectively, despite it being unlinked to any type of therapeutic trials. Another interesting finding of this study surrounds the attitudes of patients who would decline an RPOB. For breast mass biopsies, 60% of patients who would decline an RPOB would consider an AB. For liver mass biopsies, 62% of patients who would decline an RPOB would consider an AB. Although this finding is perhaps not surprising, it does identify an opportunity for enhanced efforts at tissue collection to answer specific translational questions. For example, at the first cancer recurrence, it is increasingly considered the standard of care to obtain a biopsy to confirm the diagnosis and to re-check
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Type of practice Academic Community Age ≤51 >51, ≤61 >61 Unknown Education No high school/high school graduate Some college 4-year college/postgraduate Marital status Single Married/living as married Divorced, widowed or separated Unknown Employment status Employed No employed Unknown Prior clinical trial participation Yes No Unknown Number of prior biopsies 0–2 ≥3 Unknown Transportation time <45 min ≥45 min Unknown
original articles
Annals of Oncology
Table 3. Univariate analysis of patients’ willingness to allow an additional biopsy performed for research purposes, at the time of a clinically indicated biopsy Variable
N
Consider [n (%)]
Would not consider [n (%)]
Unknown [n (%)]
RR (95% CI)
80 80
64 (80) 51 (64)
15 (19) 27 (34)
1 (1) 2 (3)
1.2 (1.0–1.5) Ref
0.03
53 55 50 2
40 (75) 44 (80) 30 (60) 1 (50)
12 (23) 11 (20) 18 (36) 1 (50)
1 (2) 0 (0) 2 (4) 0 (0)
Ref 1.0 (0.9–1.3) 0.8 (0.6–1.1)
0.11
37 35 86
25 (68) 23 (66) 65 (76)
10 (27) 11 (31) 21 (24)
2 (5) 1 (3) 0 (0)
Ref 1.1 (0.8–1.3) 0.9 (0.7–1.3)
0.63
16 118 24 2
13 (81) 86 (73) 14 (58) 2 (100)
3 (19) 30 (25) 9 (38) 0 (0)
0 (0) 2 (2) 1 (4) 0 (0)
Ref 0.9 (0.7–1.2) 0.7 (0.5–1.1)
0.35
68 91 1
16 (24) 26 (29) 0 (0)
52 (76) 62 (68) 1 (100)
0 (0) 3 (3) 0 (0)
73 84 3
57 (78) 57 (68) 1 (33)
16 (22) 26 (31) 0 (0)
0 (0) 1 (1) 2 (67)
1.1 (0.9–1.4) Ref
0.21
117 32 11
85 (73) 24 (75) 6 (55)
29 (25) 8 (25) 5 (45)
3 (3) 0 (0) 0 (0)
Ref 1.0 (0.8–1.3)
1.00
74 83 3
53 (72) 60 (72) 2 (67)
20 (27) 21 (25) 1 (33)
1 (1) 2 (2) 0 (0)
Ref 1.0 (0.8–1.2)
0.86
1.09 (0.90–1.31) Ref
P-value
0.47
P-values correspond to the Fisher’s exact test using available data.
Table 4. Distribution of attitude of patients toward research biopsies for different organs Variable
Academic (N = 80) Community (N = 80) P-value Consider [n (%)] Would not consider [n (%)] Unknown [n (%)] Consider [n (%)] Would not consider [n (%)] Unknown [n (%)]
Venipuncture Skin Breast Bone marrow Liver
75 (94) 44 (55) 32 (40) 23 (29) 19 (24)
4 (5) 36 (45) 42 (53) 56 (71) 59 (74)
1 (1) 0 (0) 6 (8) 1 (1) 2 (3)
70 (88) 51 (64) 39 (49) 21 (26) 15 (19)
9 (11) 28 (35) 40 (50) 58 (73) 62 (78)
1 (1) 1 (1) 1 (1) 1 (1) 3 (4)
0.25 0.26 0.52 0.86 0.56
Table 5. Cross-tabulation of attitudes towards biopsies for both RPOBs and ABs to the breast
Table 6. Cross-tabulation of attitudes toward biopsies for both RPOBs and ABs to the liver
Consider an AB
Consider an AB
Yes No Unknown Total
Consider a RPOB Yes No
Unknown
Total
68 1 2 71
0 1 6 7
117 35 8 160
Volume 24 | No. 7 | July 2013
49 33 0 82
Yes No Unknown Total
Consider a RPOB Yes No
Unknown
Total
33 0 1 34
0 2 3 5
107 46 7 160
74 44 3 121
doi:10.1093/annonc/mdt067 |
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Type of practice Academic Community Age ≤51 >51, ≤61 >61 Unknown Education No high school/high school graduate Some college 4-year college/postgraduate Marital status Single Married/living as married Divorced, widowed or separated Unknown Employment status Employed No employed Unknown Prior clinical trial participation Yes No Unknown Number of prior biopsies 0–2 ≥3 Unknown Transportation time <45 min ≥45 min Unknown
original articles
| Seah et al.
sites would consider undergoing an AB, opening up an avenue to collect tissue for research in a way that is acceptable to many patients. We believe that it is reasonable to routinely discuss with patients the option of an AB when a clinical biopsy is being entertained. Second, we must be sensitive to patient’s needs and concerns. The top three reasons cited for not participating in research biopsies included pain, risk of the procedure and anxiety related to the biopsy. This further emphasizes the need for patient education and efforts by clinicians to minimize these risks. Research biopsies should occur within the context of an IRB-approved protocol governing patient consent, guidelines for tissue acquisition and storage, adverse event reporting and use of tissues. We should solicit feedback from patients undergoing biopsies and work with all parties involved to continually improve pre-procedure counseling and consent discussion, minimize risk and minimize procedure-related pain and anxiety. Finally, given that about half of the patients would consider an RPOB even when asked outside of the context of a therapeutic trial, our findings suggest a greater willingness of patients to participate in research biopsies than might be otherwise assumed by providers, investigators or IRBs and could help to inform discussions about how such biopsies might be appropriately incorporated into translational studies and/or clinical trials. Our study also showed that there were no statistically significant differences in the consideration rates of RPOBs in both academic and community settings. This suggests that there is a potential opportunity to obtain tumor tissues in both settings for research purposes. In summary, our study suggests that many MBC patients would consider research biopsies even outside of the context of a clinical trial. Efforts to educate and communicate with patients about the importance of tissue in research and the RRs of tissue donation should be explored, as should continued efforts to ensure that patients understand the nature of research biopsies to minimize therapeutic misconception. Finally, further research to explore clinician’s attitudes toward research biopsies may also improve our understanding of barriers that hinder access to human tissue for scientific research.
funding This work was supported by Metastatic Research Fund— anonymous donor, Nancy and Randy Berry Junior Faculty Award and the Karen Webster & David Evans Metastatic Research Fund.
disclosure The authors have declared no conflicts of interest.
references 1. Peppercorn J, Shapira I, Collyar D et al. Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J Clin Oncol 2010; 28: 2635–2640. 2. El-Osta H, Hong D, Wheler J et al. Outcomes of research biopsies in phase I clinical trials: the MD Anderson cancer center experience. Oncologist 2011; 16: 1292–1298.
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hormone receptor (HR) and human epidermal growth factor receptor 2 status given its importance in patient management [20]. Similarly, re-biopsy may be indicated in the setting of the development of resistance to endocrine therapy in HR-positive breast cancer to determine whether the tumor still expresses HRs. Again, the mechanisms underlying endocrine resistance in breast cancer are poorly understood, partly due to a lack of available tissue for investigation. If patients were more routinely approached for a research biopsy in the context of these scenarios, eventually a rich tissue resource could be built. Our study had a number of limitations. This is a relatively small study of women treated across four institutions in the Northeast United States, limiting the multivariable analyses. Previous studies have suggested that women, particularly those with breast cancer, are more willing to undergo optional biopsies and participate in clinical trials compared with the general oncology community [2,21]. Patients participating in this survey also had a higher rate of prior clinical trial enrollment than reported for the average adult cancer population [22]. Patients with late-stage cancers may be more vested in research, and MBC patients may not be reflective of cancer patients as a whole. We did not specifically assess the health literacy of our patients. However, over 90% of our population had graduated from high school and the educational level was not a significant predictor of willingness to undergo a biopsy in our model. Moreover, it is notable that patients were clearly less willing to consider more invasive biopsies (i.e. the liver) and more willing to undergo a breast biopsy or venipuncture for research. This suggests that patients did indeed understand and considered each scenario seriously. Even if patients did completely understand what was being asked of them, our study design consisted of patients being given hypothetical scenarios where they were asked to consider participating in theoretical biopsies. We acknowledge that there may be a difference among ‘willingness to consider’, ‘willingness to consent’ and actually undergoing a research biopsy. At DFCI, we have had a clinical protocol open to allow informed patients to undergo either an RPOB or an AB that is not linked to a specific therapeutic trial. Over the past 12 months, 18 and 34 patients have undergone RPOBs and ABs, respectively. Unfortunately, we did not collect data on the approach and the decline rate to be able to estimate patient’s willingness to undergo biopsies as well as physician factors that might influence the biopsy rates. We are currently developing projects to better understand this issue. We did not assess if the type of testing and analysis (e.g. genetic testing) performed on the specimens would change patients’ perceptions in undergoing research biopsies. We also did not assess whether receipt of research results would impact patient’s acceptance of research biopsies. Finally, we did not inquire directly about patient motivations to undergo research biopsies and cannot exclude the possibility that patients may still perceive personal benefit from the biopsy (therapeutic misconception). However, we believe that a strength of our study is that we asked about research biopsies outside the context of a therapeutic trial, thus minimizing the potential for therapeutic misconception to some extent. We believe that our findings have important implications for research utilizing human tissue. First, we found that the majority of MBC patients in both academic and community
Annals of Oncology
original articles
Annals of Oncology
13. Ellis PM, Butow PN, Tattersall MH et al. Randomized clinical trials in oncology: understanding and attitudes predict willingness to participate. J Clin Oncol 2001; 19: 3554–3561. 14. Greenland S. Model-based estimation of relative risks and other epidemiologic measures in studies of common outcomes and in case-control studies. Am J Epidemiol 2004; 160: 301–305. 15. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 2005; 162: 199–200. 16. Brown AP, Wendler DS, Camphausen KA et al. Performing nondiagnostic research biopsies in irradiated tissue: a review of scientific, clinical, and ethical considerations. J Clin Oncol 2008; 26: 3987–3994. 17. Pentz RD, Harvey RD, White M et al. Research biopsies in phase I studies: views and perspectives of participants and investigators. IRB 2012; 34: 1–8. 18. Olson EM, Lin NU, Krop IE et al. The ethical use of mandatory research biopsies. Nat Rev Clin Oncol 2011; 8: 620–625. 19. Peppercorn J, Shapira I, Deshields T et al. Ethical aspects of participation in the database of genotypes and phenotypes of the National Center for Biotechnology Information: the cancer and leukemia group B experience. Cancer 2012; 118: 5060–5068. 20. Cardoso F, Fallowfield L, Costa A et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22(Suppl 6): vi25–vi30. 21. Ellis PM. Attitudes towards and participation in randomised clinical trials in oncology: a review of the literature. Ann Oncol 2000; 11: 939–945. 22. Clinical Trials: The Basic Workbook, 2002. http://www.cancer.gov/clinicaltrials/ learningabout/basicworkbook (10 November 12, date last accessed).
Annals of Oncology 24: 1859–1866, 2013 doi:10.1093/annonc/mdt113 Published online 26 March 2013
Effect of low-dose tamoxifen after surgical excision of ductal intraepithelial neoplasia: results of a large retrospective monoinstitutional cohort study A. Guerrieri-Gonzaga1†, M. Lazzeroni1†, E. Botteri2, D. Serrano1, N. Rotmensz2, M.-C. Varricchio1, M. Cazzaniga1, G. Bollani1, S. Mora1, C. Montefrancesco1, G. Pruneri3,6, G. Viale3,6, M. Intra4, V. Galimberti4, A. Goldhirsch5, V. Bagnardi2,7, B. Bonanni1 & A. DeCensi1,8* Divisions of 1Cancer Prevention and Genetics; 2Epidemiology and Biostatistics; 3Pathology and Lab Medicine; 4Breast Surgery; 5Department of Medicine, European Institute of Oncology, Milan; 6University of Milan, School of Medicine, Milan; 7Department of Statistics, University of Milan-Bicocca, Milan; 8Division of Medical Oncology, Ospedali Galliera, Genoa, Italy
Received 3 July 2012; revised 24 January 2013; accepted 11 February 2013
Background: Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines. Patients and methods: All consecutive women operated on at the European Institute of Oncology for estrogen receptor (ER)-positive DIN (474 treated with low-dose tamoxifen and 509 untreated patients) were followed up for a median of 7 years.
*Correspondence to: Dr. A. DeCensi, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. Tel: +39-010-5634501; Fax: +39-010-57481090; E-mail: [email protected] † These two authors contributed equally.
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Oakland University on June 10, 2015
3. Carey L, Mayer IA. ( personal communication). 4. Pentz RD, Xu Z, Lonial S et al. Research participants’ views of nontherapeutic biopsies. J Clin Oncol 2008; 26: Abstract 13529. 5. Agulnik M, Oza AM, Pond GR et al. Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J Clin Oncol 2006; 24: 4801–4807. 6. Simon MS, Du W, Flaherty L et al. Factors associated with breast cancer clinical trials participation and enrollment at a large academic medical center. J Clin Oncol 2004; 22: 2046–2052. 7. Mills EJ, Seely D, Rachlis B et al. Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors. Lancet Oncol 2006; 7: 141–148. 8. Avis NE, Smith KW, Link CL et al. Factors associated with participation in breast cancer treatment clinical trials. J Clin Oncol 2006; 24: 1860–1867. 9. Sateren WB, Trimble EL, Abrams J et al. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 2002; 20: 2109–2117. 10. Kaphingst KA, Janoff JM, Harris LN et al. Views of female breast cancer patients who donated biologic samples regarding storage and use of samples for genetic research. Clin Genet 2006; 69: 393–398. 11. Dowlati A, Haaga J, Remick SC et al. Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res 2001; 7: 2971–2976. 12. Pentz RD, White M, Harvey RD et al. Therapeutic misconception, misestimation, and optimism in participants enrolled in phase 1 trials. Cancer 2012; 118: 4571–4578.
Annals of Oncology
Annals of Oncology 24: 1853–1859, 2013 doi:10.1093/annonc/mdt067 Published online 13 March 2013
Attitudes of patients with metastatic breast cancer toward research biopsies D. S. Seah1, S. M. Scott2,†, J. Najita3, T. Openshaw4, K. Krag5, E. Frank1, J. Sohl1, Z. K. Stadler6, M. Garrett4, S. G. Silverman7, J. Peppercorn8, E. P. Winer1, S. E. Come2 & Nancy U. Lin1* 1
Deparment of Medical Oncology, Dana-Farber Cancer Institute, Boston; 2Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston; Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston; 4Department of Medical Oncology, Cancer Care of Maine, Bangor; 5 Department of Medical Oncology, North Short Cancer Center, Danvers; 6Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York; 7 Department of Radiology, Brigham and Women’s Hospital, Boston; 8Department of Medicine, Duke University Medical Center, Durham, USA 3
Background: Research studies involving human tissue are increasingly common. However, patients’ attitudes toward research biopsies are not well characterized, particularly when the biopsies are carried out outside the context of therapeutic trials. Patients and methods: One hundred sixty patients with metastatic breast cancer (MBC) from two academic (n = 80) and two community (n = 80) hospitals completed a 29-item self-administered survey to evaluate their willingness to consider providing research purposes only biopsies (RPOBs) (as a stand-alone procedure) and additional biopsies (ABs) (additional needle passes at the time of a clinically indicated biopsy). Results: Eighty-two (51%) of 160 patients would consider having RPOBs, of which 42 (53%) and 40 (50%) patients were from academic and community hospitals, respectively. Patients who had more prior biopsies were less likely to consider RPOBs (RR = 0.6, 95% CI: 0.4–1.0, P = 0.03). Of 160 patients, 115 (72%) patients would consider having ABs. Of these, 64 (80%) and 51 (64%) patients from academic and community hospitals, respectively, would consider ABs (RR = 1.2, 95% CI: 1.0–1.5, P = 0.03). Conclusions: Many patients with MBC in both academic and community settings report willingness to consider undergoing biopsies for research. Further research is needed to understand ethical, logistical and provider-based barriers to broader participation in such studies. Key words: metastatic breast cancer, patient’s preferences, research biopsies
introduction In the era of molecularly targeted therapy, the inclusion of pharmacodynamic and tissue-based correlative end points in clinical trials is increasingly common. Although preclinical models provide insights about tumor biology, the direct evaluation of patients’ tumor tissue is required to determine whether a target is present in humans to validate whether novel therapeutics ‘hit the target’ when administered at doses that are tolerable in humans and whether postulated resistance mechanisms are operative in the clinical setting. Research biopsies are procedures through which tissue is collected for correlative studies, with no intent to use the information for the clinical management of the patient [1]. The biopsy may either be performed as a stand-alone procedure [research purposes only biopsy (RPOB)] or involve *Correspondence to: Prof Nancy U. Lin, Department of Medical Oncology, Division of Women’s Cancers, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Tel: +1-617-632-2335; Fax: +1-617-632-1930; E-mail: [email protected]
additional needle passes at the time of a clinically indicated biopsy [additional biopsy (AB)]. In the context of clinical trials, research biopsies may be either mandatory, where the patient can receive the investigational drug only if the patient agrees to the biopsies, or optional, where the patient can refuse the biopsies but receive the drug. A retrospective review from MD Anderson found that 86.6% of patients who had consented to mandatory biopsies subsequently had the biopsies performed. In contrast, only 4.4% of patients who were offered a biopsy on an optional basis had a biopsy performed [2]. The rate of optional biopsies in clinical trials has been higher in other institutions [3]. Previous survey-based studies have also reported that 18%–36% of patients felt that mandatory research biopsies would deter them from the trial participation [4,5]. Collectively, these data suggest that patients’ willingness to undergo research biopsies are likely influenced by the linkage to clinical trials and extrapolating these data to understand patient perceptions toward research biopsies divorced from the therapeutic trial participation may not be valid.
†
Co-first authors.
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Received 23 October 2012; revised 18 January 2013; accepted 22 January 2013
original articles
methods This study was conducted in accordance with the Declaration of Helsinki and the Dana-Farber/Harvard Cancer Center Institutional Review Board (IRB). The IRB of all participating sites approved the study protocol before patient recruitment.
participants From September 2010 to October 2011, we conducted a cross-sectional self-administered paper survey in the breast oncology practices of two community [Cancer Care of Maine (MCC) and North Shore Cancer Center (Danvers, MA) (NSCC)] and two academic centers [Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) and Beth Israel Deaconess Medical Center (BIDMC)]. Eligibility criteria included a diagnosis of MBC, being above 18 years old, and an ability to understand written English. Patients were identified from oncologists providing a list of MBC patients or through pharmacy records of patients on metastatic regimens. Consecutive patients were approached and the purpose of the study explained. Patients either completed the questionnaire onsite or returned home to complete it. Patients were informed that a $5 gift certificate would be given upon returning the questionnaire.
questionnaire The questionnaire was developed based on the authors’ experience with the recruitment of patients into clinical trials and a literature review. Inputs from doctors, patients and a patient advocate were sought. The questionnaire was piloted in 38 patients with MBC to ensure the clarity of content and acceptability to patients. The final questionnaire was a 29-item survey (supplementary Figure S1, available at Annals of Oncology online). The primary outcome was patients’ attitudes toward undergoing an RPOB or an AB. Patients were asked to rate if they would consider undergoing an RPOB or an AB on a 5-point Likert scale (Definitely, Probably, Maybe, Probably Not, Definitely Not). Patients were counted as willing to undergo an RPOB or an AB if they gave a rating of Definitely or Probably. The questionnaire also collected information on age, education, marital status, prior trial participation, number of prior biopsies and transportation time to the clinic to evaluate the associations with sociodemographic factors, prior experience with biopsies, prior experience with research studies and travel time to the clinic as potential barriers of research participation.
| Seah et al.
statistical methods The primary analysis treated willingness to consider an RPOB as a dichotomous variable, collapsing categories (Definitely or Probably versus Maybe, Probably Not or Definitely Not). The sample size of 160 was chosen to provide at least 80% power to detect a difference of 25% among groups in terms of the proportion of patients who would consider an RPOB. Groups were defined by the practice type (academic versus community). To describe the relationship among patient characteristics and willingness to consider an RPOB, univariate and multivariate analyses were carried out. In addition to the group, independent variables included demographic factors, prior clinical trial participation, number of prior biopsies and transportation time to the clinic. Relative risks (RRs) were determined using the Poisson regression and 95% CI’ based on robust variance estimates [14,15]. Variables were included in multivariate analyses if they were statistically significant at the 0.05 level in univariate analyses. Willingness to consider an AB was analyzed similarly. Comparisons of categorical variables were made using a Fisher’s exact test or a Chi-square test where appropriate. All tests were two-sided at the 0.05 significance level.
results Of 165 women who were invited to complete the questionnaire, 161 (98%) agreed to participate. Four people declined participation; three cited lack of interest and one cited too much paperwork. One patient did not return the questionnaire. Fifty-six (35%), 24 (15%), 32 (20%) and 48 (30%) patients were recruited from DFCI/BWH, BIDMC, NSCC and MCC respectively. The median age was 57 years (range: 28–87). Patient characteristics are reported in Table 1.
research purpose only biopsies Fifty-three percent and 50% of patients from academic and community sites, respectively, would consider an RPOB (P = 0.75) (Table 2). The only univariate variable that was statistically significant among patients who would and would not consider an RPOB was the number of previous biopsies (P = 0.03). Patients who had more prior biopsies were less likely to consider an RPOB. With the exception of the number of previous biopsies, multivariate analysis revealed no significant association with any other variable.
additional biopsies In contrast, 80% and 64% of patients from academic and community sites, respectively, would consider undergoing an AB (P = 0.03; Table 3). In the univariate analysis, the only variable associated with patients’ willingness to undergo an AB was the practice type (P = 0.03). With the exception of the type of practice, multivariate analysis again revealed no significant association with any other variable.
research biopsies of different organs Patients in both academic and community sites responded that they were less likely to consider an RPOB in the organs involved that are considered more invasive such as bone marrow or liver biopsies. A statistically significant difference between the two practice types was not observed (Table 4).
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Although there have been numerous studies evaluating barriers to patient enrollment in therapeutic trials [6–9], there are limited data examining patients’ willingness and barriers to undergo research biopsies [10], especially outside the context of a therapeutic trial [11–13]. We believe that insights into patients’ perceptions associated with correlative research tumor biopsies that are unlinked to clinical trials would provide a more accurate assessment of patient perceptions about research biopsies. Our study reports the results of a survey of the attitudes of metastatic breast cancer (MBC) patients toward undergoing research biopsies. Our research aims to assess whether patients would consider RPOBs and/or ABs outside the context of a clinical trial and to evaluate the factors that are associated with consideration of both RPOBs and ABs. Understanding patients’ attitudes may help us improve strategies to further increase patients’ willingness to consent to research biopsies.
Annals of Oncology
original articles
Annals of Oncology Table 1. Patient characteristics Characteristic
Academic (N = 80)
Community (N = 80)
0.01
reasons for not participating in research biopsies 0.17
0.002
0.95
discussion 0.01
<0.0001
1.00
0.88
N/A
<0.0001
When patients were asked to consider an RPOB of the breast, 82 (51%) of 160 patients would not consider it. When these same patients were asked to consider undergoing an AB,
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Patients were asked to list a few reasons why they would not consider participating in RPOBs. For patients in academic sites (n = 14), reasons included; pain or discomfort (n = 9), risk of biopsy (n = 4), no direct benefit (n = 4), anxiety related to biopsy (n = 4) and inconvenience of the procedure (n = 4). Among 23 patients in community sites who responded, their reasons included; pain or discomfort (n = 14), risk of biopsy (n = 11), inconvenience of the procedure (n = 9), anxiety related to biopsy (n = 8) and no direct benefit (n = 4). Among patients from academic sites who listed reasons for not participating in ABs (n = 5), their reasons included; risk of biopsy (n = 3), pain or discomfort (n = 2), no direct benefit (n = 1) and anxiety related to biopsy (n = 1). Among patients from community sites (n = 8), their reasons included; pain or discomfort (n = 6), anxiety related to biopsy (n = 5), risk of biopsy (n = 5), inconvenience (n = 1) and no direct benefit (n = 1).
Tissue from research biopsies are essential to our understanding of tumor biology, and understanding patients’ attitudes toward research biopsies may improve our strategies to increase their willingness to consent to research biopsies, leading to more access to tumor tissue. We carried out a crosssectional survey of patients with MBC treated in academic and community hospital clinics to ascertain their willingness to undergo research biopsies either in the setting of having additional needle passes in clinically indicated biopsies (AB) or as a stand-alone procedure (RPOB). We found that 51% of patients would consider RPOBs outside the context of a clinical trial. This is a substantial proportion of patients who would potentially contribute to research purely for altruistic reasons. In addition, patients’ consideration of an RPOB did not vary by setting. We also found that most patients (72%) would consider an AB, though the likelihood was higher among patients at academic hospitals (80% versus 64%, P = 0.03). Several groups have evaluated factors associated with participation in clinical trials, showing that practice type, age, education, race, insurance type and employment status are important factors [6,8,9,13]. In our study, the practice type was associated with a patient’s willingness to undergo an AB but was not associated with the likelihood of considering an RPOB. It is conceivable that patients who are treated at academic centers are more exposed to the research environment and feel inclined toward contributing to research, especially if they perceive that the cost in terms of time or risk is low, as in the case of ABs. In addition, it is possible that physicians’ attitudes toward ABs may differ between academic
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Age Mean (SD) 54.7 (10.0) 59.1 (12.4) Median (Min–Max) 55 (33–87) 59 (28–85) Unknown 2 0 Race [n (%)] Black/African American 3 (4) 1 (1) White 71 (89) 79 (99) Other 2 (3) 0 (0) Unknown 4 (5) 0 (0) Highest level of education [n (%)] No high school 0 (0) 1 (1) Some high school 2 (3) 0 (0) High school graduate 8 (10) 26 (33) Some college 9 (11) 14 (18) 2-year college 6 (8) 6 (8) 4-year college 28 (35) 21 (26) Postgraduate school 25 (31) 12 (15) Unknown 2 (3) 0 (0) Marital status [n (%)] Single 8 (10) 8 (10) Married/long-term 58 (73) 60 (75) partner Divorced 9 (11) 7 (9) Separated 0 (0) 1 (1) Widowed 3 (4) 4 (5) Unknown 2 (3) 0 (0) Employment status [n (%)] Not employed 37 (46) 54 (68) Employed 42 (53) 26 (33) Unknown 1 (1) 0 (0) Prior clinical trial participation [n (%)] No 27 (34) 57 (71) Yes 51 (64) 22 (28) Unknown 2 (3) 1 (1) Prior breast biopsy? [n (%)] No 2 (3) 2 (3) Yes 78 (98) 78 (98) Number of prior biopsies [n (%)] 0 biopsies 2 (3) 2 (3) 1–2 biopsies 57 (71) 56 (70) ≥3 biopsies 18 (23) 14 (18) Unknown 3 (4) 8 (10) Biopsy other than breast? [n (%)] Skin 7 (9) 8 (10) Liver 12 (15) 8 (10) Lung 10 (13) 5 (6) Bone 19 (24) 8 (10) Bone marrow 4 (5) 4 (5) Other 24 (30) 11 (14) Transportation time to appointment [n (%)] <45 min 23 (29) 51 (64) ≥45 min 55 (69) 28 (35) Unknown 2 (3) 1 (1)
P-value
49 (60%) of 82 patients replied differently and would consider a research biopsy in this setting (Table 5). When considering an RPOB of the liver, 121 (76%) of 160 patients would not consider it. However, of this group, 74 (62%) of 121 patients would consider having an AB of the liver (Table 6).
original articles
Annals of Oncology
Table 2. Univariate analysis of patients’ willingness to undergo a research biopsy for research purposes alone Variable
N
Consider [n (%)]
Would not consider [n (%)]
Unknown [n (%)]
RR (95% CI)
P-value
80 80
42 (53) 40 (50)
36 (45) 39 (49)
2 (3) 1 (1)
1.1 (0.8–1.4) Ref
0.75
53 55 50 2
25 (47) 31 (56) 25 (50) 1 (50)
28 (53) 22 (40) 24 (48) 1 (50)
0 (0) 2 (4) 1 (2) 0 (0)
Ref 1.2 (0.9–1.8) 1.1 (0.7–1.6)
0.53
37 35 86
18 (49) 19 (54) 44 (51)
18 (49) 16 (46) 40 (47)
1 (3) 0 (0) 2 (2)
Ref 1.0 (0.7–1.5) 1.1 (0.7–1.7)
0.95
16 118 24 2
8 (50) 61 (52) 12 (50) 1 (50)
8 (50) 55 (47) 11 (46) 1 (50)
0 (0) 2 (2) 1 (4) 0 (0)
Ref 1.1 (0.6–1.8) 1.0 (0.6–1.9)
1.00
68 91 1
37 (54) 45 (49) 0 (0)
29 (43) 45 (49) 1 (100)
2 (3) 1 (1) 0 (0)
1.12 (0.83–1.51) Ref
0.52
73 84 3
35 (48) 45 (54) 2 (67)
37 (51) 37 (44) 1 (33)
1 (1) 2 (2) 0 (0)
0.9 (0.7–1.2) Ref
0.52
117 32 11
67 (57) 11 (34) 4 (36)
48 (41) 20 (63) 7 (64)
2 (2) 1 (3) 0 (0)
Ref 0.6 (0.4–1.0)
0.03
74 83 3
40 (54) 41 (49) 1 (33)
32 (43) 41 (49) 2 (67)
2 (3) 1 (1) 0 (0)
1.1 (0.8–1.5) Ref
0.52
and community sites and may influence patients’ perceptions. However, this question has not been studied previously. Another interesting finding is that patients who had more prior biopsies were less likely to consider an RPOB (P = 0.03). This suggests that prior biopsy experiences may have been negative and further research into patients’ experience may be required. However, this variable was not associated with willingness to consider an AB. Ethical concerns about including mandatory research biopsies in therapeutic trials have been raised because of the potential for coercion or the lack of patient understanding about the intent of the biopsy [1,12,16,17]. Others have endorsed the inclusion of required biopsies provided that participants are fully informed and the study is designed to address the scientific questions at hand [18,19]. Most of the literature on patients’ perspectives on research biopsies has been in the context of phase 1 trials [2,12] with little data outside of the context of a clinical trial (e.g. without potential for confounding based on a desire to receive an experimental agent) to inform the debate [2,12]. One study interviewed 40 phase 1 trial patients, with 70% of participants indicating that they would undergo optional
| Seah et al.
non-therapeutic biopsies within a clinical trial, suggesting that non-therapeutic biopsies are not barriers to research participation [4]. In a follow-up study, Pentz et al. reported that two-thirds of patients misunderstood the lack of benefit of a research biopsy in the context of a phase 1 trial, raising concerns that patients would not agree to biopsies outside of a trial if they had a true understanding of the lack of personal benefit. Although cross-study comparisons are limited given major differences in the study populations, it is notable that 72% and 51% of MBC patients in our study indicated a willingness to undergo an AB and an RPOB, respectively, despite it being unlinked to any type of therapeutic trials. Another interesting finding of this study surrounds the attitudes of patients who would decline an RPOB. For breast mass biopsies, 60% of patients who would decline an RPOB would consider an AB. For liver mass biopsies, 62% of patients who would decline an RPOB would consider an AB. Although this finding is perhaps not surprising, it does identify an opportunity for enhanced efforts at tissue collection to answer specific translational questions. For example, at the first cancer recurrence, it is increasingly considered the standard of care to obtain a biopsy to confirm the diagnosis and to re-check
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Type of practice Academic Community Age ≤51 >51, ≤61 >61 Unknown Education No high school/high school graduate Some college 4-year college/postgraduate Marital status Single Married/living as married Divorced, widowed or separated Unknown Employment status Employed No employed Unknown Prior clinical trial participation Yes No Unknown Number of prior biopsies 0–2 ≥3 Unknown Transportation time <45 min ≥45 min Unknown
original articles
Annals of Oncology
Table 3. Univariate analysis of patients’ willingness to allow an additional biopsy performed for research purposes, at the time of a clinically indicated biopsy Variable
N
Consider [n (%)]
Would not consider [n (%)]
Unknown [n (%)]
RR (95% CI)
80 80
64 (80) 51 (64)
15 (19) 27 (34)
1 (1) 2 (3)
1.2 (1.0–1.5) Ref
0.03
53 55 50 2
40 (75) 44 (80) 30 (60) 1 (50)
12 (23) 11 (20) 18 (36) 1 (50)
1 (2) 0 (0) 2 (4) 0 (0)
Ref 1.0 (0.9–1.3) 0.8 (0.6–1.1)
0.11
37 35 86
25 (68) 23 (66) 65 (76)
10 (27) 11 (31) 21 (24)
2 (5) 1 (3) 0 (0)
Ref 1.1 (0.8–1.3) 0.9 (0.7–1.3)
0.63
16 118 24 2
13 (81) 86 (73) 14 (58) 2 (100)
3 (19) 30 (25) 9 (38) 0 (0)
0 (0) 2 (2) 1 (4) 0 (0)
Ref 0.9 (0.7–1.2) 0.7 (0.5–1.1)
0.35
68 91 1
16 (24) 26 (29) 0 (0)
52 (76) 62 (68) 1 (100)
0 (0) 3 (3) 0 (0)
73 84 3
57 (78) 57 (68) 1 (33)
16 (22) 26 (31) 0 (0)
0 (0) 1 (1) 2 (67)
1.1 (0.9–1.4) Ref
0.21
117 32 11
85 (73) 24 (75) 6 (55)
29 (25) 8 (25) 5 (45)
3 (3) 0 (0) 0 (0)
Ref 1.0 (0.8–1.3)
1.00
74 83 3
53 (72) 60 (72) 2 (67)
20 (27) 21 (25) 1 (33)
1 (1) 2 (2) 0 (0)
Ref 1.0 (0.8–1.2)
0.86
1.09 (0.90–1.31) Ref
P-value
0.47
P-values correspond to the Fisher’s exact test using available data.
Table 4. Distribution of attitude of patients toward research biopsies for different organs Variable
Academic (N = 80) Community (N = 80) P-value Consider [n (%)] Would not consider [n (%)] Unknown [n (%)] Consider [n (%)] Would not consider [n (%)] Unknown [n (%)]
Venipuncture Skin Breast Bone marrow Liver
75 (94) 44 (55) 32 (40) 23 (29) 19 (24)
4 (5) 36 (45) 42 (53) 56 (71) 59 (74)
1 (1) 0 (0) 6 (8) 1 (1) 2 (3)
70 (88) 51 (64) 39 (49) 21 (26) 15 (19)
9 (11) 28 (35) 40 (50) 58 (73) 62 (78)
1 (1) 1 (1) 1 (1) 1 (1) 3 (4)
0.25 0.26 0.52 0.86 0.56
Table 5. Cross-tabulation of attitudes towards biopsies for both RPOBs and ABs to the breast
Table 6. Cross-tabulation of attitudes toward biopsies for both RPOBs and ABs to the liver
Consider an AB
Consider an AB
Yes No Unknown Total
Consider a RPOB Yes No
Unknown
Total
68 1 2 71
0 1 6 7
117 35 8 160
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49 33 0 82
Yes No Unknown Total
Consider a RPOB Yes No
Unknown
Total
33 0 1 34
0 2 3 5
107 46 7 160
74 44 3 121
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Type of practice Academic Community Age ≤51 >51, ≤61 >61 Unknown Education No high school/high school graduate Some college 4-year college/postgraduate Marital status Single Married/living as married Divorced, widowed or separated Unknown Employment status Employed No employed Unknown Prior clinical trial participation Yes No Unknown Number of prior biopsies 0–2 ≥3 Unknown Transportation time <45 min ≥45 min Unknown
original articles
| Seah et al.
sites would consider undergoing an AB, opening up an avenue to collect tissue for research in a way that is acceptable to many patients. We believe that it is reasonable to routinely discuss with patients the option of an AB when a clinical biopsy is being entertained. Second, we must be sensitive to patient’s needs and concerns. The top three reasons cited for not participating in research biopsies included pain, risk of the procedure and anxiety related to the biopsy. This further emphasizes the need for patient education and efforts by clinicians to minimize these risks. Research biopsies should occur within the context of an IRB-approved protocol governing patient consent, guidelines for tissue acquisition and storage, adverse event reporting and use of tissues. We should solicit feedback from patients undergoing biopsies and work with all parties involved to continually improve pre-procedure counseling and consent discussion, minimize risk and minimize procedure-related pain and anxiety. Finally, given that about half of the patients would consider an RPOB even when asked outside of the context of a therapeutic trial, our findings suggest a greater willingness of patients to participate in research biopsies than might be otherwise assumed by providers, investigators or IRBs and could help to inform discussions about how such biopsies might be appropriately incorporated into translational studies and/or clinical trials. Our study also showed that there were no statistically significant differences in the consideration rates of RPOBs in both academic and community settings. This suggests that there is a potential opportunity to obtain tumor tissues in both settings for research purposes. In summary, our study suggests that many MBC patients would consider research biopsies even outside of the context of a clinical trial. Efforts to educate and communicate with patients about the importance of tissue in research and the RRs of tissue donation should be explored, as should continued efforts to ensure that patients understand the nature of research biopsies to minimize therapeutic misconception. Finally, further research to explore clinician’s attitudes toward research biopsies may also improve our understanding of barriers that hinder access to human tissue for scientific research.
funding This work was supported by Metastatic Research Fund— anonymous donor, Nancy and Randy Berry Junior Faculty Award and the Karen Webster & David Evans Metastatic Research Fund.
disclosure The authors have declared no conflicts of interest.
references 1. Peppercorn J, Shapira I, Collyar D et al. Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J Clin Oncol 2010; 28: 2635–2640. 2. El-Osta H, Hong D, Wheler J et al. Outcomes of research biopsies in phase I clinical trials: the MD Anderson cancer center experience. Oncologist 2011; 16: 1292–1298.
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hormone receptor (HR) and human epidermal growth factor receptor 2 status given its importance in patient management [20]. Similarly, re-biopsy may be indicated in the setting of the development of resistance to endocrine therapy in HR-positive breast cancer to determine whether the tumor still expresses HRs. Again, the mechanisms underlying endocrine resistance in breast cancer are poorly understood, partly due to a lack of available tissue for investigation. If patients were more routinely approached for a research biopsy in the context of these scenarios, eventually a rich tissue resource could be built. Our study had a number of limitations. This is a relatively small study of women treated across four institutions in the Northeast United States, limiting the multivariable analyses. Previous studies have suggested that women, particularly those with breast cancer, are more willing to undergo optional biopsies and participate in clinical trials compared with the general oncology community [2,21]. Patients participating in this survey also had a higher rate of prior clinical trial enrollment than reported for the average adult cancer population [22]. Patients with late-stage cancers may be more vested in research, and MBC patients may not be reflective of cancer patients as a whole. We did not specifically assess the health literacy of our patients. However, over 90% of our population had graduated from high school and the educational level was not a significant predictor of willingness to undergo a biopsy in our model. Moreover, it is notable that patients were clearly less willing to consider more invasive biopsies (i.e. the liver) and more willing to undergo a breast biopsy or venipuncture for research. This suggests that patients did indeed understand and considered each scenario seriously. Even if patients did completely understand what was being asked of them, our study design consisted of patients being given hypothetical scenarios where they were asked to consider participating in theoretical biopsies. We acknowledge that there may be a difference among ‘willingness to consider’, ‘willingness to consent’ and actually undergoing a research biopsy. At DFCI, we have had a clinical protocol open to allow informed patients to undergo either an RPOB or an AB that is not linked to a specific therapeutic trial. Over the past 12 months, 18 and 34 patients have undergone RPOBs and ABs, respectively. Unfortunately, we did not collect data on the approach and the decline rate to be able to estimate patient’s willingness to undergo biopsies as well as physician factors that might influence the biopsy rates. We are currently developing projects to better understand this issue. We did not assess if the type of testing and analysis (e.g. genetic testing) performed on the specimens would change patients’ perceptions in undergoing research biopsies. We also did not assess whether receipt of research results would impact patient’s acceptance of research biopsies. Finally, we did not inquire directly about patient motivations to undergo research biopsies and cannot exclude the possibility that patients may still perceive personal benefit from the biopsy (therapeutic misconception). However, we believe that a strength of our study is that we asked about research biopsies outside the context of a therapeutic trial, thus minimizing the potential for therapeutic misconception to some extent. We believe that our findings have important implications for research utilizing human tissue. First, we found that the majority of MBC patients in both academic and community
Annals of Oncology
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Annals of Oncology
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Annals of Oncology 24: 1859–1866, 2013 doi:10.1093/annonc/mdt113 Published online 26 March 2013
Effect of low-dose tamoxifen after surgical excision of ductal intraepithelial neoplasia: results of a large retrospective monoinstitutional cohort study A. Guerrieri-Gonzaga1†, M. Lazzeroni1†, E. Botteri2, D. Serrano1, N. Rotmensz2, M.-C. Varricchio1, M. Cazzaniga1, G. Bollani1, S. Mora1, C. Montefrancesco1, G. Pruneri3,6, G. Viale3,6, M. Intra4, V. Galimberti4, A. Goldhirsch5, V. Bagnardi2,7, B. Bonanni1 & A. DeCensi1,8* Divisions of 1Cancer Prevention and Genetics; 2Epidemiology and Biostatistics; 3Pathology and Lab Medicine; 4Breast Surgery; 5Department of Medicine, European Institute of Oncology, Milan; 6University of Milan, School of Medicine, Milan; 7Department of Statistics, University of Milan-Bicocca, Milan; 8Division of Medical Oncology, Ospedali Galliera, Genoa, Italy
Received 3 July 2012; revised 24 January 2013; accepted 11 February 2013
Background: Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines. Patients and methods: All consecutive women operated on at the European Institute of Oncology for estrogen receptor (ER)-positive DIN (474 treated with low-dose tamoxifen and 509 untreated patients) were followed up for a median of 7 years.
*Correspondence to: Dr. A. DeCensi, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. Tel: +39-010-5634501; Fax: +39-010-57481090; E-mail: [email protected] † These two authors contributed equally.
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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