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Evaluation of a Streamlined Oncologist-Led BRCA Mutation Testing and Counseling Model for Patients With Ovarian Cancer
Abstract
There is a growing demand for BRCA1/2 mutation (BRCAm) testing in patients with ovarian cancer; however, the limited number of genetic counselors presents a potential barrier. To facilitate more widespread BRCAm testing in ovarian cancer, pretest counseling by the oncology team could shorten testing turnaround times and ease the pressure on genetic counselors.
The prospective, observational Evaluating a Streamlined Onco-genetic BRCA Testing and Counseling Model Among Patients With Ovarian Cancer (ENGAGE) study evaluated a streamlined, oncologist-led BRCAm testing pathway. The analysis population comprised 700 patients with ovarian cancer at 26 sites in the United States, Italy, and Spain. The primary objectives were to assess turnaround time and, using questionnaires, to evaluate stakeholder satisfaction (patients, oncologists, and geneticists or genetic counselors) with the oncologist-led BRCAm testing pathway.
The median overall turnaround time was 9.1 weeks (range, 0.9 to 37.1 weeks), with median turnaround times in the United States, Italy, and Spain of 4.1 weeks (range, 0.9 to 37.1 weeks), 20.4 weeks (range, 2.9 to 35.4 weeks), and 12.0 weeks (range, 2.0 to 36.7 weeks), respectively. Patient satisfaction with the oncologist-led BRCAm testing pathway was high, with > 99% of patients expressing satisfaction with pre- and post-BRCAm test counseling. Oncologist satisfaction with the BRCAm testing pathway was also high, with > 80% agreeing that the process for performing BRCAm testing worked well and that counseling patients on BRCAm testing was an efficient use of their time. Oncologists expressed higher levels of satisfaction with the BRCAm testing pathway than did geneticists or genetic counselors.
The results of the ENGAGE study demonstrate that an oncologist-led BRCAm testing process is feasible in ovarian cancer. Development of local BRCAm testing guidelines similar to the one used in this study could allow faster treatment decisions and better use of resources in the management of patients with ovarian cancer.
BRCA1/2 mutation (BRCAm) status is an established predictive biomarker of potential benefit from treatment with poly(ADP-ribose) polymerase (PARP) inhibitors.1 Maintenance therapy with oral PARP inhibitors prolongs progression-free survival and overall survival in patients with platinum-sensitive relapsed ovarian cancer and a BRCAm.2-4 The PARP inhibitor olaparib is available for the treatment of advanced ovarian cancer with or without a BRCAm5,6; rucaparib and niraparib are also available.7,8
A BRCAm is found in approximately 15% of newly diagnosed ovarian cancers9,10 and is associated with earlier disease onset.11 Establishing the BRCAm status of patients with ovarian cancer provides useful information regarding the prognosis and clinical course of the disease, and it is essential in identifying patients most likely to benefit from PARP inhibitor therapy.1
Previously, BRCAm testing was offered only to patients with a family history of breast and/or ovarian cancer; however, recent evidence shows that > 40% of women with a BRCAm have no such family history.1,9 National guidelines now recommend that BRCAm testing be provided to all patients diagnosed with epithelial ovarian cancer,12-14 although some variation between guidelines remains.15 Despite these recommendations, genetic testing is currently underused in women with ovarian cancer.16
Genetic counseling is recommended both when genetic testing is offered to the patient and after genetic test results are disclosed to the patient.12 However, the capacity of genetic counselors is rate limiting and presents a potential barrier to the implementation of BRCAm testing for patients with ovarian cancer.17,18 For example, in the United Kingdom, the average waiting time for a genetics appointment is 12 to 15 weeks.19 Given the high volume of BRCAm tests now being ordered, a new, more streamlined testing approach is needed to shorten testing turnaround times and to ease the pressure on genetic counselors.
The Evaluating a Streamlined Onco-genetic BRCA Testing and Counseling Model Among Patients With Ovarian Cancer (ENGAGE) study evaluated a streamlined, oncologist-led BRCAm testing model. ENGAGE builds on a pilot study initiated as part of the Mainstreaming Cancer Genetics program by the Institute of Cancer Research and the Royal Marsden Hospital, London, United Kingdom.19 In the pilot study, use of a streamlined, oncologist-led (ie, mainstream) BRCAm testing model was associated with a fourfold reduction in the 20-week average turnaround time of the conventional testing pathway.19
The ENGAGE study is an international, multicenter, prospective, observational study designed to evaluate the feasibility of a streamlined BRCAm testing model in patients diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer. The study was conducted at 26 sites in the United States (n = 11), Italy (n = 8), and Spain (n = 7).
Eligible patients were ≥ 18 years of age and had a diagnosis of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients were excluded if they had low-grade epithelial ovarian cancer or nonepithelial ovarian cancer, had undergone prior BRCAm testing, or were enrolled in an interventional clinical trial for any malignancy.
The institutional review boards or independent ethics committees of all investigational sites approved the protocol. The study was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice, and the applicable legislation on noninterventional studies.
The clinical team (ie, oncologists and oncology nurses) received training on discussing the role of BRCAm testing and on genetic counseling techniques and provided patients with pre-BRCAm test counseling (Fig 1 and Data Supplement). If requested by the patient, additional pre-BRCAm test counseling was provided by a geneticist or genetic counselor. After testing, the oncologist and/or geneticist reviewed and interpreted the test results and reported them to the patient. An appointment with a geneticist or genetic counselor was recommended for patients with a positive BRCAm test.
Fig 1. ENGAGE trial procedures. (*) Blood sample collected and sent to an external laboratory or participating site for germline BRCA1/2 mutation testing, followed by genetics review; (†) clinical team includes the oncologist and/or nursing staff; (‡) end-of-study form is filled in by the clinical team to confirm the patient’s study status as either completed or not completed (includes loss to follow-up, death, patient decision).
Patient satisfaction with pre- and post-BRCAm test counseling was assessed using the Satisfaction with Genetic Counseling Scale (SGCS), which comprises 12 items and assesses six dimensions (Data Supplement).20 The quality of pre-BRCAm test counseling was also assessed by patients using the Oncogenetic Counseling Elements Questionnaire (14 questions; Data Supplement). After the BRCAm test, patient satisfaction was also assessed using the Modified Royal Marsden Satisfaction Questionnaire (15 questions; Data Supplement).
Oncologists (or oncology nurses) and geneticists or genetic counselors evaluated the BRCAm testing pathway using the Oncologist Satisfaction Survey (14 questions) and the Genetic Counselor Satisfaction Survey (seven questions; Data Supplement). Satisfaction questionnaires were completed after one, five, and 10 patients had been counseled. All treatment decisions and clinical assessments were made at the discretion of the treating physician, in accordance with usual care.
The three primary objectives were assessment of turnaround time, patient assessment of pre-BRCAm test counseling quality and satisfaction with the streamlined BRCAm testing pathway, and evaluation by the oncologist (or oncology nurse) and geneticist or genetic counselor of their satisfaction with the BRCAm testing pathway.
The overall turnaround time was defined as the time from initial clinical team counseling until provision of the BRCAm test result to the patient by the oncologist, geneticist or genetic counselor, or testing laboratory, or provision of post-BRCAm test counseling by an oncologist or geneticist or genetic counselor (whichever occurred later). Turnaround times for each step in the pathway were also assessed.
Secondary objectives included assessment of the association between the BRCAm testing turnaround time and patient satisfaction with pre-BRCAm test counseling, site characteristics, patient demographic and disease characteristics, and outcome of the test.
All patients who consented to participate in the study and who met the eligibility criteria were included in the analysis population. All data were summarized using descriptive statistics, and no statistical tests were performed.
The main analysis of pre-BRCAm test questionnaires was conducted on questionnaires completed within 14 days after clinical team counseling. The main analysis of post-BRCAm test questionnaires was conducted within 14 days of one of the following: the date on which BRCAm test results were given to the patient, the date of consultation with an oncologist, or the date of counseling by a geneticist or genetic counselor after receipt of BRCAm test results.
Because satisfaction questionnaires were not completed consistently by oncologists and geneticists or genetic counselors after one, five, and 10 patients had been counseled, the assessment points were amended to after two or fewer, three to seven, and eight or more patients had been counseled, respectively.
Overall, 52 oncologists completed 110 oncologist satisfaction survey questionnaires (35, 43, and 32 questionnaires were completed after one, five, and 10 patients had been counseled, respectively, with one or more oncologists involved in patient counseling per site). Pre-BRCAm test counseling was provided only by oncologists in Europe but by either oncologists (40.7%) or oncology nurses (59.3%) in the United States.
Overall, 18 geneticists or genetic counselors completed 27 genetic counselor satisfaction survey questionnaires (15, eight, and four surveys were completed after one, five, and 10 patients had been counseled, respectively).
ENGAGE was conducted between April 21, 2015, and September 30, 2016, and 710 patients were enrolled. The analysis population comprised 700 patients; 10 patients were excluded because they did not comply fully with the inclusion criteria.
The study was completed by 634 patients (90.6%); reasons for premature discontinuation were death (n = 24), loss to follow-up (n = 19), patient voluntary discontinuation (n = 14), and other reasons (n = 9).
The main analysis included 530 SGCS questionnaires at pre-BRCAm testing, 414 SGCS questionnaires at post-BRCAm testing, 514 Oncogenetic Counseling Elements Questionnaires at pre-BRCAm testing, and 414 Modified Royal Marsden Patient Satisfaction Questionnaires after BRCAm testing.
Patient demographic and clinical characteristics are presented in Table 1. The proportion of patients with a family history of breast or ovarian cancer differed among countries (41.9% in the United States, 34.3% in Italy, and 23.6% in Spain). Two women received additional counseling by a geneticist or genetic counselor after the oncologist-led counseling and before BRCAm testing; in both cases, this was conducted less than 1 week after the initial oncology team counseling.
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The turnaround times expected by participating physicians using standard procedures are presented in the Data Supplement. Using the streamlined BRCAm testing pathway, the median overall turnaround time was 9.1 weeks (range, 0.9 to 37.1 weeks; Fig 2). Analysis of each step of the testing pathway revealed that the overall turnaround time was driven mainly by the time from the collection of the blood sample for BRCAm testing to the provision of the test results to the patient (median, 8.6 weeks [range, 0.7 to 35.6 weeks]; Fig 2). The median time from collection of the blood sample to receipt of the test results by the referring clinician was 4.7 weeks (range, 0.0 to 32.1 weeks). In terms of the other steps, patient consent to a BRCAm test was usually obtained during initial oncology team counseling, and the blood sample for BRCAm testing was usually taken shortly after the initial oncology team counseling (Fig 2). Oncologist counseling usually occurred at the same time as the provision of the BRCAm test results to the patient (Fig 2). Counseling by a geneticist or genetic counselor was provided a median of 0.0 weeks (range, 0.0 to 30.9 weeks) after patients received a positive BRCAm result.
Fig 2. Turnaround times for each step of the streamlined BRCAm testing pathway. (*) Negative durations correspond to patients who consented to a BRCAm test before initial oncology team counseling or for whom the blood sample was taken before initial oncology team counseling. BRCAm, BRCA1/2 mutation.
Turnaround times differed among countries (Fig 2). The median overall turnaround time was longer in Europe than the United States, which is reflected in the longer median time from performing the BRCAm test to providing the result either to the referring clinician or to the patient.
Patient satisfaction with streamlined BRCAm testing was high. Mean SGCS scores at both pre- and post-BRCAm testing were > 3.5 for all six dimensions, with minimal differences seen between pre- and post-BRCAm testing (Data Supplement). Overall, 99.2% of patients were satisfied with pre-BRCAm test counseling (Fig 3), and 99.8% of patients were satisfied with post-BRCAm test counseling by a geneticist or genetic counselor or oncologist.
Fig 3. Patient satisfaction with pre-BRCA1/2 mutation (BRCAm) test counseling. Results shown for eight questions from the patients’ assessment of quality report form (Oncogenetic Counseling Elements Questionnaires) and for one summary question from the patients’ satisfaction report form (Satisfaction with Genetic Counseling Scale) before BRCAm testing. Q, question; VUS, variant of uncertain significance.
Patients considered the quality of pre-BRCAm test counseling to be high, with > 90% of patients recording on their Oncogenetic Counseling Elements Questionnaire that their oncologist or nurse discussed the purpose of the BRCAm test, how the BRCAm test could affect their treatment, the BRCA gene and its function, the implications of a positive BRCAm test result, and the impact their test result could have on their family (Fig 3 and Data Supplement). In addition, pre-BRCAm test counseling was comprehensive, with oncologists or nurses spending a median of 20.0 minutes (range, 2 to 115 minutes) discussing the BRCAm test.
For the Modified Royal Marsden Patient Satisfaction Questionnaire, 96.6% of patients agreed or strongly agreed that they were pleased to have had the genetic test, and 93.7% of patients agreed or strongly agreed that they were happy to have had the genetic test at one of their existing oncology appointments, rather than at a separate appointment with the genetics team (Data Supplement).
Oncologist satisfaction with the streamlined BRCAm testing pathway was high. Of the oncologists who completed surveys after 10 patients had been counseled, 90.6% agreed or strongly agreed that it is very important for patients with ovarian cancer to be offered BRCAm testing, and 84.3% agreed or strongly agreed that the process for performing BRCAm testing worked well (Data Supplement).
Oncologists expressed higher levels of satisfaction with the BRCAm testing pathway than did geneticists or genetic counselors. When all surveys were considered, 48.1% of geneticists or genetic counselors welcomed having oncologists conducting pre-BRCAm test counseling, and 46.2% of geneticists or genetic counselors agreed or strongly agreed that patients seemed to receive accurate information during the pre-BRCAm test counseling (Data Supplement).
The overall BRCAm testing turnaround time did not have a notable impact on the dimension scores of the SGCS. No clear associations were found between the turnaround time and the instrumental, affective, satisfaction with the information provided during counseling, fulfillment of expectations, and overall feeling of satisfaction dimensions. An association was found between the turnaround time and the procedural dimension score, with a shorter turnaround time associated with higher patient satisfaction with administrative procedures.
Additional analyses demonstrated that the median overall turnaround time was longer with local versus central laboratory providers, and with the use of a study-sponsored central laboratory versus a local hospital-affiliated or commercial laboratory (Data Supplement).
Remote delivery of negative BRCAm test results was more common in the United States than in Europe, thereby reducing the time to delivery of results (Data Supplement).
Data on which team member provided the BRCAm test result to the patient are summarized in the Data Supplement. Regardless of the result (positive, negative, or variant of uncertain significance [VUS]), patients in Europe were more likely than those in the United States to have a consultation with the oncology team or with a geneticist or genetic counselor after receiving their BRCAm test results, which would tend to increase the turnaround time.
A BRCAm was identified in 95 of 690 evaluable patients (13.8%; Fig 4). The prevalence of BRCA1 mutations (65.3%) was higher than that of BRCA2 mutations (33.7%), with one patient (1.1%) having both BRCA1 and BRCA2 mutations. Of 91 evaluable patients with a BRCAm, 53.8% had a family history of breast or ovarian cancer, whereas 46.2% did not.
Fig 4. Breakdown of BRCA1/2 mutation test results. VUS, variant of uncertain significance; Wt, wild type.
The streamlined oncology-led BRCAm testing pathway we report here was associated with high levels of acceptance and satisfaction among patients with ovarian cancer. Patient satisfaction was high regardless of testing outcome, and the overall turnaround time did not have a notable impact on patient satisfaction. Patients’ therapies were not dependent on BRCAm test results because most patients were either in remission or stable, or undergoing primary chemotherapy for newly diagnosed ovarian cancer, meaning that any delays may have been less likely to cause dissatisfaction. By contrast, rapid receipt of test results is more critical in cancers such as breast cancer, where prophylactic surgical decisions must be made.
There was low uptake of pre-BRCAm test counseling with a geneticist or genetic counselor, with only two patients requesting this additional counseling, which suggested high patient satisfaction with the oncologist-led pretest counseling. It is not feasible to train enough genetic counselors to meet the growing demand for genetic testing,21 and use of an oncologist-led BRCAm testing pathway has the potential to avoid the substantial delays associated with waiting for an appointment with a geneticist or genetic counselor.19 In this study, BRCAm testing usually occurred shortly after the initial oncology team counseling (Fig 2), whereas the average time from patient consent to BRCAm testing was expected to be > 1 month in approximately 25% of patients using standard procedures (Data Supplement).
The streamlined BRCAm testing pathway also has convenience implications, with the vast majority of patients in ENGAGE agreeable to having the BRCAm test at an existing oncologist appointment, rather than having to make a separate appointment with a genetic counselor.
Although clinicians expressed high satisfaction with the streamlined BRCAm testing pathway, geneticists or genetic counselors showed less enthusiasm for this approach. For example, ≤ 50% of surveyed geneticists or genetic counselors responded that patients seemed to receive accurate information about the BRCAm test in the pretest counseling session. For the streamlined BRCAm testing pathway to succeed, it is important that oncologists and geneticists or genetic counselors work collaboratively and that oncologists receive high-quality training on how to conduct pre-BRCAm test counseling. To achieve streamlining, oncologists may wish to adapt and tailor the testing process to their institution in collaboration with geneticists or genetic counselors. It should be noted that the purpose of the oncologist-led pretest counseling was to provide enough information on why the patient should have the test, rather than full genetic counseling, which is appropriate once the test result is known. In addition, counseling was provided in the context of an existing cancer diagnosis, where there is general agreement that BRCAm testing is appropriate, rather than in the context of a theoretical risk.
Variations in turnaround times were observed among the participating countries. One factor underlying the differences in sample processing time was the longer overall turnaround time seen with the use of a study-sponsored central laboratory than with a local laboratory affiliated with a hospital site or a commercial laboratory. Methods of communicating results to patients also differed among countries, with patients in the United States more likely to have negative results delivered remotely. Even if negative results are delivered remotely, patients should still be offered a face-to-face appointment to discuss their results.
The results of ENGAGE support the premise that BRCAm status should be based on patient criteria rather than on family history alone.1 Among women in ENGAGE who were found to have a BRCAm, only 54% had a family history of breast or ovarian cancer. Various factors may limit the usefulness of a family history, including a small family size, early deaths in family members, prophylactic surgeries, and a lack of communication among family members.12
Given that the ENGAGE study was not limited to a specific BRCAm test, the streamlined oncologist-led BRCAm testing pathway is feasible regardless of the test used. Somatic BRCAm testing is increasingly common and of growing importance; some institutions prefer to test for somatic mutations first, with those patients found to have a mutation in a tumor subsequently undergoing germline testing.1 Although BRCAm constitute the majority of deleterious mutations associated with an increased risk of epithelial ovarian, fallopian tube, and primary peritoneal cancer, multigene panel testing may be appropriate in some settings to evaluate for all currently known mutations.12
BRCA VUS was identified in 11.2% of patients in ENGAGE, with approximately 70% of surveyed patients responding that their oncologist or nurse had discussed the implications of VUS during pre-BRCAm test counseling. The level of understanding of both oncologists and patients with regard to the complexities of VUS must be evaluated adequately when adopting novel BRCAm testing pathways.22
Strategies are needed to meet the growing demand for genetic testing.21 One suggested approach is that after brief training, clinicians perform the initial genetic testing, after which patients with a positive result or VUS could be referred to a geneticist or genetic counselor as needed.21 The results of the ENGAGE study support such a strategy.
The results of the ENGAGE study demonstrate that an oncologist-led BRCAm testing process is feasible in patients diagnosed with ovarian, fallopian tube, and primary peritoneal cancer. The streamlined BRCAm testing model can shorten turnaround times by providing combined genetic testing and counseling, with high acceptance and satisfaction among both patients and clinical staff. Development of local BRCAm testing guidelines, involving oncologists, oncology nurses, and geneticists or genetic counselors and following a pathway similar to the one used in this study, could allow faster treatment decisions and better use of resources in the management of patients with ovarian cancer.
Supported by AstraZeneca.
Presented in a poster discussion session (interim data) at European Society for Medical Oncology 2016 Congress; 7-11 October 2016; Copenhagen and as a poster (final data) at 2017 ASCO Annual Meeting; 2-6 June 2017; Chicago, IL.
Clinical trial information: NCT02406235.
Listen to the podcast by Dr Tung at ascopubs.org/jco/podcasts
Conception and design: Sudeep Karve
Provision of study materials or patients: Nicoletta Colombo, Gloria Huang, Giovanni Scambia, Eva Chalas, Sandro Pignata, James Fiorica, Linda Van Le, Sharad Ghamande, Santiago González-Santiago, Isabel Bover, Begoña Graña Suárez, Andrew Green
Collection and assembly of data: Nicoletta Colombo, Gloria Huang, Giovanni Scambia, Eva Chalas, Sandro Pignata, James Fiorica, Linda Van Le, Sharad Ghamande, Santiago González-Santiago, Isabel Bover, Begoña Graña Suárez, Andrew Green
Data analysis and interpretation: Nicoletta Colombo, Gloria Huang, Eva Chalas, Philippe Huot-Marchand, Yann Bourhis, Sudeep Karve, Christopher Blakeley
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Honoraria: Genentech, Astra Zeneca, PharmaMar
Consulting or Advisory Role: Genentech, PharmaMar, Amgen, AstraZeneca, Clovis Oncology, Pfizer, MSD, Tesaro
Research Funding: AstraZeneca (Inst)
Honoraria: AstraZeneca
Research Funding: Array BioPharma (Inst), AstraZeneca (Inst), Baxalta (Inst)
Travel, Accommodations, Expenses: AstraZeneca
No relationship to disclose
Honoraria: AstraZeneca
Speakers' Bureau: AstraZeneca
Research Funding: AstraZeneca (Inst), Pfizer (Inst), Tesaro (Inst), National Cancer Institute (Inst)
Honoraria: AstraZeneca, Roche, Tesaro
Travel, Accommodation, Expenses: Roche
Research Funding: Roche
No relationship to disclose
No relationship to disclose
Consulting or Advisory Role: Advaxis
Research Funding: Merck Serono, AstraZeneca, Clovis Oncology, Tesaro, Morphotek, Gradalis, Oxigene
No relationship to disclose
No relationship to disclose
No relationship to disclose
Honoraria: Tesaro
Speakers' Bureau: Tesaro
Travel, Accommodations, Expenses: Tesaro
Employment: Mapi (subcontractor to AstraZeneca)
Employment: Mapi (subcontractor to AstraZeneca)
Employment: AstraZeneca
Stock or Other Ownership: AbbVie
Employment: AstraZeneca, Worldwide Clinical Trials
Stock or Other Ownership: Pfizer
ACKNOWLEDGMENT
We thank the following ENGAGE study co-investigators who contributed to patient recruitment and data collection:
Italy: Laura Cortesi (University Hospital Azienda Ospedaliero-Universitaria Policlinico di Modena), Sabino De Placido (Università Federico II di Napoli), Serafina Mammoliti (IRCCS Hospital San Martino), Franco Odicino (University of Brescia), and Paolo Zola (University of Turin); Spain: José Ángel Arranz Arija (Hospital Gregorio Marañón), Alfonso Yubero Esteban (Hospital Clínico Universitario Lozano Blesa), Tomás Pascual (Hospital La Princesa), and Andrés Redondo (Hospital Universitario La Paz); United States: John Chan (California Pacific Medical Center Research Institute/Palo Alto Medical Foundation), Paul DiSilvestro (Women and Infants Hospital), Veena John (Monter Cancer Center, NS-LIJHS), Donna McNamara (Hackensack University Medical Center), and Susan Zweizig (University of Massachusetts Memorial Medical Center).
We thank Nazneen Rahman (Institute of Cancer Research, London), who contributed to the study design and data review; Ilian Tchakov and Jerzy Tyczynski (formerly AstraZeneca), who contributed to the study design; Alvin Milner (AstraZeneca), who contributed to data review and manuscript preparation; and Kamil Jedynski, Yasmina Tazir, and Hilary Bagguley (AstraZeneca), who contributed to study management and execution. Writing assistance was provided by Gillian Keating from Mudskipper Business Limited, funded by AstraZeneca.
Current affiliation for Gloria Huang is Yale School of Medicine and Yale Cancer Center, New Haven, CT, and current affiliation for Sudeep Karve is AbbVie Inc, North Chicago, IL.
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