genetic cancer risk assessment for breast and ovarian cancer: …. uptake of risk... · genetic...
TRANSCRIPT
Jeffrey N. Weitzel, M.D.
Genetic Cancer Risk Assessment for
Breast and Ovarian Cancer:
Uptake of Risk Reducing
Surgery in South America
Genetics in Clinical Cancer Care: From Family Reunions
to the Frontline of Developmental Therapeutics
Disclosure:
Speakers Bureau for AstraZeneca
Clinical Management of BRCAMutation-Positive Patient
Possible testing for
other adult relatives
Increased
surveillance
Prophylactic
surgery
Targeted
therapy
Chemo-
prevention
Positive BRCA1 or BRCA2
test result
Weitzel et al. CEBP 2007
14 CCGCRN clinics
746 registry participants
189 BRCA+
21 large deletions
Recurrent mutations
15 accounted for >75%
Supported development
of a novel genetic tool
(HISPANEL) to address
cost-related disparities
Hereditary Breast Cancer and Novel
Hispanic BRCA Mutations;
supported by Grant#RSGT0926301
from the American Cancer Society
From Genetic Epidemiology to Clinical Translation
Access to care influences knowledge of genetic epidemiology
◼ 47 oncogenetic practices
across the U.S and Latin
America
◼ More than 25,000 participants
◼ 4,100 in Latin America
◼ multi-generation pedigree,
genomic data, biospecimens,
and prospective F/U
◼ Opportunity to participate in
global cancer genomics
translational research
The Clinical Cancer Genomics Community Research Network
Cancer. 2015;121:372-8 PMCID: PMC4304938
Clinical Profile of Disparity:Young and advanced disease at diagnosis
BRCA mutations prevalent
and a possible partial explanation
for excess of TNBC in Mexico
Significant Clinical Impact of recurrent BRCA mutations
in Mexico. Villarreal et al. Cancer 2014
Other Genes (~10%)
Genomic Epidemiology of Hereditary Breast Cancer
BRCA2
~30%
BRCA1
~50%
PTEN TP53
ATM, CDH1,
PALB2, CHEK2
5-10% Hereditary
Polygenic risk(~10%)
Pathogenic Variants in PALB2, CHEK2 Genes Among
1054 BRCA-Negative Hispanics With Breast Cancer
Gene Variant Cases with variant/
total ancestry matched
cases (%)#
ExAC controls with
variant/ total controls in
ExAC (%)&$
OR (95% CI) P Value
CHEK2 c.707T>C: pL236P 12/ 612 (1.96) 35 / 5603 (0.63) 3.2 (1.5-6.5) 0.0016
PALB2 c.2167_2168del: p.M723fs 9 / 612 (1.14) 5 / 5608(0.09) 12.9 (3.5-51.2) 0.00005
PALB2 c.2411_2412del: p. S804fs 3 / 612 (0.49) 1 / 5601 (0.02) 27.5 (2.1-1431.2) 0.0035
Analysis using individually sequenced controls from City of Hope and the Multiethnic Cohort
Gene Variant Cases with variant /
total (%)*
Controls with variant /
total (%)
OR (95% CI) P Value
CHEK2 c.707T>C: pL236P 14 / 1045 (1.34) 4 / 1189(0.34) 4.1 (1.5 – 22.0) 0.039
PALB2 c.2167_2168del: p.M723fs 9 / 1045 (0.86) 0 / 1189 (0) <0.0001
PALB2 c.2411_2412del: p. S804fs 3 /1045 (0.29) 1 / 1189 (0.08) 3.7 (0.0 - >100.0) 1.0
Weitzel et al., Cancer, 2019
Key elements for GCRA implementation in
TecSalud
Implementation of GCRA in TecSalud - 2015
Dr. Dione Aguilar y Méndez
Results
Total Patients at Risk with Results 2016-2020: 288/384
Total Family members at Risk with Results 2016- 2020: 100/102
Total Percentage of Positive Results:
• Patients at Risk: 14.81%
• Family Members at Risk: 44.1%
Detected mutations:
• BRCA1
• BRCA2
• TP53
• CHEK2
• PALB2
• ATM
2016 2017 2018 2019 Total
Patients tested 71 86 99 129 317
Relatives tested 0 7 68 29 96
Preventive surgeries 0 2 16 16 34
PM 0 2 5 11 18
BSO 0 2 11 5 18
GCRA
champions
Strategies to obtain risk reduction surgeries
• Coverage of surgeries (not covered) by Seguro Popular
o Bilateral mastectomies in a single procedure for mutation carriers
(prioritization for testing)
o BSO labeled as “adjuvant” measure in a 2-year period after initial
diagnosis
o 11 PM, 12 BSO
• NGO support (Fundacion Santos y de la Garza Evia)
o Prophylactic surgeries for patients with hereditary BC
o Physicians’ pro bono services
o 6 PM (w/reconstruction), 3 BSO
o 20 candidates for BSO in 2020
• Collaboration with general hospital (Hospital Materno-
Infantil)
o Familiy mutation carriers
o Low or no-cost procedures
o 8 referrals: 1 PM, 1 BSO
• 1,517 Hispanic breast cancer patients from US
and Latin America (LatAm) (Mexico, Colombia,
Peru, and Puerto Rico)
• Enrolled in the CCGCRN through 2016
• Median follow-up = 2.6 yrs.
• BRCA carriers: 270 (18%)
• BRCA negative: 1247 (82%)
0%
20%
40%
60%
80%
100%
BRCAcarriers Non-BRCAcarriers
Riskreducingsurgeries
CCRM RRSO
OR SE pvalue
Country ofresidence (USvsLatAm) 5.2 16.04 <0.01
Previous pregnancies (none vs>1) 0.3 0.48 0.01
Family history ofcancer 2.8 0.83 0.2
Age 0.9 0.01 0.6
Maritalstatus 1.4 0.37 0.3
Previous mastectomy 1.7 0.37 0.13
Factors associated with CRRM
OR SE pvalue
Country ofresidence (USvsLatAm) 10.1 0.38 <0.01
Age (older) 0.9 0.008 <0.01
Ipsilateral mastectomy 2.8 0.16 <0.01
Previous pregnancies (none vs>1) 1.5 0.21 0.05
Family history ofcancer 1.7 0.53 0.05
Maritalstatus(married vsother) 0.7 0.17 0.12
BRCA +
BRCA –
RRM n= 123 (39%); US (53%) vs. LatAm (29%) p < 0.01
RRSO: n= 93 (43%); US (67%) vs. LatAm (21%) p < 0.01
GCRA appears to influence risk appropriate RRS uptake,
especially for BRCA carriers, and CRRM is associated with
ipsilateral (treatment) mastectomy among BRCA negative
patients.
The rate of RRM and RRSO among Hispanic women is lower
than that reported in previous studies of other populations, and
is significantly associated with residence in the US vs LatAm.
This may be a reflection of disparities in access to care between
countries and healthcare systems, as well as o health literacy
and cultural barriers.
•Networking/ Presentations at Organization and Research Meetings
•Interviews
•Roundtables
Needs Assessment,Identify
Champions/Sites
•On-site meetings with
leadership and key staff •Academic detailing for
clinicians/Staff identified
for GCRA Program•Web-based follow up
meetings
Engagement/ Readiness Planning •GCRA proficiency training
for clinicians (1CCGCoP)
•Membership in GCRA Registry Protocol
•(2CCGCRN ) •BRCA Genetic Tools
(HISPANEL/full analysis)
Capacity Building Tools/Resources
•CCGCoP Practice Support Activities
•CCGCRN face-to-face and Web meetings
•Implementation Site Visits
Implementation Support,
Monitoring, Quality Assurance
RE-AIM
•Reach• Efficacy
•Adoption
•Implementation•Maintenance Effectiveness,
Quality/Maintenance of GCRA Services
Program Implementation
AssessmentsRepeat as
indicated by RE-AIM
findings for Scale up
Genomic Cancer Risk Assessment (GCRA) Implementation Intervention
•Incorporate community based participatory research (patient, advocacy engagement)
•Adapt the model for GCRA implementation at additional sites in Mexico and other Latin American Countries
Next Steps/Future Directions
1 CCGCoP – Clinical Cancer Genomics Intensive Course and Community of Practice2 CCGCRN – Clinical Cancer Genomics Community Research Network
GRAÇIAS Project
• Hereditary breast and ovarian cancer affects all world populations
• Common ancestry, geography and world history are reflected in the
presence and prevalence of founder mutations
• Beyond BRCA, PALB2 and CHEK2 are most relevant, and recurrent
• Training in genomic cancer risk assessment and counseling is
important for dissemination and implementation of GCRA
• The remarkable advances in genetic analysis technologies, with ever
more economy, should be brought to bear to enhance access globally
• Differences in post-GCRA uptake of RRS may be a reflection of
disparities in access to care between countries and healthcare
systems, as well as health literacy and cultural barriers.
• Strategies to improve the uptake of risk-reducing procedures among
Hispanic women at an increased risk of cancer are needed
• International collaboration essential: Build bridges – Not walls
Summary
CCGCRN – A growing International Consortium
Marcia Cruz-Correa/Sherie Umpierre
Adrian Daneri
Azucena del Toro
Sandra Franco/Yenni Rodriguez
Abugattas/Arias/Mora
CCGCRN – A growing International Consortium
Francisco Gutierrez Delgado
GRAÇIAS Project
CCG and Latin American
Collaborative Research team
• Hereditary Breast Cancer and Novel Hispanic
BRCA Mutations; Grant #RSGT0926301 from
the American Cancer Society
• Avon Foundation support for HISPANEL
validation testing in Mexico
• Breast Cancer Research Foundation support
for pilot dissemination and implementation
studies of GCRA in Latin America
• Clinical Cancer Genomics Community of
Practice and GCRA training courses supported
by NCI R25-CA171998-01A1
• Clinical Cancer Genomics Community
Research Network; NCI RC4CA153828
Acknowledgements: