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: