Germline Genetic Testing for Women With Breast Cancer: Shifting the Paradigm From Whom to Test to Whom NOT to Test

Tung, Nadine; Desai, Neelam V.

doi:10.1200/jco.21.01761

Cited by 15 publications

(12 citation statements)

References 23 publications

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“… 27 In response, some clinicians have suggested that universal testing would entail challenges and potential harms; therefore, guidelines should be revised to include women with breast cancer at age of diagnosis of 60 years or younger or 65 years or younger, but still exclude older patients with no family history. 7 , 8 Yet in the studies cited pointing to potentially inappropriate mastectomies or unnecessary oophorectomies performed for moderate-risk variants, the majority of patients described were aged 50 years or younger. In the present study, PGV prevalence was distributed similarly across all age groups, and for most patients older than 65 years, clinicians reported a change in clinical recommendation made and positive impact on patient health outcome as a result of testing.…”

Section: Discussionmentioning

confidence: 99%

“…In 2019, the American Society of Breast Surgeons released a consensus guideline to recommend that genetic testing be offered to all patients with a personal history of breast cancer . In response, some clinicians have suggested that universal testing would entail challenges and potential harms; therefore, guidelines should be revised to include women with breast cancer at age of diagnosis of 60 years or younger or 65 years or younger, but still exclude older patients with no family history . Yet in the studies cited pointing to potentially inappropriate mastectomies or unnecessary oophorectomies performed for moderate-risk variants, the majority of patients described were aged 50 years or younger.…”

Section: Discussionmentioning

confidence: 99%

“…3 Germline testing for BRCA1, BRCA2 (BRCA1/2), CDH1, PALB2, PTEN, and TP53 is currently recommended for certain patients with breast cancer by the National Comprehensive Cancer Network (NCCN) guidelines; however, studies of universal testing with multigene panels suggest that guidelines should be broadened to include testing of all individuals with solid tumors and include genes beyond those with proven breast cancer associations. [4][5][6][7][8] Previously, we reported that in a cohort of 959 patients with breast cancer stratified according to the 2017 NCCN guidelines (version 1.2017), 9 approximately 50% of PGVs would have been missed if only patients meeting the guidelines were tested. 10 The guidelines have since been updated (version 1.2022) to recommend testing at any age for triple-negative breast cancer, or to aid in eligibility determination for treatment with poly (ADP-ribose) polymerase (PARP) inhibitors for patients with metastatic breast cancer and for early-stage high-risk patients with ERBB2-negative breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, risk assessment tools such as the BRCAPRO statistical model use a patient’s personal cancer status and family history to assist in recommendation for genetic testing . Germline testing for BRCA1 , BRCA2 ( BRCA1/2 ), CDH1 , PALB2 , PTEN , and TP53 is currently recommended for certain patients with breast cancer by the National Comprehensive Cancer Network (NCCN) guidelines; however, studies of universal testing with multigene panels suggest that guidelines should be broadened to include testing of all individuals with solid tumors and include genes beyond those with proven breast cancer associations …”

Section: Introductionmentioning

confidence: 99%

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Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

et al. 2022

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ImportanceNational Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration.ObjectiveTo examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making.Design, Setting, and ParticipantsPatients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022.ExposureNew and/or previous diagnosis of breast cancer.Main Outcomes and MeasuresDisease management recommendations that were changed as a result of genetic testing results are reported.ResultsClinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]).Conclusions and RelevanceIn this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

et al. 2022

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“…This has impact in terms of treatment decision-making, as it was reported that up to 30% of patients who had universal genetic testing had modifications to their treatment based on their carrier status [ 10 ]. This proportion may increase further with the recent approval of Poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors as a treatment option for breast cancer patients who are germline BRCA carriers [ 12 , 13 ]. In terms of cost, universal BRCA genetic testing was reported to be cost effective in upper and upper-middle income countries [ 14 ], and if the cost of testing is lowered further to a threshold of USD172 per test, it can be cost-effective in low-middle income countries as well [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Psychosocial outcome and health behaviour intent of breast cancer patients with BRCA1/2 and PALB2 pathogenic variants unselected by a priori risk

et al. 2022

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There is an increasing number of cancer patients undertaking treatment-focused genetic testing despite not having a strong family history or high a priori risk of being carriers because of the decreasing cost of genetic testing and development of new therapies. There are limited studies on the psychosocial outcome of a positive result among breast cancer patients who are at low a priori risk, particularly in women of Asian descent. Breast cancer patients enrolled under the Malaysian Breast Cancer Genetic Study between October 2002 and February 2018 were tested for BRCA1, BRCA2 and PALB2 genes. All 104 carriers identified were invited by a research genetic counsellor for result disclosure. Of the 104 carriers, 64% (N = 66) had low a priori risk as determined by PENN II scores. Psychosocial, risk perception and health behaviour measures survey were conducted at baseline (pre-result disclosure), and at two to six weeks after result disclosure. At baseline, younger carriers with high a priori risk had higher Cancer Worry Scale scores than those with low a priori risk but all scores were within acceptable range. Around 75% and 55% of high a priori risk carriers as well as 80% and 67% of low a priori risk carriers had problems in the “living with cancer” and “children” psychosocial domains respectively. All carriers regardless of their a priori risk demonstrated an improved risk perception that also positively influenced their intent to undergo risk management procedures. This study has shown that with sufficient counselling and support, low a priori risk carriers are able to cope psychologically, have improved perceived risk and increased intent for positive health behaviour despite having less anticipation from a family history prior to knowing their germline carrier status.

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Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer

Reiner,

Watt,

Malone

et al. 2024

JAMA Netw Open

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ImportanceHeterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.ObjectiveTo determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.Design, Setting, and ParticipantsThis case-control study included CBC cases and matched unilateral breast cancer controls from The Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024.ExposuresCHEK2 1100delC and deleterious variants in ATM, BRCA1, and BRCA2.Main Outcome and MeasureDevelopment of CBC, measured as a rate ratio (RR).ResultsA total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious ATM variants was 4 times higher than for women without deleterious ATM variants (RR, 4.84; 95% CI, 1.11-21.08; P = .04); no women with ER-negative CBC carried deleterious ATM variants. The ER-positive CBC rates for women with deleterious variants in BRCA2 or CHEK2 1100delC were 5 to 6 times higher than for women without deleterious variants in BRCA2 or CHEK2 1100delC, respectively (BRCA2: RR, 5.88; 95% CI, 2.61-13.26, P &lt; .001; CHEK2 1100delC: RR, 6.06; 95% CI, 1.26-29.04; P = .02). The ER-negative CBC rate for women with deleterious BRCA1 variants was 26 times higher than for women without deleterious BRCA1 variants (RR, 26.16; 95% CI, 8.01-85.44; P &lt; .001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development.Conclusions and RelevanceIn this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.

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Germline Genetic Testing for Women With Breast Cancer: Shifting the Paradigm From Whom to Test to Whom NOT to Test

Cited by 15 publications

References 23 publications

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

Psychosocial outcome and health behaviour intent of breast cancer patients with BRCA1/2 and PALB2 pathogenic variants unselected by a priori risk

Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer

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