Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS < 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.

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Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06095-w ◽

2021 ◽

Author(s):

Jasmine Sukumar ◽

Mahmoud Kassem ◽

Doreen Agnese ◽

Robert Pilarski ◽

Bhuvaneswari Ramaswamy ◽

...

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Case Series ◽

Breast Cancers ◽

Panel Testing ◽

Pathogenic Variants ◽

First Case ◽

Gene Panel Testing ◽

Personalized Approach ◽

Double Heterozygosity

Abstract Background Concurrent germline (g) pathogenic variants related to hereditary breast cancer represent a rare occurrence. While double heterozygosity in gBRCA1 and gBRCA2 has been reported in the past, herein we describe the first case of three known concurrent pathogenic variants identified in a family with a strong history of breast cancer. Case presentation The proband is a 55-year-old female diagnosed with synchronous bilateral breast cancers. She underwent a multi-gene panel testing indicating the presence of 3 concurrent heterozygous germline deleterious variants in BRCA1 (c.181T > G), BRCA2 (c.4398_4402delACATT), and CHEK2 (1100delC). The patient’s two daughters (34 and 29 years-old) were found to be transheterozygous for inherited pathogenic variants in BRCA1 (c.181T > G) and CHEK2 (1100delC) genes. Conclusion The cancer risk and phenotypic manifestations associated with transheterozygous or multiple concurrent deleterious germline variants in hereditary breast cancer requires further investigation. A personalized approach to counseling, screening, and risk reduction should be undertaken for these individuals.

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Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10526 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10526-10526

Author(s):

Grace Wei ◽

Marilin Rosa ◽

Maxine Chang ◽

Brian J. Czerniecki ◽

Xia Wang

Keyword(s):

Breast Cancer ◽

Cancer Diagnosis ◽

Breast Cancer Diagnosis ◽

Cancer Predisposition ◽

Tumor Evolution ◽

Breast Cancers ◽

Her2 Expression ◽

Expression Levels ◽

Genetic Test Results ◽

Predisposition Genes

10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

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900 Effects Of COVID-19 Pandemic Restrictions on the 2ww Breast Referrals in A UK Specialist Breast Service

British Journal of Surgery ◽

10.1093/bjs/znab259.213 ◽

2021 ◽

Vol 108 (Supplement_6) ◽

Author(s):

O Tokode ◽

S Rastall

Keyword(s):

Breast Cancer ◽

Waiting Times ◽

Age Groups ◽

Breast Cancer Diagnosis ◽

Hospital Staff ◽

Breast Cancers ◽

Telephone Triage ◽

Telephone Consultation ◽

Mean Waiting Time ◽

Delays In Diagnosis

Abstract Aim Recommendations were issued to the hospital Trusts to configure service delivery to balance cancer care with patient and hospital staff safety during the COVID-19 pandemic. It was felt the service restrictions might lead to delays in diagnosis and treatment of cancer patients. We conducted an audit to compare 2ww breast referrals in our center between May to July of 2019 and 2020. Method We triaged all referrals to face-face consultation or telephone consultation in our center during the pandemic. Patients with suspicious symptoms were offered face-face consultation after the telephone triage. Results Data analysis showed that the referrals fell by 28.3% (N 1569 versus N 1125). The largest reduction was noted in May (34.4% versus 24.2%). Mean waiting time in 2019 was 19.86 (± 7.14) and 11.43 (± 3.48) in 2020. The proportion of patients referred for suspected breast cancers increased across all age groups in 2020 (range +10.4% to 16.2%). Significantly more breast cancers were diagnosed in 2020 (7.1% versus 5.1%). No breast cancer was diagnosed in under 25 patients. 29.1% of the 522 patients telephoned were discharged, and others were seen in the clinic. Conclusions The COVID-19 infection’s management caused a fall in 2ww referrals and shortened waiting times but increased breast cancer diagnosis. Many 2ww referrals during the COVID-19 infection were unnecessary. The telephone consultation reduced waiting times but may have deferred clinic visitation for most patients.

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167P Role of the multi-gene panel testing for detection of pathogenic variants in patients with hereditary bilateral breast cancer

Annals of Oncology ◽

10.1016/j.annonc.2021.08.448 ◽

2021 ◽

Vol 32 ◽

pp. S432-S433

Author(s):

C. Filorizzo ◽

D. Fanale ◽

L. Incorvaia ◽

N. Barraco ◽

M. Bono ◽

...

Keyword(s):

Breast Cancer ◽

Bilateral Breast Cancer ◽

Gene Panel ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing

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Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

Oncology Reviews ◽

10.4081/oncol.2021.544 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Hikmat Abdel-Razeq

Keyword(s):

Breast Cancer ◽

Brca1 And Brca2 ◽

Healthy Women ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

History Of ◽

Risk Reducing ◽

Current Guidelines ◽

Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

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Multi gene panel testing for hereditary breast cancer - is it ready to be used?

Medicine and Pharmacy Reports ◽

10.15386/mpr-1083 ◽

2019 ◽

Cited By ~ 1

Author(s):

Andreea Catana ◽

Adina Patricia Apostu ◽

Razvan-Geo Antemie

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Gene Panel ◽

Variants Of Uncertain Significance ◽

Panel Testing ◽

Brca Genes ◽

Prophylactic Measures ◽

Gene Panel Testing ◽

Uncertain Significance ◽

High Level

Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients.

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Interval breast cancer is associated with other types of tumors

Nature Communications ◽

10.1038/s41467-019-12652-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Felix Grassmann ◽

Wei He ◽

Mikael Eriksson ◽

Marike Gabrielson ◽

Per Hall ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Risk Score ◽

Breast Cancer Diagnosis ◽

Cancer Genes ◽

Common Variants ◽

Breast Cancer Patients ◽

Interval Breast Cancer ◽

Increased Risk ◽

History Of ◽

Screening And Prevention

Abstract Breast cancer (BC) patients diagnosed between two screenings (interval cancers) are more likely than screen-detected patients to carry rare deleterious mutations in cancer genes potentially leading to increased risk for other non-breast cancer (non-BC) tumors. In this study, we include 14,846 women diagnosed with BC of which 1,772 are interval and 13,074 screen-detected. Compared to women with screen-detected cancers, interval breast cancer patients are more likely to have a non-BC tumor before (Odds ratio (OR): 1.43 [1.19–1.70], P = 9.4 x 10−5) and after (OR: 1.28 [1.14–1.44], P = 4.70 x 10−5) breast cancer diagnosis, are more likely to report a family history of non-BC tumors and have a lower genetic risk score based on common variants for non-BC tumors. In conclusion, interval breast cancer is associated with other tumors and common cancer variants are unlikely to be responsible for this association. These findings could have implications for future screening and prevention programs.

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