Breast Cancer

Germline variants of Brazilian women with breast cancer and detection of a novel pathogenic ATM deletion in early-onset breast cancer

It is estimated that 5-10% of breast cancer cases are hereditary. The identification of pathogenic germline variants allows individualized preventive health care, improvement of clinical management and genetic counseling. Studies in ethnically admixed Latin American populations have identified regions with increased frequency of deleterious variants in breast cancer predisposing genes. In this context, the Brazilian population exhibits great genetic heterogeneity, and is not well represented in international databases, which makes it difficult to interpret the clinical relevance of germline variants. We evaluated the frequency of pathogenic/likely pathogenic (P/LP) germline variants in up to 37 breast cancer predisposing genes, in a cohort of 105 breast and/or ovarian cancer Brazilian women referred to two research centers between 2014 and 2019. A total of 22 patients (21%) were found to carry P/LP variants, and 16 VUS were detected in 15 patients (14.3%). Additionally, a novel pathogenic ATM intragenic deletion was identified in an early-onset breast cancer. We also detected a BRCA1 pathogenic variant (c.5074+2T>C) in higher frequency (10×) than in other studies with similar cohorts. Our findings contribute to the characterization of the genetic background of breast cancer predisposition in the Brazilian population as a useful resource to discriminate between deleterious variants and VUS, thus enabling improvement in the preventive health care and clinical management of carriers.

Two-hit events occurred independently in bilateral breast cancers in a germline double heterozygous carrier for BRCA1 and BRCA2

Abstract While patients with hereditary breast and ovarian cancer with germline double heterozygosity (GDH) for BRCA1 and BRCA2 are rare, carcinogenesis in these cases remains unclear. We examined two-hit events of heterochronous bilateral breast cancers in a patient with GDH for BRCA1 and BRCA2 . A 65-year-old woman developed right breast cancer (triple-negative type) at the age of 49 and left breast cancer (triple-negative type) at 55. Family history indicated that multiple relatives on her mother’s side also developed breast cancer. BRCA1/2 genetic testing (BRACAnalysis®) showed that she had variants in both the BRCA1 and BRCA2 ( BRCA1 :c.5193 + 2dup, BRCA2 :c.6952C > T/p.Arg2318Ter). According to the data from the test, the former was interpreted as likely pathogenic at Myriad Inc. Further examination regarding two-hit events in her bilateral breast cancers was obtained by somatic mutation analysis using DNA isolated from cut slide specimens of formalin-fixed and paraffin-embedded tumor samples. We first confirmed the pathogenicity of the BRCA2 variant by detecting unusual splicing of BRCA2 that entirely skipped exon 19 using cultured T cells of the proband. Loss of heterozygosity in BRCA1 was observed in her right breast cancer. On the other hand, a somatic nonsense pathogenic variant in BRCA2 (variant allele frequency = 15%) and a two-hit event in APC (VAF = 80%) were also found in her left breast cancer. These data provide evidence of different carcinogenesis between left and right breast cancer. Clinical and pathogenic characteristics of cancers with GDH for BRCA1 and BRCA2 depend on the genes somatically mutated in wild alleles.

Emerging roles of KIR2DL4 in cancer immunotherapy

Abstract Killer-cell immunoglobulin-like receptor 2DL4 (KIR2DL4), a member of the killer cell immunoglobulin-like receptors (KIRs) family, plays an important role in the regulation of the immune system, which is expressed primarily on natural killer (NK) cells. Human leucocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is the only known ligand of KIR2DL4. Accumulating evidence has shown that KIR2DL4 has emerged as a potential target for enhancing the antitumor immune response. Elevated expression of KIR2DL4 has been observed in certain tumor types, including melanoma, lung cancer, and ovarian cancer, indicating its role in tumor evasion. Our previous study had shown that blockade of KIR2DL4 interaction in NK cells can re-sensitize breast cancer to trastuzumab treatment, which indicated that KIR2DL4 was a pivotal immune checkpoint of NK cells. Currently, there are several therapeutic approaches targeting KIR in cancer immunotherapy. However, there are no efficient cancer immunotherapy strategy targeting KIR2DL4. In this review, we aim to summarize and discuss the potential role of KIR2DL4 as a target for cancer immunotherapy. A better understanding of KIR2DL4 might be helpful to develop effective KIR2DL4-targeted therapies, which could provide new treatment options for cancer patients.

Analysis of the conditions for applying BRCA genetic testing to women with breast cancer using the Japanese HBOC consortium and the Japanese organization of hereditary breast and ovarian cancer (JOHBOC) registry project database

Abstract Background Considering past research in Europe and the USA, the conditions for medical insurance coverage of BRCA1/2 genetic testing (GT) in Japan have been established as follows: 1. Breast cancer onset at 45 years or younger age; 2. Triple-negative breast cancer (TNBC) onset at 60 years or younger age; 3. Onset of two or more primary breast cancers; 4. Family history of breast cancer, ovarian cancer, or pancreatic cancer up to the third degree; 5. Male breast cancer, 6. Ovarian, fallopian, or peritoneal cancers. However, data to determine the importance and extent of each factor in the current conditions are insufficient. Consequently, this study aimed to assess the validity of insurance coverage conditions in Japan, elucidate the relationship between these conditions, and explore the possibility of proposing new indicators. Methods A total of 5987 breast cancer patients were enrolled from 92 centers participating in the HBOC consortium and the JOHBOC registry project. Of these, 5904 patients were analyzed after excluding 48 male breast cancer patients due to insufficient numbers for analysis and 35 patients whose age at breast cancer onset was unknown or unregistered. We compared 1,091 cases in which pathogenic variants (PVs) (BRCA1(B1s): 543, BRCA2(B2s): 548) were detected with 4580 cases in which no variants (non-Vs) were detected. Variants of uncertain significance (VUS: 233 cases) were not classified as either PVs or non-Vs for subsequent analysis. We investigated the validity of each condition under which an HBOC diagnosis could be considered for medical insurance coverage. Results Regardless of the insurance coverage conditions, the detection rate of pathogenic variants (DRPV) of all analyzed cases was 19.2%. The DRPV under the insurance coverage conditions for GT—‘Age of breast cancer onset ≤ 45 years,’ ‘TNBC onset at ≤ 60 years,’ ‘ ≥ 2 primary breast cancers,’ ‘Patients with breast cancer concurrent with ovarian cancer,’ and ‘ ≥ 1 family history of breast or ovarian cancer up to the third degree’—was 25.4%, 31.6%, 24.6%, 48.8%, and 25.6%, respectively. Those within the insurance coverage group showed a pathogenic variant detection rate of 21.1%, compared to only 5.6% outside of the coverage. Our analysis indicates that medical insurance coverage conditions effectively identify candidates for GT. Furthermore, when examining the number of conditions met and the positivity rate, the positivity rate was 11.2%, with only one condition met. This rate increases exponentially as more conditions are met, underscoring the importance of multiple matching conditions. Additionally, those with comorbid ovarian cancer or a family history of ovarian cancer are more likely to have a pathogenic variant. Additionally, we reevaluated cases who did not meet the medical insurance conditions. TNBC occurrence was significantly associated with B1s, even when restricted to onset age ≥ 61 years. Familial history of prostate cancer also significantly associated with B2s. Conclusion This study determined that the Japanese medical insurance coverage conditions effectively identified candidates eligible for GT. Consequently, it is imperative to disseminate information to all patients with breast cancer covered by insurance, emphasizing the opportunity for GT, particularly if they have ovarian cancer complications or a family history of ovarian cancer.

High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands

Abstract Background Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands. Methods PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome. Results PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000–0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521–5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs. Conclusion These findings imply the necessity to construct a novel testing scheme to complement cascade testing.

Promoters of BRCA testing under insurance coverage for non-metastatic breast cancer patients in Japan: a retrospective cohort study

We investigated the barriers to and promoters of taking BRCA testing, after the start of national healthcare insurance coverage for non-metastatic breast cancer patients in Japan. This was a multi-center, retrospective, cohort study. We included stage 0 to III breast cancer patients who were diagnosed and met the criteria for insurance coverage of BRCA testing between April 2020 and December 2021. We examined the association between BRCA testing and possible exposures: breast cancer diagnosis at 45 years or younger, triple-negative breast cancer (TNBC) diagnosis at the age of 60 or younger, two or more primary breast cancers, family history of breast cancer or ovarian cancer in the third degree of relatives, male breast cancer, medical expense limits, and parity. We used logistic regression analysis. We included 222 patients and 123 (55.4%) of them underwent the test. In univariate analysis, a family history of ovarian cancer (odds ratio (OR) 10.59; 95% CI 1.35-82.96, p = 0.025), diagnosis of breast cancer at the age of 45 or younger (OR 2.78; 95% CI 1.52-5.14, p = 0.0009), and diagnosis of TNBC at the age of 60 or younger (OR 3.95; 95% CI 1.55-10.07, p = 0.004) were associated with taking the test. After multivariate logistic regression analysis, a family history of ovarian cancer (adjusted OR 12.80; 95% CI 1.51-108.80, p = 0.0195), diagnosis of breast cancer at the age of 45 or younger (adjusted OR 4.43; 95% CI 1.98-9.90, p = 0.0003), and TNBC at the age of 60 or younger (adjusted OR 5.28; 95% CI 1.90-14.66, p = 0.0014) were consistently associated. For non-metastatic breast cancer patients whose BRCA testing is covered by insurance, costs would no longer be a definite barrier. Physicians should keep in mind that a family history of ovarian cancer, breast cancer diagnosis at 45 years of age or younger and TNBC diagnosis at 60 years of age or younger are strong promoters.

Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants

Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer

When considering BRCA1/2 genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked. Among 945 patients who received genetic testing of BRCA1/2 at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers. FH of prostate, pancreatic, and skin cancer was significantly higher in the BRCA2 pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows: BRCA1 PV/ BRCA2 PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (P < 0.0001, Kruskal-Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (P = 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (P = 0.00129), respectively. When considering BRCA1/2 genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.

Risk of endometrial cancer among breast cancer survivors in Japan: a matched cohort study

Breast cancer (BC) survivors may have an increased risk of endometrial cancer due to shared risk factors and tamoxifen use. However, the risk among women in Japan and that for each endocrine therapy regimen remains unknown when comparing BC survivors to women without BC. We conducted a matched-cohort study using the JMDC claims database, covering company employees and their family members in Japan. Between January 2005 and December 2019, women aged 18-74 years with BC were matched to women without BC in a 1:4 ratio by age and database entry timing. Endometrial cancer risk was compared using stratified Cox regression. In addition, starting the follow-up at one year after matching, we assessed risk by endocrine treatment (tamoxifen, aromatase inhibitor [AI], and no endocrine therapy) using unstratified Cox regression. Among 23,729 BC survivors and 95,659 matched women (median age, 49.5 years), there were 56 vs 40 endometrial cancer cases (0.73 vs 0.13 cases/1,000 person-years, respectively), with adjusted hazard ratios of 7.71 (95% confidence interval 4.56-13.0). In the analysis by endocrine treatment, tamoxifen (n = 9,183; median 46.3 years), AI (n = 4,582; 58.1 years), and no endocrine therapy (n = 5,763; 49.4 years) cases were 26, 5, and 10 (0.92, 0.43, and 0.61 cases/1,000 person-years, respectively), and the adjusted hazard ratios were 5.67 (3.20-10.0), 2.17 (0.79-5.95), and 3.56 (1.66-7.65), respectively, compared to women without BC. BC survivors in Japan had an increased risk of endometrial cancer compared to women without BC. The risk was higher in women prescribed tamoxifen and those with no endocrine therapy.

Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis

AbstractBreast cancer is a common cancer affecting a large number of patients. Notably, 5–10% of all breast cancer patients are genetically predisposed to cancers. Although the most common breast cancer susceptibility genes areBRCA1andBRCA2, which are also associated with the risk of developing ovarian and pancreatic cancer, advances in next-generation sequencing (NGS) analysis technology enabled the discovery of several non-BRCAgenes responsible for breast and ovarian cancers. Studies on hereditary breast and ovarian cancer (HBOC) involve not only determining the predisposition to developing cancer, but also considering the current treatment for breast cancer, prevention of next cancer, risk diagnosis, and adoption of protective measures for relatives. We present a comprehensive review of HBOC, which will be a useful resource in the clinical setting. Many hereditary tumors, including HBOC, are syndromes characterized by the development of different types of cancer in succession. Taking advantage of knowing predisposition of susceptibility to cancer, it is important to continue and update cancer management protocols, which includes the adoption of preventive measures, countermeasures, and treatments, to accurately assess and prevent the impact of cancer on the quality of life of the next generation of patients.

Genetic medicine is accelerating in Japan

Abstract Background In 2018, BRACAnalysis® was covered by medical insurance in Japan as a companion diagnostic test for the poly ADP-ribose polymerase inhibitor olaparib. In April 2020, eligibility for BRCA1/2 genetic testing was expanded to the diagnosis of hereditary breast and ovarian cancer syndrome, and medical management including prophylactic surgery and surveillance were covered by public insurance for BRCA1/2 mutation carriers who developed breast or ovarian cancer. The amount of BRCA1/2 genetic testing has been increasing recently, but the number of subjects and the impact of testing for patients’ outcomes remain unclear. Patients and methods This study explored the potential number of patients who will be eligible for new insurance coverage for BRCA1/2 genetic testing. We analyzed 868 patients from 938 surgeries between January 2014 and September 2020 from our database. Results Overall, 372 patients (43%) were eligible for new insurance coverage for BRCA1/2 genetic testing. The most common category was family history of breast or ovarian cancer within third-degree relatives. We found that 202 patients (23%) had family history of breast or ovarian cancer. In addition, the progression-free survival was significantly lower in triple-negative breast cancer patients aged 60 years or younger compared with the other patients (P = 0.0005). Conclusion The genetic medicine for primary breast cancer patients with BRCA1/2 germline mutation is accelerating rapidly in Japan. Therefore, establishing a system for the genetic medicine would be urgent.

Adverse effects of tamoxifen treatment on bone mineral density in premenopausal patients with breast cancer: a systematic review and meta-analysis