Case series of Li-Fraumeni syndrome: carcinogenic mechanisms in breast cancer with TP53 pathogenic variant carriers.

BACKGROUND: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67-83%) to develop HER2 + breast cancer than noncarriers (16-25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype. METHODS: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS. RESULTS: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR - /HER2 + . The median age at the onset of breast cancer was slightly younger in HR - /HER2 + tumors than in HR + /HER2 - tumors (31 years and 35.5 years, respectively). CONCLUSIONS: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16-25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.

Childbirth after perioperative systemic therapy in patients with breast cancer: a retrospective single institutional study in Japan.

BACKGROUND: The number of breast cancer patients of childbearing age has been increasing. Therefore, we investigated the characteristics and the childbearing status of the patients who received systemic therapy for breast cancer during their childbearing age to better understand the clinical impact of childbirth. METHODS: Female patients with breast cancer younger than 40 years old who underwent surgery and received perioperative systemic therapy from 2007 to 2014 were included in this study. We compared the characteristics of patients with and without childbirth after treatment. RESULT: Of 590 patients, 26 delivered a child, and 355 did not bear a child during the median observation period of 8.1 years, whilst 209 had unknown childbirth data. The childbirth group had a lower mean age at surgery (32.2 vs. 35.1, P < 0.001). The proportion of patients who desired childbirth and used assisted reproductive technology was significantly higher in the childbirth group (65.4 vs. 23.9% and 45.2 vs. 5.1%, respectively, P < 0.001). The patients in the childbirth group had significantly less advanced disease (P = 0.002). In the childbirth group, the age at childbirth was significantly older in patients who received combined endocrine therapy and chemotherapy (40.8 years) than in patients who received either alone (endocrine therapy: 36.9 years, chemotherapy: 36.7 years, P = 0.04). However, survival was not different between those with and without childbirth. CONCLUSION: It is critical to recognize the desire for childbirth in patients with breast cancer who are receiving systemic therapy and to provide them with necessary fertility information before treatment to support their decision-making.

Detection of BRCA1 Pathogenic Variant in a 24-Year-Old Endometrial Cancer Patient: Risks of Several Hereditary Tumor Syndromes Assessed Using Germline Multigene Panel Testing.

A 24-year-old woman suspected of Lynch syndrome was found to carry a BRCA1 pathogenic variant, based on germline multigene panel testing (MGPT). The patient was diagnosed with endometrial carcinoma and underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and omentectomy at the age of 23. Based on her father's history of colorectal cancer and her history of early onset endometrial cancer, mismatch repair protein immunohistochemistry analysis was performed. However, no loss of expression for mismatch repair proteins was found. Given her family history of ovarian and breast cancers, MGPT was recommended to identify the presence of any hereditary tumor syndromes. This testing revealed a BRCA1 pathogenic variant (exon13: c.1016delA, p.Lys339ArgfsX2) and diagnosed as hereditary breast and ovarian cancer syndrome (HBOC). Subsequently, the patient's mother also underwent single-site analysis for this variant, and the same pathogenic variant was detected. The patient and her mother are at high risk of developing BRCA1-associated HBOC-related cancers. Based on family history, clinical surveillance is currently underway for this patient and her mother. Currently, MGPT offers the potential for comprehensive genetic cancer risk assessment and may provide a more rational approach for the genetic assessment of those individuals whose personal and family cancer histories do not fit neatly into a single syndrome. This case suggests that if a patient is at high risk for hereditary tumor syndromes, MGPT should be considered to improve disease management strategies in clinical settings.

Characteristics, treatment trends, and long-term outcomes of Japanese patients with pregnancy-associated breast cancer (PABC).

PURPOSE: To clarify the characteristics, treatment trends, and long-term outcomes of patients with pregnancy-associated breast cancer (PABC). METHODS: PABC includes breast cancer diagnosed during pregnancy (PBC) and breast cancer diagnosed within 1 year after childbirth or during lactation (LBC). We compared clinical characteristics of 126 patients with LBC and 49 patients with PBC who underwent surgery at our hospital from 1946 to 2018. Survival was compared between patients with LBC and those with PBC in terms of breast cancer-specific disease-free survival (BC-DFS) and overall survival (OS). RESULTS: Patients with LBC were more likely to have family history, lymph node metastasis, lymphatic invasion, and to receive chemotherapy than patients with PBC. Patients with LBC showed poorer BS-DFS and OS than patients with PBC. Among patients with LBC, those treated after 2005 were older at surgery, had a smaller tumor size, received more systemic therapy, and had a more favorable prognosis than patients treated before 2004. Family history, breast cancer within 1 year after childbirth, and surgery before 2004 as well as cStage, lymph node metastasis, and lymphatic invasion were significantly associated with poor prognosis in patients with LBC. In the multivariate analysis for BC-DFS and OS among patients with PABC, LBC vs PBC did not remain as an independent prognostic factor while cStage remained. CONCLUSION: Patients with LBC had a poorer prognosis than those with PBC, most likely due to disease progression rather than biological characteristics. Early detection and optimization of systemic treatments are critical for improving the outcomes of patients with LBC.

Pathogenicity assessment of variants for breast cancer susceptibility genes based on BRCAness of tumor sample.

Genes involved in the homologous recombination repair pathway-as exemplified by BRCA1, BRCA2, PALB2, ATM, and CHEK2-are frequently associated with hereditary breast and ovarian cancer syndrome. Germline mutations in the loci of these genes with loss of heterozygosity or additional somatic truncation at the WT allele lead to the development of breast cancers with characteristic clinicopathological features and prominent genomic features of homologous recombination deficiency, otherwise referred to as "BRCAness." Although clinical genetic testing for these and other genes has increased the chances of identifying pathogenic variants, there has also been an increase in the prevalence of variants of uncertain significance, which poses a challenge to patient care because of the difficulties associated with making further clinical decisions. To overcome this challenge, we sought to develop a methodology to reclassify the pathogenicity of these unknown variants using statistical modeling of BRCAness. The model was developed with Lasso logistic regression by comparing 116 genomic attributes derived from 37 BRCA1/2 biallelic mutant and 32 homologous recombination-quiescent breast cancer exomes. The model showed 95.8% and 86.7% accuracies in the training cohort and The Cancer Genome Atlas validation cohort, respectively. Through application of the model for variant reclassification of homologous recombination-associated hereditary breast and ovarian cancer causal genes and further assessment with clinicopathological features, we finally identified one likely pathogenic and five likely benign variants. As such, the BRCAness model developed from the tumor exome was robust and provided a reasonable basis for variant reclassification.

Five screening-detected breast cancer cases in initially disease-free BRCA1 or BRCA2 mutation carriers.

Individuals carrying pathogenic BRCA1 or BRCA2 mutations have an increased lifetime risk of breast and/or ovarian cancer. The incidence of breast cancer amongst disease-free BRCA mutation carriers under surveillance and the clinical and pathological characteristics of those who subsequently develop the disease remain unclear in Japan. We reviewed the records of 155 individuals with BRCA1 or BRCA2 mutations identified by genetic testing between January 2000 and December 2016. At the time of genetic testing, 26 individuals with one of these mutations had no history of breast cancer and were therefore enrolled in a surveillance program that included biannual ultrasonography, clinical breast examination, annual mammography, and conditional magnetic resonance imaging for the early detection of primary breast cancer. During the surveillance period, 5 individuals with BRCA1 or BRCA2 mutations were diagnosed with primary breast cancer. The mean surveillance duration until breast cancer diagnosis was 48 months. The incidence of primary breast cancer during surveillance in initially disease-free BRCA mutation carriers was 4.23%/year. In two cases, the tumors were only detectable on MRI. The case 5 patient who presented with a tumor that was detected by self-examination, which then grew rapidly, had stage IIB triple-negative breast cancer. In conclusion, our results show that some challenges exist in the early detection of breast cancers in BRCA1 or BRCA2 mutation carriers. There are also some difficulties in approaching those individuals in Japanese society.

Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.

In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

Surgical excision without whole breast irradiation for complete resection of ductal carcinoma in situ identified using strict, unified criteria.

BACKGROUND: The definition of complete resection of ductal carcinoma in situ (DCIS) is difficult to standardize because of the high variety of surgical breast conserving procedures, specimen handling, and pathological examinations. Using strictly controlled criteria in a single institute, the present study aimed to determine the ipsilateral breast cancer rate when radiotherapy is omitted following complete resection of DCIS. METHODS: We retrospectively examined 363 consecutive DCIS patients who underwent breast-conserving surgery, and of these, 125 (34.4%) had complete resection according to the criteria. We finally included 103 patients who omitted radiotherapy. Ipsilateral and contralateral breast cancer events were assessed. RESULTS: The median follow-up period was 118 months. The incidences of ipsilateral and contralateral breast cancer and ipsilateral invasive breast cancer at 10 years were 10.8%, 9.1%, and 3.6%, respectively. No patient died of breast cancer. CONCLUSION: If complete resection of DCIS can be ensured, the annual incidence of ipsilateral breast cancer, even without irradiation, can be limited to approximately 1%, which equals the incidence of contralateral breast cancer.

Long-term prognoses and outcomes of axillary lymph node recurrence in 2,578 sentinel lymph node-negative patients for whom axillary lymph node dissection was omitted: results from one Japanese hospital.

BACKGROUND: Axillary dissection omission for sentinel lymph node-negative patients has been a practice at Cancer Institute Hospital, Japanese Foundation for Cancer Research since 2003. We examined the long-term results of omission of axillary dissection in sentinel lymph node-negative patients treated at our hospital, as well as their axillary lymph node recurrence characteristics and outcomes. METHODS: Our study included 2,578 patients with cTis or T1-T3N0M0 primary breast cancer for whom dissection was omitted because they were sentinel lymph node negative. The median observation period was 75 months. RESULTS: In sentinel lymph node-negative patients for whom dissection was omitted, the rates of axillary lymph node recurrence, distant recurrence, and breast cancer mortality were 0.9, 2, and 1 %, respectively. Eighteen patients underwent additional dissection if axillary lymph node recurrence was observed at the first recurrence. Four triple-negative (TN) patients experienced distant recurrence after additional dissection. All four patients were administered anticancer agents after axillary lymph node recurrence and experienced recurrence within 1 year of additional dissection. The axillary lymph node recurrence rate was 0.8 % for luminal and 4.5 % for TN subtypes. CONCLUSIONS: The long-term prognoses of patients for whom dissection was omitted owing to negative sentinel lymph node metastases were similar to those reported previously-low recurrence and mortality rates. The frequency of axillary lymph node recurrence and the post-recurrence outcome differed between luminal and TN cases, with recurrence being more frequent in patients with the TN subtype. TN patients also had poorer prognoses, even after receiving additional dissection and anticancer agents after recurrence.

Non-sentinel lymph node analysis with one-step nucleic acid amplification in breast cancer patients.

BACKGROUND: One-step nucleic acid amplification (OSNA) examines lymph node metastasis in a semiquantitative manner with molecular biology techniques. In this study, we conducted a whole-node analysis of non-sentinel lymph nodes (SLNs) using the OSNA method in SLN metastasis-positive breast cancer patients. METHODS: With the OSNA method, we compared the rates of positivity of non-SLN metastasis in cases with both SLN micro- and macrometastases. RESULTS: The rates of non-SLN metastasis positivity in those with SLN micrometastasis and macrometastasis were 44% and 48%, respectively, and this difference was not significant. When the study of non-SLN metastasis positivity was focused only on macrometastases, the rates of non-SLN metastasis positivity in patients with SLN micrometastasis and macrometastasis were 19% and 22%, respectively, and there was no significant difference. CONCLUSION: Regardless of the copy number of SLN metastases, non-SLN metastases were found in approximately half of the cases.