OBJECTIVE: Isolated locoregional recurrence of breast cancer (ILRR) and contralateral breast cancer (CBC) affect up to 20% of all breast cancer (BC) patients in the first 20 years after primary diagnosis. Treatment options comprise surgical interventions and further systemic therapies depending on the histological subtype. Patients with hereditary breast or ovarian cancer (HBOC) undergo MRI, mammography, and ultrasound in the aftercare of BC, while non-HBOC (nHBOC) patients do not regularly receive MRI. Since early detection is crucial for morbidity and mortality, the evaluation and constant improvement of imaging methods of the breast is necessary.
METHODS: We retrospectively analyzed the data of 1499 former BC patients that received imaging of the breast at a tertiary-care university hospital between 2015 and 2020. The analysis comprised various patient characteristics, such as breast density, age, tumor size and subtype, and their influence on BC detection rates by the different imaging methods.
RESULTS: Within the patient sample, 176 individuals (11.7% of former BC patients) were diagnosed with either ILRR or CBC. CBC was observed in 32.4% of patients, while both ILRR and secondary breast cancer occurred in 20.5% and 23.9% of all patients. Sensitivity of MRI, mammography, and ultrasound for recurrent malignancy was 97.9%, 66.3%, and 67.8%, respectively. ILRR and CBC detection rates were similar for patients with and without HBOC history. Lower breast density and larger tumor size increased the detection rates of all imaging modalities.
CONCLUSIONS: In breast cancer survivors, MRI might improve the early detection of ILRR and CBC in both HBOC and nHBOC patients.

Breast cancer is the most prevalent malignancy among women worldwide, and the increasing number of survivors is due to advances in early diagnosis and treatment efficacy. Consequently, the risk of developing contralateral breast cancer (CBC) among these survivors has become a concern. While surgical intervention with lumpectomy is a widely used primary approach for breast cancer, post-operative breast asymmetry is a potential concern. Many women opt for symmetrizing reduction procedures to improve aesthetic outcomes and quality of life. However, despite careful radiological screening, there is a chance of accidentally finding CBC. To address this, tissue excised during symmetrizing surgery is examined pathologically. In some cases, CBC or in situ lesions have been incidentally discovered in these specimens, prompting a need for a more thorough examination. Resection in pieces and the absence of surgical marking and pathological inking of the margin have made it challenging to precisely identify tumor location and assess tumor size and margin status, hampering adjuvant treatment decisions. A new protocol introduced in July 2022 aims to enhance the precision of CBC diagnosis, allowing for tailored treatment plans, including re-excision, systemic adjuvant therapy, or radiation therapy.

Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy.
We performed a genome-wide association analysis in the Women\'s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.
The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

This study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients.
We conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service\'s eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCA mutation group, the BRCAx group, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients.
Among 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11-13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76-4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted.
Breast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.

OBJECTIVE: While breast cancer studies often aggregate Asian/Pacific Islander (API) women, as a single group or exclude them, this population is heterogeneous in terms of genetic background, environmental exposures, and health-related behaviors, potentially resulting in different cancer outcomes. Our purpose was to evaluate risks of contralateral breast cancer (CBC) among subgroups of API women with breast cancer.
METHODS: We conducted a retrospective cohort study of women ages 18 + years diagnosed with stage I-III breast cancer between 2000 and 2016 in the Surveillance, Epidemiology and End Results registries. API subgroups included Chinese, Japanese, Filipina, Native Hawaiian, Korean, Vietnamese, Indian/Pakistani, and other API women. Asynchronous CBC was defined as breast cancer diagnosed in the opposite breast 12 + months after first primary unilateral breast cancer. Multivariable-adjusted subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) were estimated and stratified by API subgroups.
RESULTS: From a cohort of 44,362 API women with breast cancer, 25% were Filipina, 18% were Chinese, 14% were Japanese, and 8% were Indian/Pakistani. API women as an aggregate group had increased risk of CBC (SHR 1.15, 95% CI 1.08-1.22) compared to NHW women, among whom Chinese (SHR 1.23, 95% CI 1.08-1.40), Filipina (SHR 1.37, 95% CI 1.23-1.52), and Native Hawaiian (SHR 1.69, 95% CI 1.37-2.08) women had greater risks.
CONCLUSIONS: Aggregating or excluding API patients from breast cancer studies ignores their heterogeneous health outcomes. To advance cancer health equity among API women, future research should examine inequities within the API population to design interventions that can adequately address their unique differences.

OBJECTIVE: We examined the impact of non-adherence to adjuvant endocrine therapy (ET) on the risk and site of recurrence among older women with early stage, hormone receptor positive (HR+) breast cancer (EBC).
METHODS: A population-based cohort of women age ≥ 65 years with T1N0 HR + EBC who were diagnosed between 2010 and 2016 and treated with breast-conserving surgery (BCS) + ET was identified. Treatment and outcomes were ascertained through linkage with administrative databases. ET non-adherence was examined as a time-dependent covariate in multivariable cause-specific Cox regression models to evaluate its effect on the risks of ipsilateral local recurrence (LR), contralateral breast cancer, and distant metastases.
RESULTS: The population cohort includes 2637 women; 73% (N = 1934) received radiation (RT) + ET and 27% (N = 703) received ET alone. At a median follow-up of 8.14 years, the first event was LR in 3.6% of women treated with ET alone and 1.4% for those treated with RT + ET (p < 0.001); the risk of distant metastases was < 1% in both groups. The proportion of time adherent to ET was 69.0% among those treated with RT + ET and 62.8% for those treated with ET alone. On multivariable analysis, increasing proportion of time non-adherent to ET was associated with increased risk of LR ((HR = 1.52 per 20% increase in time; 95%CI 1.25, 1.85; p < 0.001), contralateral BC (HR = 1.55; 95%CI 1.30, 1.84; p < 0.001), and distant metastases (HR = 1.44; 95%CI 1.08, 1.94; p = 0.01) but absolute risks were low.
CONCLUSIONS: Non-adherence to adjuvant ET was associated with an increased risk of recurrence, but absolute recurrence rates were low.

OBJECTIVE: Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer.
METHODS: A cohort of 1017 breast cancer patients (inclusion 2002-2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).
RESULTS: Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86-9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24-4.04). No other genotypes or haplotypes were associated with clinical outcome.
CONCLUSIONS: CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.

BACKGROUND: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited.
METHODS: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC).
RESULTS: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2-5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7-2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1).
CONCLUSIONS: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.

After a diagnosis of unilateral breast cancer, increasing numbers of patients are requesting contralateral prophylactic mastectomy (CPM), the surgical removal of the healthy breast after diagnosis of unilateral breast cancer. It is important for the community of breast cancer specialists to provide meaningful guidance to women considering CPM. This manifesto discusses the issues and challenges of CPM and provides recommendations to improve oncological, surgical, physical and psychological outcomes for women presenting with unilateral breast cancer: (1) Communicate best available risks in manageable timeframes to prioritise actions; better risk stratification and implementation of risk-assessment tools combining family history, genetic and genomic information, and treatment and prognosis of the first breast cancer are required; (2) Reserve CPM for specific situations; in women not at high risk of contralateral breast cancer (CBC), ipsilateral breast-conserving surgery is the recommended option; (3) Encourage patients at low or intermediate risk of CBC to delay decisions on CPM until treatment for the primary cancer is complete, to focus on treating the existing disease first; (4) Provide patients with personalised information about the risk:benefit balance of CPM in manageable timeframes; (5) Ensure patients have an informed understanding of the competing risks for CBC and that there is a realistic plan for the patient; (6) Ensure patients understand the short- and long-term physical effects of CPM; (7) In patients considering CPM, offer psychological and surgical counselling before surgery; anxiety alone is not an indication for CPM; (8) Eliminate inequality between countries in reimbursement strategies; CPM should be reimbursed if it is considered a reasonable option resulting from multidisciplinary tumour board assessment; (9) Treat breast cancer patients at specialist breast units providing the entire patient-centred pathway.

UNASSIGNED: Breast cancer is the most frequent cancer of women. Metachronous contralateral breast cancer (MCBC) is a cancer in the contralateral breast after 6 months of the initial diagnosis of the first breast cancer. It is an important public health issue because of an increased incidence of a primary breast cancer and improved survival. There is a paucity of data in the Northwestern region of the country. The study was to document the incidence, the method of detection, clinicopathological features, and the treatment of MCBC in our hospital.
UNASSIGNED: It was a 7-year prospective study from January 2011 to December 2017. Patients who had treatment for nonmetastatic breast cancer, American Joint Committee on Cancer (AJCC) Stages 1-111, were followed up. Those that developed MCBC were studied. Age, the method of detection, stage at presentation, pathological types, hormone receptor status, and treatment were documented. Data obtained were analysed using SPSS version 21.0. Results were presented as simple percentages and charts.
UNASSIGNED: Of 1285 women with nonmetastatic breast cancer, 47 had MCBC (incidence of 3.7%); 30 (63.8%) were aged 21-50 years; 23 (48.9%) detected by self-breast examination; 13 (27.7%) by clinical breast examination; seven (14.9%) by mammography; and four (8.5%) by breast ultrasound scan. Fourteen (29.8%) were AJCC stage I; 23 (48.9%), stage II; seven (14.9%), stage III; and three (6.4%), stage IV. Thirty-nine (83%) were invasive ductal carcinoma; 22 (50.0%) were estrogen receptor/progesterone receptor (ER/PR) positive, human epidermal receptor (HER)-2 neu negative; nine were (20.5%) ER/PR and HER-2 neu positive; six (13.6%) were ER/PR negative, HER-2 neu positive, whereas seven (15.9%) were triple negative. Forty-three (91.5%) had modified radical mastectomy and 19 (40.4%) had cytotoxics.
UNASSIGNED: With an average of six cases in a year, MCBC is common in our hospital. Majority (63.8%) were young. The commonest method of detection was by self-breast examination. Majority (78.3%) presented at an early stage. Most (91.5%) still had modified radical mastectomy.