Germline breast cancer susceptibility gene mutations and breast cancer outcomes

Abstract Background It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis. Methods The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic. Results We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29–4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40–6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64–6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22–3.51; P = 0.007). Conclusions Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation

Prognostic Comparison between Oncotype DX® and a 23-Gene Classifier, RecurIndex®, on the Taiwan Breast Cancer Population

The applicability of the Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) recurrence score (RS) in Asian populations is unclear. A 23-gene classifier, RecurIndex® (Amwise Diagnostics, Pte. Ltd., Singapore), has been developed based on the gene expression profiles of early-stage breast cancer patients of ethnic Han Chinese population in Taiwan. This study aimed to compare the performance of the Oncotype DX® RS with the RecurIndex® recurrence index (RI) for predicting relapse-free survival. Therefore, we calculated both the RI and RS for 110 early stage breast cancer patients, with the cut-off value for high-risk recurrence set at 26 and 29 for the RS and the RI, respectively. With relapse-free interval (RFI) as the primary endpoint, the concordance between RS and RI was 78.2% (Kappa value = 0.297). For a median follow-up interval of 27 months, there was a statistically significant difference in RFI between the high- and low-risk groups defined by the RI (p = 0.04) but not between risk groups defined by the RS (p = 0.66). In conclusion, whereas there was high concordance between the RecurIndex® RI and the Oncotype DX RS, the current data showed that the RI had a better discrimination for recurrence risk than the RS. Subsequent studies with larger sample sizes will be needed to confirm the superiority of the RI over the RS in the Asian population

Neoadjuvant Trastuzumab Concurrent with Nonanthracycline-based Regimens for HER2-positive Locally Advanced Breast Cancer

Trastuzumab, a humanized monoclonal antibody directed against the external domain of the HER-2 protein, has shown remarkable activity against HER-2 positive breast cancer. Consequently, the use of adjuvant trastuzumab plus chemotherapy in patients with HER2-positive stage breast cancer (stage I to III) has become the standard treatment option. However, the role of trastuzumab in neoadjuvant treatment therapy is still uncertain. An increasing number of clinical trials and inadequate analysis show the benefit of adding trastuzumab to chemotherapy in the neoadjuvant setting. We report a case of HER2-positive locally advanced breast cancer in a patient who received cytotoxic agents concomitant with trastuzumab as neoadjuvant therapy, and also review the published literature. The patient achieved pathological complete response, and remained disease-free for more than 5 years

Long-term survival and stage I breast cancer subtypes

Background: This study is to evaluate the associations between long-term survival and stage I breast cancer by examining the hormonal receptor (HR) and human epidermal growth factor receptor-2 (HER2) status. Materials and methods: A total of 1595 breast cancer patients who were seen from 1990 to 2008 with surgery as first treatment and pathology stage I (T1N0) were included in this study. HR and HER2 status were used to approximate breast cancer subtypes. Additionally, ten-year relapse-free survival (RFS) rate and failure patterns of each subtype were evaluated. Multivariate analyses were performed in each subtype to identify the risk factors of recurrence. Results: Luminal-like (HR positive and HER2 negative) stage I patients showed a 10-year RFS rate of 89.5%, HER2 positive 92.9%, triple negative 91.1%, and unclassified subtype 86.2% (p = 0.089), respectively. The 10-year overall survival was 94.1% in luminal-like subtype, 90.1% in HER2, 94.5% in triple negative, and 85.3% in unclassified subtype. The independent recurrence risk factors in luminal-like subtype were ≤40 years of age (hazard ratio [HR] 2.2, 95% confidence interval [CI], 1.1–4.4), nuclear grade III (HR 2.7, CI, 1.4–5.3), and tumor >1.5 cm (HR 1.8, CI 1.0–3.4), and in unclassified subtype ≤40 years of age, tumor >1.5 cm, and adjuvant hormonal therapy. No risk factors were identified in HER2 or triple negative subtype. Conclusions: The factors associated with poor prognosis of stage I breast cancer vary by subtype. No risk factors were identified in HER2 subtype or triple negative patients. Tumor size >1.5 cm, age ≤40 years and nuclear grade 3 are the risk factors associated with poor prognosis in luminal-like subtype

The use of moderately hypofractionated post-operative radiation therapy for breast cancer in clinical practice: A critical review.

Post-operative radiation therapy (RT) reduces loco-regional recurrence rates and mortality in most patients with non-metastatic breast cancer. The aim of this critical review is to provide an overview of the applicability of moderately hypofractionated RT for breast cancer patients, focusing on factors influencing clinical decision-making. An international group of radiation oncologists agreed to assess, integrate, and interpret the existing evidence into a practical report to guide clinicians in their daily management of breast cancer patients. We conclude that moderately hypofractionated RT to the breast, chest wall (with/without breast reconstruction), and regional lymph nodes is at least as safe and effective as conventionally fractionated regimens and could be considered as the treatment option for the vast majority of the patients.For those who are still concerned about its generalised application, we recommend participating in ongoing trials comparing moderately hypofractionated RT to conventionally fractionated RT for breast cancer patients in some clinical circumstances

Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer

<div><p>We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%–98.8%) and 80.9% (74.6%–81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%–98.5%), and 90.9% (50.8%–98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8–14.1; <i>p</i> = 0.0017) for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%–100%) and 80.3% (70.7%–89.9%, <i>p</i> = 0.06) in a Singapore dataset, and 89.5% (81.9%–94.1%) and 73.6% (67.2%–79.0%, <i>p</i> = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.</p></div

Baseline characteristics of the 683 patients.

<p>Baseline characteristics of the 683 patients.</p