A progressive and refractory case of breast cancer with Cowden syndrome.

BACKGROUND: Cowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome. CASE PRESENTATION: A 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a "tiger-stripe" appearance. The patient's mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence. CONCLUSION: We report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.

Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling.

PURPOSE: Neoadjuvant endocrine therapy (NAET) for estrogen receptor-positive primary breast cancer causes adequate tumor shrinkage, and is expected to be helpful for breast-conserving surgery, but the adaptation criteria, especially in regard to treatment duration, have never been elucidated. Re-visiting past gene expression profiles, we explored the data for specialized pre-therapeutic predictors and validated the results using our in-house clinical cohorts. METHODS: We sorted the genes related to a > 30% tumor volume reduction through NAET from a cDNA microarray data-set of GSE20181, then selected the top 40 genes. We validated these gene expression levels using pre-therapeutic biopsy samples obtained from patients treated with long-term NAET (over 4 months; N = 40). A short-term (2-8 weeks; N = 37) NAET cohort was also validated to clarify whether expression of these genes is also related to a rapid response of Ki67 and PEPI score. RESULTS: In the long-term group, higher expression of KRAS, CUL2, FAM13A, ADCK2, and LILRA2 was significantly associated with tumor shrinkage, and KRAS, MMS19, and IVD were related to lower PEPI score (≤ 3). Meanwhile in the short-term group, none of these genes except CUL2 showed a direct correlation with Ki67 reduction or PEPI score. This suggested that tumor shrinkage by NAET might be induced by response to the hypoxic environment (CUL2, FAM13A, KRAS) and activation of tumor immune system (LILRA2), without involving inhibition of proliferation. CONCLUSION: Expression of specific genes may allow selection of the most responsive patients for maximum tumor shrinkage with NAET.

Fibroblast growth factor receptor-1 protein expression is associated with prognosis in estrogen receptor-positive/human epidermal growth factor receptor-2-negative primary breast cancer.

Recently, research into the development of new targeted therapies has focused on specific genetic alterations to create advanced, more personalized treatment. One of the target genes, fibroblast growth factor receptor-1 (FGFR1), has been reported to be amplified in estrogen receptor (ER)-positive subtype breast cancer, and is considered one possible mechanism of endocrine resistance through cross-talk between ER and growth factor receptor signaling. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, transcript and protein expression, and examined the relationships between FGFR1 status and clinicopathological parameters, including prognosis in 307 ER-positive/HER2-negative primary breast cancer patients treated with standard care at our institute. Most notably, a high level of FGFR1 protein expression was observed in 85 patients (27.7%), and was positively associated with invasive tumor size (P = 0.039). Furthermore, univariate analysis revealed that high FGFR1 protein expression was significantly correlated with poor relapse-free survival rate (P = 0.0019, HR: 2.63, 95% confidence interval: 1.17-5.98), and showed a tendency towards an increase in recurrent events if the observation period extended beyond the 5 years of the standard endocrine treatment term. FGFR1 gain/amplification was found in 43 (14.0%) patients, which was only associated with higher nuclear grade (P = 0.010). No correlation was found between FGFR1 mRNA expression levels and any clinicopathological factors. Overall, the level of FGFR1 protein expression may be a biomarker of ER-positive/HER2-negative primary breast cancer with possible resistance to standard treatment, and may be a useful tool to identify more specific patients who would benefit from FGFR-1 targeted therapy.

Predictive and prognostic significance of BRCAness in HER2-negative breast cancer.

BACKGROUND: BRCAness is characterized as the phenotypes shared between some sporadic tumors and BRCA1/2 mutation cancers resulting in defective homologous recombination. The predictive or prognostic value of BRCAness in HER2-negative breast cancer patients who have received neoadjuvant chemotherapy (NAC) is not fully elucidated. METHODS: We retrospectively selected 101 high-risk HER2-negative patients diagnosed with stage I-III breast cancer who underwent NAC treatment and evaluated BRCA1-like phenotype using multiplex ligation-dependent probe amplification assay. In an analysis of BRCAness, 95 out of 101 patients were analyzed. RESULTS: In total, 70 (74%) patients had sporadic-type tumors and 25 (26%) had BRCA1-like tumors according to pre-treatment samples. The BRCA1-like phenotype was not associated with pathological complete response (pCR) rate in the entire cohort. In survival analysis, pre-treatment BRCA1-like phenotype was not associated with survival. On the other hand, post-treatment BRCA1-like patients apparently showed shorter relapse-free survival (log-rank P = 0.016) and breast cancer-specific survival (P < 0.001) compared with sporadic features. In multivariate analysis, only the post-treatment BRCA1-phenotype was significant prognostic factors (HR 5.67, 95% CI 1.19-29.3). Furthermore, we found phenotype change between BRCA1-like and sporadic type through NAC in 19% of non-pCR patients. Post-treatment Ki67 significantly decreased in the persistent sporadic tumors during treatment or sporadic tumors changed after NAC (P < 0.0001, P = 0.0078, respectively). CONCLUSIONS: BRCAness may be useful biomarkers to predict prognosis for HER2-negative breast cancer refractory to standard chemotherapy. Our results pave the way for identifying patients who require alternative therapies.

Cardiac computed tomography-derived myocardial tissue characterization after anthracycline treatment.

AIMS: Understanding cardiac function after anthracycline administration is very important from the perspective of preventing the onset of heart failure. Although cardiac magnetic resonance and echocardiography are recognized as the 'gold standard' for detecting cardiotoxicity, they have many shortcomings. We aimed to investigate whether cardiac computed tomography (CCT) could replace these techniques, assessing serial changes in cardiac tissue characteristics as determined by CCT after anthracycline administration. METHODS AND RESULTS: We prospectively investigated 15 consecutive breast cancer patients who were scheduled to receive anthracycline therapy. We performed echocardiography and CCT before and 3, 6, and 12 months after anthracycline treatment. The mean cumulative administered anthracycline dose was 269.9 ± 14.6 mg/m2 (doxorubicin-converted dose). Of the 15 enrolled patients who received anthracycline treatment for breast cancer, none met the definition of cardiotoxicity. The CCT-derived extracellular volume fraction tended to continue to increase after anthracycline treatment and had relatively similar dynamics to the left ventricular ejection fraction and global longitudinal strain as determined by echocardiography. CONCLUSIONS: Our findings indicated that CCT could provide adequate information about the characteristics of myocardial tissue after anthracycline administration. CCT may improve the understanding of cardiotoxicity by compensating for the weaknesses of echocardiography. This technique could be useful for understanding cardiac tissue characterization as a 'one-stop shop' evaluation, providing new insight into cardiooncology.

Analysis of plasma HER2 copy number in cell-free DNA of breast cancer patients: a comparison with HER2 extracellular domain protein level in serum.

BACKGROUND: HER2 (human epidermal growth factor receptor 2) status has been evaluated in breast cancer (BC) tissues by immunohistochemistry or in situ hybridization. We evaluated HER2 copy number (CN) assay in plasma cell-free DNA (cfDNA) from blood samples and compared it with protein measurements of HER2 extracellular domain (ECD) in serum. METHODS: Serum HER2-ECD levels were measured by chemi-luminescence immunoassay using anti-HER2 monoclonal antibodies. Analyses were performed on 120 cases of primary BC, 30 cases of metastatic BC and 34 cases treated by neoadjuvant chemotherapy (NAC). This study was approved by Medical Research Review Advancement No. 1857 for Kumamoto University. RESULTS: There was a positive correlation between HER2-CN ratios and HER2-ECD levels, in primary (n = 54) and metastatic (n = 30) HER2-positive BC (P = 0.003 and P < 0.001, respectively). HER2-ECD levels were significantly higher in patients with a larger number of metastatic sites (P = 0.02). The usefulness of HER2 levels in discriminating primary and metastatic HER2-positive BC evaluated by ROC curve analysis was better in the HER2-ECD assay than in the HER2-CN assay. In 34 patients who received NAC, there was a small decrease in HER2-CN ratios between before and after NAC (P = 0.10), while there was an obvious decrease in HER2-ECD levels between before and after NAC (P < 0.001). CONCLUSION: Compared to HER2-ECD levels, the clinical usefulness of HER2-CN ratio was somewhat inferior. Improved measurement methods and further examination of the association with long-term prognosis and the response to anti-HER2 treatment analyzed by HER2-CN and HER2-ECD assay are required.

Exosomal miRNA profiles of triple-negative breast cancer in neoadjuvant treatment.

Triple-negative breast cancer (TNBC) is characterized by aggressive clinicopathological features and is associated with a poor prognosis. Identifying patients that are non-responsive to chemotherapy remains a critical goal for effective personalized therapies. In the present study, the predictive value of exosomal microRNAs (miRNAs) was investigated in patients with TNBC. Exosomes were isolated from patients with TNBC undergoing neoadjuvant chemotherapy. Microarray-based miRNA profiles were compared between patients with pathological complete response (pCR; n=12) and non-pCR (n=12). Furthermore, the miRNA profiles of non-pCR patients with breast cancer recurrence were compared with those with no recurrence. A total of 16 differentially expressed exosomal miRNAs were identified between the patients with pCR and non-pCR by microarray analysis. Of these, a combined signature of four miRNAs (miR-4448, miR-2392, miR-2467-3p and miR-4800-3p) could be used to discriminate between pCR and non-pCR patients with TNBC with an area under the curve value of 0.7652. Furthermore, this study found 43 differentially expressed miRNAs between the patients with non-pCR and recurrence and non-pCR patients without recurrence. In network analysis, 'pathway in cancer', 'focal adhesion' and 'cell cycle' were identified as the crucial pathways in patients with non-pCR who also developed recurrence. Several exosomal miRNAs may be useful biomarkers to predict treatment efficacy for TNBC. The present study identified patients who were resistant to standard chemotherapy and therefore more likely to develop breast cancer recurrence.

Cardiac computed tomography-derived extracellular volume fraction in late anthracycline-induced cardiotoxicity.

Cardiotoxicity in the late phase after anthracycline drugs administration remains to be defined. Of the 44 patients who received anthracycline treatment, 7 were found to have cancer therapeutics-related cardiac dysfunction (CTRCD). The global longitudinal strain determined by echocardiography and myocardial extracellular volume fraction (ECV) determined by cardiac computed tomography (CCT) of the CTRCD(+) group were significantly higher than those of the control group and CTRCD(-) group, whereas there were no significant differences between the control and CTRCD(-) groups. Our findings indicated that CCT may be a tool comparable to echocardiography, indicating the effective evaluation of CTRCD by CCT.

Neoadjuvant endocrine therapy for estrogen receptor-positive primary breast cancer.

Neoadjuvant endocrine treatment (NAE) for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer improves the surgical outcome, and its therapeutic response is useful for predicting prognosis. The indication for NAE is patients who have highly hormone-sensitive breast cancer. The optimal treatment duration depends on the required endpoint. In the case of tumor reduction or introduction to breast-conserving surgery (BCS), a treatment period of at least 6 months is required. Several clinical trials are underway to develop treatment strategies based on shortterm responsiveness to NAE to improve the prognosis of hormone receptor (HR)-positive/HER2-negative breast cancer. This article outlines the current status of NAE and new treatment strategies based on the responsiveness during NAE or clinical and biological feature on residual tumor after NAE.

APOBEC3B gene expression as a novel predictive factor for pathological complete response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B) is a gene editing enzyme with cytidine deaminase activity and high expression of its mRNA in breast tumors have been shown to be associated with progressive cases and poor prognosis. In this study, we aimed to examine the relationship between the expression of APOBEC3B and the effect of neoadjuvant chemotherapy (NAC) using pretreatment biopsy tissue, and examined whether the expression of APOBEC3B influenced chemotherapy efficacy. METHODS: We retrospectively selected a total of 274 patients with primary breast cancer who received NAC in more than 4 courses and underwent surgery at our institute. We assessed the expression of APOBEC3B mRNA using pretreatment biopsy specimens of NAC by quantitative real-time PCR (qRT-PCR) and examined the relationship between APOBEC3B mRNA expression and sensitivity to chemotherapy using pathological complete response (pCR) as an indicator. Further, we assessed the prognostic value of APOBEC3B in the patients receiving NAC. RESULTS: APOBEC3B mRNA expression levels were successfully assessed in 173 (63.1%) of the 274 specimens. The total pCR rate was 36.4% (n = 63). An association between APOBEC3B expression levels and pCR was observed (Wilcoxon test, P ≤ 0.0001). The patients were divided into two groups, low (n = 66) and high (n = 107), according to the APOBEC3B expression levels, using the cut-off value calculated by the receiver operating characteristics (ROC) curve for pCR. The rate of pCR was significantly higher among the patients in the high group than among those in the low group (47.7% vs 18.2%, P ≤ 0.0001). High APOBEC3B expression was significantly associated with high nuclear grade (P = 0.0078), high Ki-67 labeling index (P = 0.0087), estrogen receptor (ER) negativity (P ≤ 0.0001) and human epidermal growth factor receptor 2 (HER2) negativity (P = 0.032). Tumor size (P = 0.011), ER (P ≤ 0.0001), HER2 (P = 0.0013) and APOBEC3B expression (P = 0.037) were independent predictive factors for pCR in multivariate analysis. However, there was no association between APOBEC3B expression and prognosis. CONCLUSIONS: Our study showed that APOBEC3B mRNA expression correlated with sensitivity to NAC in breast cancer patients. In contrast to previous studies, APOBEC3B mRNA expression was not associated with breast cancer prognosis in patients receiving NAC.