Breast

Breast cancer risk associated with BRCA1 / 2 variants in the Pakistani population Abstract Background Majority of the BRCA1 and BRCA2 mutations are associated with the risk of sporadic and familial breast cancer. Since these genes are significant in DNA repair mechanisms, we focused homology-directed DNA repair (HDDR) and BRCA complex. Methods We selected BRCA1 variant (rs80356932, 4491C/T) and BRCA2 variant (rs80359182, 319T/C) from the interaction region of BRCA complex and studied in 100 breast cancer patients and 100 controls using tetra-ARMS-PCR. Results Here we show that BRCA1 and BRCA2 variants are significantly associated with high breast cancer risk (BRCA1 rs80356932; Genotype T/T OR 8.66, 95% CI 3.16–23.71, p < 0.0001; Allele-T, OR 2.48, 95% CI 1.62–3.81, p< 0.0001 and BRCA2 rs80359182; Genotype C/C OR 4.32, 95% CI 1.95–9.53, p = 0.0001; Allele-C, OR 2.19, 95% CI 1.43–3.34, p = 0.0002). Additionally, bioinformatics analysis showed that BRCA2-tryptophan > arginine substitutions result in altered interaction of BRCA1/PALB2/BRCA2/protein complex and impaired HDDR pathway. We also observed that breast cancer risk was significantly increased in over-weighted and obese women. Conclusions Our results indicate that high risk of breast cancer is significantly associated with BRCA1 and BRCA2 variants, and mutations may alter the protein interactions of BRCA complex that results in tumor genesis.

OFS plus AI or SERM vs. SERM alone in premenopausal women with hormone receptor-positive breast cancer: a prospective cohort study using the real-world database Abstract Background Ovarian function suppression (OFS) plus other endocrine treatment was recommended to hormone receptor (HR)-positive breast cancer by some guidelines recently. We performed this study to validate the survival benefits of OFS plus aromatase inhibitors (AI) or selective estrogen receptor modulators (SERM) in the real world. Methods All premenopausal, HR-positive breast cancer patients diagnosed between 1996 and 2017 were identified. Eligible patients were classified into three groups according to their adjuvant endocrine treatment, including OFS plus AI, OFS plus SERM and SERM alone. The primary outcome is invasive disease-free survival (iDFS), whereas the secondary outcome is overall survival (OS). Cox proportional hazards models and propensity score adjusted models were used to compare the survival benefits in three groups. Results We included 2838 patients, of which 246 received OFS plus AI, 175 received OFS plus SERM, and 2417 received SERM alone. Compared with SERM alone, OFS plus AI was associated with an improved iDFS (HR 0.59, 95% CI 0.36–0.96) and OS (HR 0.26, 95% CI 0.08–0.85). OFS plus SERM, however, was not significantly associated with extended iDFS or OS. Among patients older than 40 years old, OFS plus AI was more effective than OFS plus SERM (HR 0.38, 95% CI 0.17–0.88) or SERM alone (HR 0.44, 95% CI 0.23–0.84) in terms of iDFS. Conclusions Our findings suggest that OFS plus AI treatment may extend both iDFS and OS among premenopausal patients with hormone receptor-positive breast cancer in the real world.

Neoadjuvant chemotherapy and timing of sentinel lymph node biopsy in different molecular subtypes of breast cancer with clinically negative axilla Abstract Purpose This study aims to determine the optimal time to perform sentinel lymph node biopsy (SLNB) for patients with clinically node-negative (cN0) disease following neoadjuvant chemotherapy (NAC). Method From April 2008 to April 2018, 592 patients with breast cancer underwent after NAC were included in this study. Patients with cN0 before and ycN0 disease after NAC received SLNB and axillary lymph node dissection (ALND) in case of positive sentinel lymph nodes (SLNs). For patients with clinically node-positive (cN+) disease, the axillary surgery is based on the doctor's decision. Result In general, 17.6% (104/592) of patients achieved total pathologic complete response (pCR), which was 6.9%, 33.3%, 32.3% and 15.3%, respectively, among patients with hormone receptor (HR) positive/ human epidermal growth factor receptor-2 (HER-2) negative (HR+/HER2−) subtype, triple-negative (TN) subtype, HER-2 positive (HER2+) subtype with and without targeted therapy (p < 0.001). Among the 525 cN+ patients, the axillary nodal pCR (apCR) rate was 34.5%, and the apCR rate was significantly higher in patients with HER2+ (58.6% with and 28.2% without targeted therapy respectively) and TN subtype (53.2%) than that in patients with HR+/HER2−subtype (21.2%, p < 0.001). Among the 67 cN0 patients, the positive rate of SLNs was 19.4% (13/67), which was 28.1% (9/32), 13.3% (2/15) and 10.0% (2/20), respectively, among patients with HR+/HER2−, TN and HER2 + subtypes. Conclusion The pCR rates were significantly related to molecular subtype. Combining the apCR rates in different molecular subtypes of cN+ patients and the excellent locoregional control of AOSOG Z0011 and AMAROS trials in cN0patients, it would be preferable to perform SLNB prior to NAC for cN0 patients with HR+/HER2− subtype, and SLNB after NAC for those cN0 patients with TN and HER2+ subtype to increase the chance of avoiding ALND. Among cN0 patients, TN and HER2 + subtypes would benefit more from axillary de-escalating surgery after NAC than HR+/HER2− subtype.

Can quantitative evaluation of mammographic breast density, "volumetric measurement", predict the masking risk with dense breast tissue? Investigation by comparison with subjective visual estimation by Japanese radiologists Abstract Background Sensitivity to detect breast cancer (BC) is not high in a dense breast due to masking in mammography. To evaluate the breast density, a volumetric measurement system has been recently developed that measures the percent fibroglandular tissue volume (percent FGV, hereafter termed as "FG%") to the breast volume (BV). This study was designed to investigate whether evaluation using FG% can accurately predict the masking risk by comparing with the current standard method of subjective visual estimation (SVE). Methods Using pre-biopsy mammograms of 114 cases histopathologically diagnosed with BC in our facility, SVE based on BI-RADS (5th edition) and volumetric measurements of FG% were conducted. Performance to predict the masking risk was evaluated using the area under the receiver operating characteristic curve (AUC). Relationship between these parameters and the masking risk was evaluated by the adjusted multivariate linear regression analysis. Results The AUC of SVE values was 0.742 (95% CI 0.641–0.822), while that of FG% was as significantly low as 0.560 (95% CI 0.427–0.685) (P = 0.0014). The SVE values correlated with the detection of BC in mammography (P = 0.0035), but there was no significant relationship with FG% (P = 0.74). The median BV and FGV were 313 cm3 (IQR 191–440) and 63 cm3 (IQR 44–102), respectively. The FGV was comparable to the data for Caucasian women reported in previous studies, but the BV was one-half of the previous data. Conclusion The current volumetric measurement system to evaluate FG% to BV was found to be insufficient in the performance to predict the masking risk in Japanese women with relatively small-sized breasts.

Hypofractionated whole breast radiotherapy with or without hypofractionated boost in early stage breast cancer patients: a mono-institutional analysis of skin and subcutaneous toxicity Abstract Background Our study evaluated skin and subcutaneous toxicity analyzing its correlation with patient- and treatment-related factors in a large mono-institutional series of women with early stage breast cancer treated with adjuvant hypofractionated whole breast radiotherapy (WBRT) with or without a sequential hypofractionated boost (HB). Methods Two hundred and nineteen patients, median age 62 years, received adjuvant hypofractionated WBRT in 16 fractions to a total dose of 42.4 Gy. Patients with negative prognostic factors received a HB of 2.65 Gy for 4 or 5 (patients with focal positive surgical margins) fractions. Systemic adjuvant treatments were hormonal therapy (HT) and/or chemotherapy (CHT) and/or Trastuzumab. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE 4.03) scale at 5th, 10th, 16th, 20th day from the start of radiotherapy (RT) and 1, 6 and 12 months after the end of RT. Univariate and multivariate analysis estimated toxicity predictive factors. Results No case of treatment interruption and no acute or late G3 toxicities occurred. In the univariate analysis HB administration resulted a risk factor for acute toxicity, while CHT administration and number of excised lymph nodes ≥ 10 resulted a risk factor for late toxicity. In the multivariate analysis none of the evaluated factors emerged a risk factor for acute and/or late toxicity. Conclusions Our results confirmed that hypofractionated WBRT even followed by a HB resulted safe and well tolerated. Longer follow-up is warranted to estimate late toxicity and treatment outcomes.

Invasive breast cancers in adolescent and young adult women show more aggressive immunohistochemical and clinical features than those in women aged 40–44 years Abstract Background Limited knowledge exists concerning the clinicopathological features of breast cancers (BCs) occurring in adolescent and young adult (AYA) women. We evaluated tumor characteristics in AYA women in comparison with those in middle-aged premenopausal women. Methods From consecutive AYA patients (< 35-year-old) with invasive BC in a single institute, 82 patients first treated with surgery were examined. As the control group, 82 tumors from middle-aged premenopausal patients (40–44 years) were selected by matching pathological T and N factors. We compared habitual factors, immunohistochemical parameters, and patient outcome between the two groups. Results Most of the study population (148 of 164, 90.2%) were in the early clinical stages (stage I or II). In the AYA group, the number of childbirths was smaller (p < 0.0001), while the volume of alcohol consumption was larger (p < 0.0001), and palpable primary tumors were more frequent (p < 0.01) than in the control group. The positivities of estrogen receptor, progesterone receptor, and androgen receptor were lower (p < 0.001, p = 0.03, and p < 0.001, respectively), and the triple-negative (TN) BCs rates were higher (p < 0.01) in the AYA group. Distant recurrence-free survival (DRFS) curves were different in the whole population (p = 0.02) and in hormone receptor-positive cases (p = 0.01). Conclusions We confirmed that BCs occurring in AYA women had more aggressive features than those of the older premenopausal women in terms of a high proportion of TN subtypes and a lower DRFS.

Intimacy and sexuality in women with breast cancer: professional guidance needed Abstract Background Approximately 60–70% of breast cancer survivors experience sexuality problems resulting from treatment. This study investigated information and communication preferences with professionals on the topic intimacy and sexuality of women diagnosed with breast cancer. Methods Members of the Dutch Breast Cancer Patient Association were surveyed regarding their experiences and preferences about information on intimacy and sexuality. An online questionnaire was developed that included five close-ended and one open-ended question regarding: information received; type of professional preferred; method and timing of communication on the topics of intimacy and sexuality. Quantitative data were analysed using descriptive statistics. A deductive framework analysis was performed on the open-ended answers to enrich the data of the close-ended questions. Results In total, 667 female breast cancer (ex-)patients participated. In 46% of the women, the information received matched their needs. Most women preferred to receive information about the impact on intimacy and sexuality from a nurse (66.4%) or primary doctor (27.9%). The preferred method of communication was a conversation with a professional together with their partner (51.6%) or a personal conversation with a professional. Respondents emphasized the importance of appropriate timing of information, preferably at least shortly after the treatment started (45.1%). Conclusions This study shows that intimacy and sexuality should be repeatedly included in consultations, at every stage of the disease but especially shortly after treatment started. Women with breast cancer expect that professionals (preferably nurse or primary doctor) initiate this subject via a personal conversation (alone or with their partner).

p110α and p110β isoforms of PI3K are involved in protection against H 2 O 2 induced oxidative stress in cancer cells Abstract Purpose Phosphatidylinositol-3 kinases (PI3Ks) are involved in regulating cell growth, proliferation, differentiation, apoptosis and survival. p110α and p110β, two ubiquitously expressed isoforms of PI3K signalling, are involved in growth factor mediated signaling and survival by generating second messengers. Earlier, we have generated GFP-fusion proteins of p110α and p110β and expressed them in normal and cancer cell-lines to investigate their subcellular localization and their role in various activities. Here, we sought to examine the role of p110α and p110β isoforms in protecting MCF-7 breast cancer cells against oxidative stress. Material methods We performed cytotoxicity assays, DNA transfection, Plasmid DNA preparation, western blotting, flourscence microscopy and statistical analysis. Results To know whether p110α and p110β are involved in protecting MCF-7 breast cancer cells against oxidative stress, we subjected MCF-7 cells to H2O2 treatment and observed a dose dependent decrease in cell viability and a marked increase in the levels of pro-apoptotic markers which include PARP, Bcl-2, Bax and procaspase-9. We then over-expressed recombinant GFP-fusion p110α and p110β proteins in MCF-7 cells and observed a significant decrease in apoptosis and a concomitant increase in pAkt levels. Conclusion We report the involvement of p110α and p110β isoforms of Class 1A PI3K signalling in rescue from oxidative stress-induced apoptosis in MCF-7 cells in Akt dependent manner.

Toll-like receptor 4 and breast cancer: an updated systematic review Abstract Toll-like receptors (TLRs) may play dual roles in human cancers. TLR4 is a key molecule which may participate in both friend and foe roles against breast cancer. This review article collected recent data regarding the mechanisms used by TLR4 in the eradication of breast cancer cells and induction of the tumor cells, and discussed the mechanisms involved in the various functions of TLR4. The literature searches revealed that TLR4 is a key molecule that participates in breast cancer cell eradication or induction of breast cancer development and also transformation of the normal cells. TLR4 eradicates breast cancer cells via recognition of their DAMPs and then induces immune responses. Over-expression of TLR4 and also alterations in its signaling, including association of some intrinsic pathways such as TGF-β signaling and TP53, are the crucial factors to alter TLR4 functions against breast cancer.

Identification of differentially expressed genes and typical fusion genes associated with three subtypes of breast cancer Abstract Background This study aimed to identify the differentially expressed genes (DEGs) and the typical fusion genes in different types of breast cancers using RNA-seq. Methods GSE52643 was downloaded from Gene Expression Omnibus, which included 1 normal sample (MCF10A) and 7 breast cancer samples (BT-474, BT-20, MCF7, MDA-MB-231, MDA-MB-468, T47D, and ZR-75-1). The transcript abundance and the DEGs screening were performed by Cufflinks. The functional and pathway enrichment was analyzed by Gostats. SnowShoes-FTD was applied to identify the fusion genes. Results We screened 430, 445, 397, 417, 369, 557, and 375 DEGs in BT-474, BT-20, MCF7, DA-MB-231, MDA-MB-468, T47D, and ZR-75-1, respectively, compared with MCF10A. DEGs in each comparison group (such as CD40and CDH1) were significantly enriched in the functions of cell adhesion and extracellular matrix organization and pathways of CAMs and ECM receptor interaction. UCP2 was a common DEG in the 7 comparison groups. SFRP1 and MMP7 were significantly enriched in wnt/–catenin signaling pathway in MDA-MB-231. FAS was significantly enriched in autoimmune thyroid disease pathway in BT-474. Besides, we screened 96 fusion genes, such as ESR1-C6orf97 in ZR-75-1, COBRA1-C9orf167 in BT-20, and VAPB-IKZF3 and ACACA-STAC2 in BT-474. Conclusions The DEGs such as SFRP1, MMP7, CDH1, FAS, and UCP2 might be the potential biomarkers in breast cancer. Furthermore, some pivotal fusion genes like ESR1-C6orf97 with COBRA1-C9orf167 and VAPB-IKZF3 with ACACA-STAC2 were found in Luminal A and Luminal B breast cancer, respectively.