Autoantibodies against one or more of these tumour-associated antigens appears to indicate the presence of early-stage breast cancers. Autoantibody assays against a panel of antigens could be used as an aid to mammography in the detection and diagnosis of early primary breast cancer, especially in younger women at increased risk of breast cancer where mammography is known to have reduced sensitivity and specificity.
DEC1, also known as SHARP-2 or Stra13, plays important roles in embryonic development, proliferation, apoptosis and cell differentiation in the mouse. DEC1 was recently identified as hypoxically induced in cDNA microarray studies of the human renal carcinoma cell line RCC4, to be regulated through hypoxia-inducible factor (HIF)-1a and via HIF-1a, able to block adipocyte differentiation. Nevertheless, its distribution and role in hypoxia and differentiation in human breast cancer are unknown. We therefore examined the pattern and level of expression of DEC1 using immunohistochemistry in whole tissue sections in normal, in situ and invasive breast carcinomas, and correlated the level of expression of DEC1 and clinicopathological factors and hypoxic tumour markers in 253 invasive carcinomas on tissue microarrays. We observed an increase in DEC1 expression during progression from normal to in situ and invasive carcinoma. Expression was not restricted to the tumour cell element but was also observed in endothelial, fibroblasts and inflammatory cells. There was a significant positive correlation between DEC1 and tumour grade (P ¼ 0.01), HIF-1a (P ¼ 0.04) and the hypoxically regulated gene angiogenin (Po0.0001), but no significant associations were observed with patient age (P ¼ 0.15), lymph node status (P ¼ 0.8), tumour size (P ¼ 0.3), oestrogen receptor (P ¼ 0.45), epidermal growth factor receptor (P ¼ 0.27) or Chalkley vessel count (P ¼ 0.45). There was no difference in relapse-free (P ¼ 0.84) or overall (P ¼ 0.78) survival. These findings suggest that DEC1 plays an important role in the progression to invasive breast cancer and that it may provide a mechanism by which hypoxia blocks tumour differentiation, and may contribute to a more aggressive phenotype. Reversing this phenotype may alter the biological behaviour of individual tumours.
The prognosis of screened women presenting with breast cancer is unrelated to dense mammographic parenchymal pattern despite an excess of interval cancers and larger screening-detected tumors in this group. These data support the mammographic screening of women with dense parenchymal patterns.
Background In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression‐free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2‐mutated HER2‐negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. Materials and Methods Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time‐varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient‐reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. Results The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3–4 months of receiving talazoparib. Grade 3‐4 anemia lasted approximately 7 days for both arms. Overlapping grade 3‐4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (<2%). A total of 150 (52.4%) patients receiving talazoparib had AEs associated with dose reduction. Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Among patients with anemia or nausea and/or vomiting AEs, PROs favored talazoparib. After accounting for the treatment‐emergent period, talazoparib was generally associated with a lower rate of hospitalization and supportive care medication use compared with chemotherapy. Conclusion Talazoparib was associated with superior efficacy, favorable PROs, and lower HRU rate versus chemotherapy in gBRCA‐mutated ABC. Toxicities were manageable with talazoparib dose modification and supportive care. Implications for Practice Talazoparib was generally well tolerated in patients with germline BRCA‐mutated HER2‐negative advanced breast cancer in the EMBRACA trial. Common toxicities with talazoparib were primarily hematologic and infrequently resulted in permanent drug discontinuation (<2% of patients discontinued talazoparib due to hematologic toxicity). Hematologic toxicities typically occurred during the first 3–4 months of treatment and were managed by dose modifications and supportive care measures. A significant efficacy benefit, improved patient‐reported outcomes, lower rate of health resource utilization and a tolerable safety profile support incorporating talazoparib into routine management of germline BRCA‐mutated locally advanced/metastatic breast cancer.
Aim: To assess the reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. Previous studies have mostly been small, with a range of agreement from 62% to 100%. Methods: Retrospective audit of 338 tumours surgically excised within 60 days of core biopsy, that had had oestrogen receptor assessed on both the core biopsy and tumour specimens. Surgical specimens were incised when fresh to ensure good fixation. External controls including a weakly positive tumour were included in each immunohistochemistry run. Results: Oestrogen receptor expression was bimodal, with H score in both specimens of either 0 or .50 in 96% of tumours. Using H score cut-off of 10 for positivity, there was an agreement between core and excision in 334 of 338 tumours (98.8%). All discrepancies were between weakly positive and negative tumours. Intratumoral heterogeneity could explain the one tumour that was negative on core and positive on excision. H score tended to be slightly higher on core than excision (means 146 and 136). Better fixation on the core is the most likely explanation for this and for the three tumours that were positive on core and negative on excision. Repeat staining on tumours with discrepant results gave similar results in all except one case. An internal control was present in 97% of excisions and 55% of cores of oestrogen receptor-negative tumours; the internal control stained positively in all except two sections. Conclusion: Oestrogen receptor can be assessed reliably on needle core biopsies of invasive carcinomas of the breast.
Objectives To investigate the hypothesis that interval cancers arising soon after the previous screen and true interval cancers are biologically aggressive and have a relatively poor prognosis compared with other interval cancers, and to assess which prognostic features are relevant to interval cancers. Methods Analysis of prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor [ER] status and histological type), radiological features (comedo/noncomedo calcification and spiculation) and survival for 538 invasive interval breast cancer cases by type and time since previous screen. Results Late interval cancers were less likely to be lymph node positive (13 versus 43%, P ¼ 0.003). Type 1 interval cancers were more likely to be histological grade 3 than type 2 (minimal signs) and type 3 (false-negative) intervals (52 versus 35%, P ¼ 0.05). Type 3 interval cancers were more likely to have lobular features than other intervals (47 versus 20%, Po0.0001). There was no significant survival difference by interval cancer type (P ¼ 0.64) or interval year (P ¼ 0.83). At univariate analysis of all interval cancers, tumour size, grade, nodal stage, ER status, vascular invasion and comedo calcification were associated with survival. On multivariate analysis of prognostic features significant at univariate analysis, nodal stage (P value ¼ 0.009), tumour size (P ¼ 0.001), ER status (Po0.0001) and vascular invasion (Po0.0001) maintained independent significance. Conclusions Our study shows that true intervals and interval cancers arising quickly after screening do not have a worse prognosis than other interval cancers, and that interval cancers have a unique set of prognostic features.
Breast cancer is the most common cancer among women and accounts for 6% of all cancer deaths. Current screening modalities for breast cancer diagnosis include mammography, digital mammography and magnetic resonance imaging; however, there is still an urgent need to develop an alternative modality of screening for earlier diagnosis. Autoantibodies to tumor-associated autoantigens can be elicited in breast cancer patients. Tumor-associated antigens vary between cancers and can be the result of a number of different events, including mutation, overexpression or altered expression patterns. The inherent amplification of signals provided by the host's own immune system to low levels of tumor-associated antigens in early disease provides a potential route to the early diagnosis of cancer. In addition, autoantibody responses in breast cancer have been correlated with patient survival and their response to treatment.
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