Comparative aspects of canine and human inflammatory breast cancer

Inflammatory breast cancer (IBC) in humans is the most aggressive form of mammary gland cancer and shares clinical, pathologic, and molecular patterns of disease with canine inflammatory mammary carcinoma (CIMC). Despite the use of multimodal therapeutic approaches, including targeted therapies, the prognosis for IBC/CIMC remains poor. The aim of this review is to critically analyze IBC and CIMC in terms of biology and clinical features. While rodent cancer models have formed the basis of our understanding of cancer biology, the translation of this knowledge into improved outcomes has been limited. However, it is possible that a comparative “one health” approach to research, using a natural canine model of the disease, may help advance our knowledge on the biology of the disease. This will translate into better clinical outcomes for both species. We propose that CIMC has the potential to be a useful model for developing and testing novel therapies for IBC. Further, this strategy could significantly improve and accelerate the design and establishment of new clinical trials to identify novel and improved therapies for this devastating disease in a more predictable way

Receptor-defined subtypes of breast cancer in indigenous populations in Africa: a systematic review and meta-analysis.

BACKGROUND: Breast cancer is the most common female cancer in Africa. Receptor-defined subtypes are a major determinant of treatment options and disease outcomes but there is considerable uncertainty regarding the frequency of poor prognosis estrogen receptor (ER) negative subtypes in Africa. We systematically reviewed publications reporting on the frequency of breast cancer receptor-defined subtypes in indigenous populations in Africa. METHODS AND FINDINGS: Medline, Embase, and Global Health were searched for studies published between 1st January 1980 and 15th April 2014. Reported proportions of ER positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor-2 positive (HER2+) disease were extracted and 95% CI calculated. Random effects meta-analyses were used to pool estimates. Fifty-four studies from North Africa (n=12,284 women with breast cancer) and 26 from sub-Saharan Africa (n=4,737) were eligible. There was marked between-study heterogeneity in the ER+ estimates in both regions (I2>90%), with the majority reporting proportions between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Similarly, large between-study heterogeneity was observed for PR+ and HER2+ estimates (I2>80%, in all instances). Meta-regression analyses showed that the proportion of ER+ disease was 10% (4%-17%) lower for studies based on archived tumor blocks rather than prospectively collected specimens, and 9% (2%-17%) lower for those with ≥ 40% versus those with <40% grade 3 tumors. For prospectively collected samples, the pooled proportions for ER+ and triple negative tumors were 0.59 (0.56-0.62) and 0.21 (0.17-0.25), respectively, regardless of region. Limitations of the study include the lack of standardized procedures across the various studies; the low methodological quality of many studies in terms of the representativeness of their case series and the quality of the procedures for collection, fixation, and receptor testing; and the possibility that women with breast cancer may have contributed to more than one study. CONCLUSIONS: The published data from the more appropriate prospectively measured specimens are consistent with the majority of breast cancers in Africa being ER+. As no single subtype dominates in the continent availability of receptor testing should be a priority, especially for young women with early stage disease where appropriate receptor-specific treatment modalities offer the greatest potential for reducing years of life lost. Please see later in the article for the Editors' Summary

GPR30 and HER-2 Expression in Invasive and Metastatic Breast Cancer.

Abstract Background: GPR30 expression, a new estrogen receptor, has been previously associated with HER-2, tumor size and metastasis in invasive breast cancer (BC) but its role in paired normal (N), invasive (I), and metastatic (M), samples is unknown. We described GPR30 and HER-2 expression in a collection of paired N/I/M samples, derived from the same individual.Materials and Methods: GPR30 and HER-2 expression was assessed by immunohistochemistry (IHC) in tissue microarrays, containing paraffin-embedded cores from 100 patients diagnosed with invasive BC. N and M samples were also available from the same patient. GPR30 expression was evaluated by an H-score (Intensity (0, negative; 1+, weak; 2+, moderate; 3+, strong) x Percentage of stained epithelial cells). HER-2 expression was evaluated per standard criteria. Log rank tests and Wald tests were employed to assess the clinical impact of these molecular targets on patient outcome based on Kaplan-Meier Product estimator and Cox Proportional Hazard Regression.Results: GPR30 was expressed in 50%, 76%, and 72% of N, I and M, respectively, samples. HER-2 (3+) was found in 14% and 18% of I and M samples, respectively. GPR30 expression in I cases correlated with expression in M cases, and HER-2 expression in I but not M cases. GPR30 expression in M cases correlated with expression in HER-2 expression in M cases. HER-2 expression in I cases correlated with expression in M samples (P&amp;lt;0.05 for all comparisons). GPR30 and HER-2 expression were not associated with grade or stage (P&amp;gt;0.05). GPR30 expression in I or M samples was not associated with either overall survival (OS) or BC-specific survival (BCSS)(P&amp;gt;0.5). HER-2 expression was marginally associated with OS in I (P=0.06; Hazard Ratios (HR): 1.91; 95%CI: 0.956, 3.83) but not in M (P=0.23) cases. HER-2 was significantly associated with BCSS in I cases (P=0.03; HR: 2.39; 95%CI: 1.07, 5.32) and marginally in M (P=0.08) cases.Discussion: A previous study suggested that GPR30 expression predicted the development of metastasis. We found high GPR30 expression in both the primary and metastatic sample but the difference was not significant. While GPR30 expression was not associated with OS or BCSS, HER-2 expression was marginally associated with OS and significantly associated with BCSS in invasive cases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4158.</jats:p

Simultaneous liver T₁, T₂, and ADC MR fingerprinting using optimized motion-compensated diffusion preparations:An initial validation on volunteers

Purpose: To develop a novel MR fingerprinting sequence using optimized motion-compensated diffusion preparations for simultaneous T1, T2, and ADC quantification of liver tissue in a single breath-held scan. Methods: A radial spoiled gradient echo acquisition with magnetization preparation modules for T1, T2, and ADC encoding is proposed. To compensate for the signal voids generated by the diffusion preparation, the combination of (1) a breath-held scan, (2) peripheral pulse signal triggering, and (3) an optimized motion-compensated diffusion-preparation module is employed. Phantom experiments were performed to test the accuracy of the technique. The sequence was evaluated in 11 healthy subjects in comparison to conventional mapping techniques. Additional in vivo repeatability assessment experiments were performed. Results: T1, T2, and ADC quantification showed good correlation (r2 &gt; 0.9 for all cases) with reference maps in phantoms and good agreement in vivo against clinical scans (bias not significantly different from zero). A peripheral pulse trigger delay of 200 ms was used to reduce cardiovascular motion artifacts. The repeatability tests prove a low interscan coefficient of variation and a high intraclass correlation coefficient of greater than 0.9 for all cases. Conclusions: Simultaneous quantification of T1, T2, and ADC in liver tissue in a single MR fingerprinting scan of ˜16 s has been proposed, enabling a comprehensive evaluation of hepatic disease through co-registered multiparametric imaging. Further studies are warranted to test this approach in patients with suspected diffuse liver disease to evaluate its potential for liver tissue characterization and tumor staging.</p

P4-01-19: SRC-1 Expression Is a Prognostic Factor of Breast Cancer-Specific and Disease-Free Survival in Inflammatory Breast Cancer.

Abstract Background: Steroid receptor coactivator (SRC-1 to 3) proteins drive nuclear receptor transcriptional activity by modulating transcriptional processes such as chromatin modification, transcription initiation, chain elongation, and RNA splicing. In patients who display resistance to endocrine treatment, SRC-1 has been implicated in the conversion of tamoxifen anti-agonist activity to its agonist profile. SRC-1 expression is a prognostic of DFS in breast cancer, but its role in inflammatory breast cancer (IBC) remains unknown. Materials and Methods: SRC-1 protein levels were measured by immunohistochemistry in 103 IBC and 11 normal, non-cancer related samples, diagnosed at the Centre Pierre &amp; Marie Curie (Algiers, Algeria). Staining results were correlated with protein levels of ER, PR, and HER2, and clinico-pathological variables, breast cancer-specific (BCSS) and disease-free survival (DFS), and response to tamoxifen treatment. Results: SRC-1 was positive in all normal breast tissue, as well as in 66% of IBC samples. SRC-1 positivity was associated with worse OS (P&amp;lt;0.001) and DFS (P=0.004). SRC-1 expression correlated with worse BCSS (P=0.011), and marginally with DFS (P=0.046) in tamoxifen-treated patients, but strongly with DFS (P=0.007) in patients who received no endocrine therapy as indicated by Kaplan-Meier and log-Rank analyses. Multivariate analysis showed that SRC-1 (Hazard Ratios (HR): 5.2; 95%CI: 2.0−13.6; P&amp;lt;0.001) and Her2 (HR: 3.1; 95%CI: 1.2−8.1; P=0.02) expression were independent prognostic markers of BCSS. SRC-1 (HR: 4.8; 95%CI: 1.9−12.2; P&amp;lt;0.001), Her2 (HR: 2.4; 95%CI: 1.0−5.7; P=0.05), and hormone treatment (HR: 0.4; 95%CI: 0.2−0.8; P=0.01) were independent prognostic markers of DFS. Discussion: Determining prognosis and predicting response to endocrine treatment is of paramount importance in the search for personalized treatment. SRC-1 expression predicts worse OS, DFS, and, similar to non-IBC, predicts DFS independently of endocrine therapy. This study highlights the importance of SRC-1 expression as a strong prognosticator of BCSS and disease recurrence in IBC patients. *Supported by an UICC ICRET Fellowship (ICR/09/043 to Dr. Chaher) and by New Mexico State IBC funding (New Mexico Senate Bill 532). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-19.</jats:p