Louis R. Bégin

Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies

Paul Pharoah and colleagues evaluate the prognostic significance of immunohistochemical subtype classification in more than 10,000 breast cancer cases with early disease, and examine the influence of a patients survival time on the prediction of future survival.

The Prognostic Implication of the Basal-Like (Cyclin Ehigh/p27low/p53+/Glomeruloid-Microvascular-Proliferation+) Phenotype of BRCA1-Related Breast Cancer

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.

BackgroundThe prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.MethodsTwo retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.ResultsGenotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).ConclusionBRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.

Estrogen Receptor Status in BRCA1- and BRCA2-Related Breast Cancer: The Influence of Age, Grade, and Histological Type

Purpose: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. Experimental Design: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. Results: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (Pintercept = 0.0002, Pslope = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (Pslope = 0.98). Conclusions: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.

Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma.

Pp125FAK, a protein tyrosine kinase (PTK) co‐localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage‐independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up‐regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC‐3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC‐3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.

Outcome of sextant biopsy according to gland volume

OBJECTIVES To reassess positive rate of sextant biopsy according to gland size. METHODS We evaluated 1974 consecutive men with systematic sextant biopsy, among whom we examined biopsy yield according to gland-volume intervals of 10 cc. RESULTS Decreasing yield of sextant biopsy is strongly associated with increasing gland volume (P < 0.001). Highest biopsy rate (39.6%) was recorded among men with prostates smaller than 20 cc. The lowest biopsy rate (10.1%) was recorded among men with prostates between 80 and 89.9 cc. Among men with biopsy-proven cancer, age, serum prostate-specific antigen, and Gleason grade were comparable (P > 0.05) throughout the range of gland-volume intervals. CONCLUSIONS Our findings suggest that gland size represents an important determinant contributing to the yield of sextant biopsy in men at risk of harboring a nonpalpable, isoechoic cancer. Consequently, an individualized sector biopsy approach, based on prostate volume, may warrant consideration because it may ensure superior detection of clinically significant disease among all men at risk, regardless of prostate size.

Aggressive angiomyxoma of pelvic soft parts: A clinicopathologic study of nine cases

Nine cases of aggressive angiomyxoma (AAM) of the pelvic soft parts were studied by light and electron microscopy and immunohistochemistry. The tumors were confined to the vulva, vagina, pelvic floor, and perineum in the seven women. The perineum and the para-anal region were involved in the two men. The patients ranged in age from 18 to 63 years. Aggressive angiomyxoma presented as a slowly growing, polypoid or cyst-like tumor. Six of the nine cases were followed up; all of the tumors recurred within nine to 84 months, and one recurred for the second time at 144 months. Recurrences were attributed to incomplete tumor excision. None of the six patients died or had metastases. The aggressive angiomyxomas had infiltrative borders and rubbery, white or soft, gelatinous cut surfaces. Histologically, the lesions were composed of stellate and spindle-shaped neoplastic cells embedded in a collagenous and hyaluronic acid-containing stroma. Nuclear atypia and mitoses were absent. Typically, the lesions had an important vascular component, often displaying medial hypertrophy and vascular grouping. Ultrastructurally, the neoplastic cells resembled fibroblasts rather than myofibroblasts. They showed strong immunoreactivity for actin but were negative for S-100 protein, Factor VIII, carcinoembryonic antigen, and keratin. The morphoimmunocytochemical characteristics of AAM cells favor a fibroblastic origin and differentiation. Aggressive angiomyxoma should be distinguished from the more common benign and malignant myxoid neoplasms or tumor-like conditions of the pelvic soft parts. Recurrence of AAM may be avoided by wide, local excision.

Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women

In the Ashkenazim, three recurrent germline mutations have been identified in the breast carcinoma susceptibility genes BRCA1 and BRCA2: 185delAG, 5382insC (BRCA1), and 6174delT (BRCA2). The frequency of these mutations in the general Ashkenazi population approaches 2%. There is little available controlled data comparing the characteristics of breast carcinoma arising in BRCA1 mutation carriers or BRCA2 mutation carriers with that arising in noncarriers, although such data would be relevant to the urgent clinical need to develop risk‐reduction strategies for individuals at increased risk due to genetic factors.

Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer.

Purpose:BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261 breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor– and KIP1 (p27Kip1)–negative tumors, with expression of cytokeratin 5/6, cyclin E, TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node–negative and –positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

Prospective evaluation of prostate-specificantigen density and systematic biopsies for early detection of prosttic carcinoma

Significant controversies persist in regard to the need for systematic biopsies in patients with serum prostate-specific antigen (PSA) levels above 4 ng/mL (Hybritech assay), especially if they show no signs of prostatic cancer on digital rectal examination (DRE) or transrectal ultrasonography (TRUS). We evaluated 565 consecutive patients referred to us for prostatism, suspicious lesions on DRE, or an elevated serum PSA level. These patients do not represent a purely screened population. A detection rate of 38.4 percent was achieved by performing directed biopsies of suspicious lesions on DRE and/or TRUS, and systematic biopsies of all patients with serum PSA levels above 4 ng/mL. Among 142 patients with serum PSA between 4.1 and 10 ng/mL, but without suspicion for cancer on DRE and TRUS (DRE- TRUS-), a large number of patients (6.2) were subjected to systematic biopsies to detect one cancer. A receiver-operating characteristics curve for PSA density (PSAD) applied to this population confirmed that the best cut-off point for biopsies was a PSAD of 0.15, below which only two of twenty-three cancers would have been missed, sparing biopsies in 77 of 142 patients. A similar approach was applied to DRE- TRUS- patients with serum PSA levels above 10 ng/mL. The number of cancers in those with serum PSA between 10.1 and 14 ng/mL was too low to establish a PSAD cut-off point. In patients with serum PSA above 14 ng/mL, the best PSAD cut-off point for biopsies was 0.3, below which two of thirteen cancers would have been missed, sparing biopsies in 19 of 39 patients. We conclude that PSAD can safely reduce the number of patients subjected to systematic biopsies without significantly compromising cancer detection.