Ines Raoelfils

Changes and Predictive and Prognostic Value of the Mitotic Index, Ki-67, Cyclin D1, and Cyclo-oxygenase-2 in 710 Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

The current study expands upon previous work using a database of 710 patients treated with neoadjuvant chemotherapy. First, we studied phenotypic characteristics of tumors before and after chemotherapy using the following factors: the mitotic index of the Scarff-Bloom-Richardson grade, Ki-67, cyclin D1, and cyclo-oxygenase-2. Second, the predictive value of these factors on response was assessed. Third, we measured the prognostic impact of these markers post-therapy in comparison with clinical and pathological responses according to the Chevallier and Sataloff classifications. Patients were treated using different neoadjuvant chemotherapy combinations, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1-9). After neoadjuvant chemotherapy, patients underwent surgery and radiotherapy. In cases of important residual disease, some received additional courses of chemotherapy. In addition, menopausal patients with hormone receptor-positive tumors received tamoxifen for 5 years. According to our analysis, we found significant variations before and after neoadjuvant chemotherapy only for cyclin D1 and the mitotic index. Concerning the predictive value of biomarkers for response, Ki-67 and the mitotic index were predictive on univariate analysis, both for objective clinical and pathological complete responses. Because these two factors were correlated, no multivariate analyses were conducted. We then assessed the prognostic impact of the biopathological factors. When the factors were measured before chemotherapy, all were prognostic. When evaluated after chemotherapy, the mitotic index, objective clinical response, and pathological complete response were prognostic. Because these factors were correlated, no multivariate model was done. The main clinical fact is that there were significant correlations between clinical and pathological responses and variations in the biological factors studied.

Comparison of the prognostic significance of Chevallier and Sataloff's pathologic classifications after neoadjuvant chemotherapy of operable breast cancer

Pathologic complete response (pCR) is linked to a better outcome, but its definition varies among working groups. We performed this study to validate different expressions of pCR as well as to determine the role of in situ and isolated tumor cell residues. A pathologic review was conducted on 710 operable patients with breast cancer to assess the residual disease in breast and in nodes according to the Chevallier (Ch) and Sataloffs (Sa) classifications. The pCR rate was 14.3% according to the Chevallier and 25.8% according to the Sataloffs classification. Overall survival and disease-free survival have been compared according to the pathologic response. There were significant differences between the pCR Ch(1+2) or Sa(A) and the non-pCR group. No significant difference was found between classes Ch(1) versus Ch(2) and between class Sa(A) without isolated cells versus class Sa(A) with isolated cells. Conversely, tumors histologically modified by chemotherapy were associated with a better prognosis than unmodified tumors. Finally, evidence of pCR in nodes was associated with a better prognosis. pCR should be defined as an absence of node invasion, and in the breast, either absence of tumor or tumor residue less than 5% of the tumor.

Early Telomere Shortening and Genomic Instability in Tubo-Ovarian Preneoplastic Lesions

Purpose: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Experimental Design: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthons method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. Results: TOD showed marked telomere shortening compared with noncancerous controls (P < 10−7). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10−7). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers. Conclusions: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. Clin Cancer Res; 19(11); 2873–82. ©2013 AACR.

Échelle d’évaluation de la dysplasie épithéliale de l’ovaire

INTRODUCTION Precancerous ovarian epithelial dysplasia was first described after prophylactic oophorectomy (OP) for genetic risk (BRCA mutation) or because of a strong family history of ovarian and/or breast cancer. The objective of this study was to describe histopathological features of ovarian dysplasia and to propose a dysplasia scoring sheme with a cut-off. PATIENTS AND METHOD One hundred and twenty-five bilateral oophorectomies (genetic predisposition: n=35 and control group: n=90) were reviewed by two pathologists blinded to clinical data. Eleven epithelial cytological and architectural features were studied and an ovarian dysplasia score was defined to compare the degree of ovarian epithelial abnormalities between the two groups. RESULTS Mean ovarian dysplasia score was significantly higher in prophylactic oophorectomy group than in control group (9.0 versus 3.5, P<0.001). Dysplasia was more severe in OP with BRCA mutation than in OP without (11.6 in BRCA 1; 7.6 in BCRA 2; 7.1 in family history). The cut off for dysplasia was 8 with a sensitivity of 60% and a specificity of 93.3%. CONCLUSION The increased dysplasia score in OP and the gradation in dysplastic severity in OP with proven BRCA mutations may suggest that ovarian dysplasia could be a pre-malignant non invasive histopathological lesion. The 11 cytological and architectural features in the dysplasia scoring sheme could be a useful tool to study ovarian dysplasia.

N’oubliez pas les trompes ! Étude morphologique et immunohistochimique des trompes à risque génétique (mutation BRCA)

OBJECTIVES The objective of this study was to describe morphologic and immunohistochemical features of precursor tubal lesions in prophylactically removed Fallopian tubes. PATIENTS AND METHODS Hundred and forty-seven bilateral salpingectomies (genetic predisposition or group A: n=57; and control group or group B: n=90) were reviewed by two pathologists blinded to clinical data. Seven epithelial cytological and architectural features were studied to compare the degree of tubal epithelial abnormalities between the two groups. Immunohistochemical expression patterns of Ki67 and p53 were also evaluated. RESULTS Serous tubal intraepithelial lesions (STIL) have been identified in group A with stronger expression for Ki67 and p53 (especially in BRCA 1 group) than in group B. DISCUSSION AND CONCLUSION The current results show the importance of salpingo-oophrectomy in BRCA mutation carriers and the complete histopathological sampling of the Fallopian tubes.

La cancérogenèse ovarienne : théories actuelles et passées

Ovarian carcinogenesis and the early stages of malignant transformation are limited because of the lack of a candidate precursor. There have been several proposed hypotheses: first, ovary and the ovarian surface epithelium and more recently observations have increasingly focused attention of the Fallopian tube. Moreover, molecular genetic analysis has designed two main pathways of tumorogenesis. In this review, we discuss the different and perhaps complementary hypotheses about ovarian carcinogenesis.

Abstract 4854: Mutations activating proliferation pathways in ovarian cancer

Ovarian malignancies may arise through different mechanisms of oncogenesis, which influence their treatment and are important for prognosis. Essential to carcinogenesis is the activation of proliferation pathways such as those directed by PI3 kinase or KRAS. New sequencing technologies may improve the detection of somatic mutations in tumor tissue, which is complicated by the low representation of a mutation within a tissue sample inevitably containing normal cells and subpopulations of malignant cells. We analyzed selected exons in PIK3CA, PIK3R, KRAS, BRAF, EGFR and ERBB2 in 34 primary malignant ovarian tumors, including 10 serous, 4 borderline, 11 endometrioid, and 9 mixed or rare subtypes. DNA was extracted from flash-frozen tumor tissues, amplified, and sequenced on a 454-GS-Flx Genome Sequencer. Expression of PTEN, p53, Bcl2, ALDH and Ki67 were assessed by immunohistochemistry on formalin-fixed tissues. Nine mutations were observed in PIK3CA, 5 in BRAF, 4 in KRAS, and 2 in EGFR. SNPs present in the amplicons analyzed allowed allelic imbalance to be estimated, showing possible amplification of EGFR in 9 of 20 informative samples, and of PIK3CA in 6 of 19 informative samples, none of which contained a point mutation. Endometrioid tumors frequently showed anomalies in PIK3CA, Bcl2 expression, and not p53 overexpression. P53 overexpression was typical of serous tumors, and was associated with the absence of mutations in any of the genes sequenced. Borderline and low grade tumors were characterized by BRAF mutation, no imbalance at EGFR, no anomalies at PIK3CA, and less frequent p53 overexpression. The absence of BRAF mutations in high grade tumors suggested that they do not evolve from borderline tumors. PIK3CA mutations were not mutually exclusive with KRAS mutations, confirming the non-redundancy of these intertwined signaling pathways. PTEN extinction was not significantly negatively associated with either point mutations or allelic imbalance at PIK3CA, consistent with different roles for PTEN loss and PI3-kinase activation at different stages of tumorogenesis, in spite of the close association of PTEN with the PI3-kinase pathway. No significant associations were observed between ALDH and Ki67 and any parameters measured. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4854. doi:10.1158/1538-7445.AM2011-4854