Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of ...origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n = 5), peritoneal (n = 6), and ovarian (n = 30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety-three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 mutations. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of "ovarian" serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis.
To review the frequency and location of malignancies detected after prophylactic salpingo-oophorectomy in women with BRCA mutations.
Medical records and pathology findings were reviewed from ...BRCA-positive women undergoing prophylactic surgery for ovarian cancer risk reduction who underwent complete examination of the adnexa. Patients undergoing this procedure between January 1999 and January 2007 were identified.
From January 1999 to January 2007, 122 BRCA-positive patients underwent prophylactic surgery in the Division of Gynecologic Oncology at Brigham and Women's Hospital. The median age was 46.5 years (range, 33 to 76 years). Seven (5.7%) were found to have an early malignancy in the upper genital tract and all patients were age > or = 44 years at diagnosis. Of seven consecutive cancers culled between January 1999 and January 2007, all (100%) originated in the fimbrial or ampullary region of the tube; six had an early (intraepithelial) component. Two were associated with surface implants on the ovary and two required repeated sectioning to detect microscopic carcinomas in the fimbria.
The distal fallopian tube seems to be the dominant site of origin for early malignancies detected in approximately 6% of women undergoing ovarian cancer risk-reduction surgery. The greatest proportion of serous cancer risk in BRCA mutation-positive women should be assigned to the fimbria rather than the ovary, and future clinical and research protocols should employ thorough examination of the fimbria, including multiple sections from each tissue block, to maximize detection of early malignancies in this population.
Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; ...PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy.
This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus.
Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss.
Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
Abstract Toll-like receptors (TLRs) are an essential component of the innate immune system. While a number of studies have described TLR expression in the female reproductive tract, few have examined ...the temporal expression of TLRs within the human placenta. We hypothesized that the pattern of TLR expression in the placenta changes throughout the first and second trimester, coincident with physiological changes in placental function and the demands of innate immunity. We collected first and second trimester placental tissue and conducted quantitative PCR analysis for TLRs 1–10, followed by immunohistochemistry to define the cell specific expression pattern of a subset of these receptors. Except for the very earliest time points, RNA expression for TLRs 1–10 was stable out to 20 weeks gestation. However, the pattern of protein expression evolved over time. Early first trimester placenta demonstrated a strong, uniform pattern predominantly in the inner villous cytotrophoblast layer. As the placenta matured through the second trimester, both the villous cytotrophoblasts and the pattern of TLR expression within them became disorganized and patchy, with Hofbauer cells now identifiable in the tissue also staining positive. We conclude from this data that placental TLR expression changes over the course of gestation, with a tight barrier of TLRs forming a wall of defense along the cytotrophoblast layer in the early first trimester that breaks down as pregnancy progresses. These data are relevant to understanding placental immunity against pathogen exposure throughout pregnancy and may aid in our understanding of the vulnerable period for fetal exposure to pathogens.
Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the ...phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.
Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, ...remove or prevent the earliest stages of the most lethal form of ovarian cancer.
The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the 'p53 signature', suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa.
A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of 'fimbrial-ovarian' serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.
A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in ...asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women.
Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review.
Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up.
The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.
To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 ...mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin
/anti-CD45
cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death HR, 0.87; 95% confidence interval (CI), 0.79-0.95). Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.
Abstract Objective To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearchTM system, could predict for clinical outcomes in women with newly ...diagnosed or recurrent epithelial ovarian cancer. Methods Serial measurements of CTC s and paired serum CA125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearchTM protocol, and patients were divided into CTC negative (< 2 CTCs) or positive (≥ 2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed. Results At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CTCs and CA125. Conclusion Using the FDA-approved CellSearchTM system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value.
Ovarian epithelial cancer is diagnosed in approximately 25,000 women yearly in the United States, accounting for approximately 12,500 deaths. Of these tumors, serous cancer is the most lethal, due to ...its capacity to spread beyond the reproductive tract and involve the peritoneal surfaces or distant organs. Conventional classification systems designate tumor origins principally on the location of the largest tumor. However, despite the fact that the largest tumors typically involve the ovaries, demonstrations of a precise starting point for these tumors, including precursor lesions, have been inconsistent. In recent years, a major effort to prevent serous cancer in genetically susceptible women with mutations in BRCA1 or BRCA2 has spawned the practice of prophylactic salpingo-oophorectomy. This practice has surprisingly revealed that many early cancers in these women arise in the fallopian tube, and further studies have pinpointed the distal (fimbrial) portion as the most common site of origin. Emerging studies that carefully examine the fallopian tubes suggest a high frequency of early cancer in the fimbria in unselected women with ovarian and peritoneal serous carcinoma, raising the distinct possibility that a significant proportion of these tumors have a fimbrial origin. The evidence for these discoveries and their relevance to serous cancer classification, early detection and prevention are addressed in this review. A model for pelvic serous cancer is proposed that takes into account five distinct variables which ultimately impact on origin and tumor distribution: (1) location of target epithelium, (2) genotoxic stress, (3) type of epithelium, (4) mitigating genetic factors, and (5) tumor spread pattern. Ultimately, this model illustrates the importance of identifying cancer precursors, inasmuch as these entities are useful as both surrogate endpoints for their respective malignancies in epidemiologic studies and natural targets for cancer prevention.
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