paywalled: Long-term survival in patients with clear cell adenocarcinoma of ovary treated with irinotecan hydrochloride plus cisplatin therapy as first-line

Long-term survival in patients with clear cell adenocarcinoma of ovary treated with irinotecan hydrochloride plus cisplatin therapy as first-line chemotherapy

Article first published online: 28 MAY 2012

DOI: 10.1111/j.1447-0756.2012.01884.x

© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology

Issue

Journal of Obstetrics and Gynaecology Research

Early View (Online Version of Record published before inclusion in an issue)

Abstract

Aim:  Several previous reports showed that irinotecan hydrochloride plus cisplatin (CPT-P) was a candidate first-line chemotherapy regimen for clear cell adenocarcinoma of the ovary (CCC). However, long-term survival in CCC patients treated with CPT-P as first-line chemotherapy remains to be determined. The aim of the present study was to evaluate the long-term results of CPT-P as first-line chemotherapy for CCC.

Material and Methods:  We performed a retrospective review of 31 patients with CCC who were treated with CPT-P between 1996 and 2004.

Results:  The median follow-up period was 91 months.........

Conclusion:  The long-term results suggest CPT-P as a candidate in first-line chemotherapy for CCC in not only stage I, but also in optimally debulked stage II-IV patients with pT1/pT2 disease.

PLoS ONE: Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression (clear cell ovarian/high grade)

PLoS ONE: Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

"....According to FIGO grading classification, high-grade ovarian tumor cells are usually poorly histological differentiated [20], grow faster and highly metastatic [7]. In addition, prognosis of high-grade ovarian tumor is poor thereafter it often associates with poor survival rate [21], [22].The clear cell subtype ovarian cancer accounts for approximately 6% of all epithelial ovarian tumors and most cases of this subtype are high-grade tumor exhibiting an aggressive phenotype [3], [22], [23]. Our study showed that both mRNA and protein levels of PITX2 was frequently upregulated in ovarian cancer particularly in the high-grade and clear cell subtypes, indicating that PITX2may play an important role in driving aggressive phenotypes in ovarian cancer.....

paywalled: Management and Prognosis of Clear Cell Borderline Ovarian Tumor.

Management and Prognosis of Clear Cell Borderline Ovarian Tumor.:

Abstract
BACKGROUND: The clear cell borderline ovarian tumor (CCBOT) of the ovary is a rare tumor accounting for less than 1% of BOT. Fewer than 25 cases have been reported in the literature (including details on clinical management and outcomes). The aim of this study was to determine the prognosis of a series of CCBOTs collected in 2 reference centers.
PATIENTS AND METHODS: This was a retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.
RESULTS: Twelve patients were identified between 2000 and 2010. The median age of patients was 68 years (range, 36-83 years). Two had been treated conservatively and 9 radically (data unknown in 1). The tumor was unilateral in 11 cases. All patients had stage I disease. All cases were CCBOT with an adenofibromatous pattern. Stromal microinvasion or intraepithelial carcinoma was histologically associated in 2 and 3 cases, respectively. Four of the 12 patients had synchronous endometrial disorders (but no endometrioid carcinoma). No cases were histologically associated with endometriosis. Four patients were lost to follow-up. Among 8 other patients, after a median period of 28 months (range, 2-129 months), no recurrence had occurred (1 patient had died of another disease).
CONCLUSION: Clear cell borderline ovarian tumor carries a good prognosis. All tumors are (blogger's note - 'were' in this study of 12 pts) stage I; therefore, surgical staging is not necessary in most of the cases. Conservative treatment could be proposed to young patients, but uterine curettage would then be required in cases of uterine preservation.

Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

PLOS Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression:

Principal Findings
.....Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (P<0.001) ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect.

Conclusion
Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.

paywalled: Limited prognostic value of tissue protein expression levels of cyclin E in Danish ovarian cancer patients: from the Danish ‘MALOVA’ ovarian cancer study

Limited prognostic value of tissue protein expression levels of cyclin E in Danish ovarian cancer patients: from the Danish ‘MALOVA’ ovarian cancer study

The primary objective of this study was to assess the expression of cyclin E in tumour tissues from 661 patients with epithelial ovarian tumours. The second was to evaluate whether cyclin E tissue expression levels correlate with clinico-pathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the cyclin E expression levels in tissues from 168 women with borderline ovarian tumours (BOT) (147 stage I, 4 stage II, 17 stage III) and 493 Ovarian cancer (OC) patients (127 stage I, 45 stage II, 276 stage III, 45 stage IV). Using a 10% cut-off level for cyclin E overexpression, 20% of the BOTs were positive with a higher proportion of serous than mucinous tumours. Sixty-two per cent of the OCs were positive for cyclin E expression with the highest percentage found in clear cell carcinomas. 

Results based on univariate and multivariate survival analyses with a 10% cut-off value showed that cyclin E had no independent prognostic value. In conclusion, we found cyclin E expression in tumour tissue to be of limited prognostic value to Danish OC patients.

In silico analysis and immunohistochemical characterization of NaPi2b protein expression in ovarian carcinoma with monoclonal antibody Mx35.

In silico analysis and immunohistochemical characterization of NaPi2b protein expression in ovarian carcinoma with monoclonal antibody Mx35.

Abstract
INTRODUCTION: Ovarian adenocarcinoma is frequently detected at the late stage, when therapy efficacy is limited and death occurs in up to 50% of the cases. A potential novel treatment for this disease is a monoclonal antibody that recognizes phosphate transporter sodium-dependent phosphate transporter protein 2b (NaPi2b).

MATERIALS AND METHODS: To better understand the expression of this protein in different histologic types of ovarian carcinomas, we immunostained 50 tumor samples with anti-NaPi2b monoclonal antibody MX35 and, in parallel, we assessed the expression of the gene encoding NaPi2b (SCL34A2) by in silico analysis of microarray data.

RESULTS: Both approaches detected higher expression of NaPi2b (SCL34A2) in ovarian carcinoma than in normal tissue. Moreover, a comprehensive analysis indicates that SCL34A2 is the only gene of the several phosphate transporters genes whose expression differentiates normal from carcinoma samples, suggesting it might exert a major role in ovarian carcinomas. Immunohistochemical and mRNA expression data have also shown that 2 histologic subtypes of ovarian carcinoma express particularly high levels of NaPi2b: serous and clear cell adenocarcinomas. Serous adenocarcinomas are the most frequent, contrasting with clear cell carcinomas, rare, and with worse prognosis.

CONCLUSION: This identification of subgroups of patients expressing NaPi2b may be important in selecting cohorts who most likely should be included in future clinical trials, as a recently generated humanized version of MX35 has been developed.

Endometriosis and ovarian cancer – Authors' reply : The Lancet Oncology

Endometriosis and ovarian cancer – Authors' reply : The Lancet Oncology

"Both Vercellini and colleagues and Guo and colleagues raise concerns about screening, with which we agree. Our findings should not suggest to clinicians or the public that screening for ovarian cancer should be implemented for women with endometriosis. Rather, we hope that our work stimulates further research that can refine risk groups related to endometriosis on the basis of anatomical site, epidemiological risk factors, or molecular features. Vercellini and colleagues raise an interesting point about atypical endometriosis, but this diagnosis is not standardised or commonly used and can not be addressed in epidemiological studies.

..................Regardless, the attenuated associations remain statistically significant.

(another) commentary: Endometriosis and ovarian cancer : The Lancet Oncology

Endometriosis and ovarian cancer : The Lancet Oncology

correspondence: Endometriosis and ovarian cancer : The Lancet Oncology

Endometriosis and ovarian cancer : The Lancet Oncology

paywalled: Breast-feeding and risk of epithelial ovarian cancer (clear cell/endometrioid)

Breast-feeding and risk of epithelial ovarian cancer

 Abstract

PURPOSE:

Evidence suggests that breast-feeding may decrease the risk of epithelial ovarian cancer but it is not clear whether there is a relationship with duration of breast-feeding, patterns of breast-feeding, or particular histological subtypes of ovarian cancer. We sought to investigate these issues in detail.

METHODS:

Data from participants in a population-based study of ovarian cancer in western Washington State, USA (2002-2007) who had had at least one birth (881 cases and 1,345 controls) were used to assess relations between patterns of breast-feeding and ovarian cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).

RESULTS:

Women who ever breast-fed had a 22 % reduction in risk of ovarian cancer compared with those who never breast-fed (OR = 0.78, 95% CI 0.64-0.96) and risk reduction appeared greater with longer durations of feeding per child breast-fed (OR = 0.56, 95% CI 0.32-0.98 for 18 months average duration breast-feeding versus none). Introduction of supplementary feeds did not substantially alter these effects. The overall risk reduction appeared greatest for the endometrioid and clear cell subtypes (OR per month of average breast-feeding per child breast-fed = 0.944, 95% CI 0.903-0.987).

CONCLUSIONS:

Among women who have had the opportunity to breast-feed, ever breast-feeding and increasing durations of episodes of breast-feeding for each breast-fed child are associated with a decrease in the risk of ovarian cancer independent of numbers of births, which may be strongest for the endometrioid subtype.

Google search: "clear cell ovarian"

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a must! JCO Podcast - Commentary: Low-Stage Ovarian Clear Cell Carcinoma: Population-Based Outcomes in British Columbia, Canada, With Evidence for a Survival Benefit As a Result of Irradiation

 Blogger's Opinion/Notes:

•  it is very worthwhile to listen to this podcast 
• radiation therapy in ovarian cancer has a very long history and in particular biases 
•  this podcast is a stunningly frank observation regarding clear cell ovarian cancer/radiation therapy, observation/s on the recent Hoskins clear cell report  including the issues of size of studies eg. clear cell ovarian cancer (in particular) has a low incidence rate and therefore, agreeably (mine) that this is a point/statistic which cannot be changed eg. rare cell types
•  this blog has many past posts over decades of research regarding radiation/irridation therapy in clear cell/ovarian cancer
• a blog/or otherwise search on this issue would be wise to understand the points being made in these two articles
• note also the Hoskins abstract regarding survival rates in clear cell ovarian cancer which, IMHO, have been widely ignored (stats issues) for decades (eg. early stage survival rates ~90% - popular stats quotes)

                                    ~~~~~~~~~~~~

JCO Podcast

Low-Stage Ovarian Clear Cell Carcinoma: Population-Based Outcomes in British Columbia, Canada, With Evidence for a Survival Benefit As a Result of Irradiation 


Users can play the podcast directly in the audio player embedded below. If Flash is disabled on your browser, you can save the file directly to your computer or open on your mobile device by clicking on "download file."

Management of Low Stage Ovarian Clear Cell Carcinoma
by Martin Gore


(Download file - duration 0:08:22, file size 7.69 MB)

science report: Treating cancer as a chronic disease? (study of clear cell ovarian cancer....)

Treating cancer as a chronic disease?

ScienceDaily (Mar. 29, 2012) — New research from the Technion-Israel Institute of Technology Rappaport Faculty of Medicine and Research Institute and the Rambam Medical Center may lead to the development of new methods for controlling the growth of cancer, and perhaps lead to treatments that will transform cancer from a lethal disease to a chronic, manageable one, similar to AIDS.............

".......For this study, the team took cells from one woman's ovarian clear cell carcinoma and injected them either into or alongside the human stem cell-derived environment. "We noticed very early on, rather strikingly, that the human cancer cells grow more robustly when they are in the teratoma environment compared to any other means in which we grew them, such as in a mouse muscle or under the skin of a mouse," says Skorecki.

The scientists were able to tease out six different kinds of self-renewing cells, based on behavior -- how quickly they grow, how aggressive they are, how they differentiate -- and on their molecular profile. This was a previously unknown finding, that one tumor might have such a diversity of cells with crucial fundamental growth properties. Tzukerman explains that the growth of the cancer cell subpopulations can now be explained by their proximity to the human cell environment.

The researchers cloned and expanded the six distinct cell populations and injected them into the human stem cell teratomas. One key observation is that some cells, which were not self-replicating in any other model, became self-replicating when exposed to the human cells.
Skorecki said that while he wasn't surprised that the human environment affected the growth, he was in fact surprised by the magnitude of the effect: "We've known for years now that cancers are complex organs, but I didn't think the power of the human stem cell environment would be so robust, that it would make such a big difference in how the cells were grown."........

open access: Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment (note comments re: clear cell ovarian)

"....Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications....."

"....The fact that BAF250a expression is lost in only a small percentage of endometrial CCC may suggest that ARID1A mutations plays a significant role in only a small proportion of CCC, or that these mutations represent only a small component of the genesis of this specific tumor type. It may also bolster the argument that endometrial CCC represents a phenotype that arises via a multitude of different pathways (3,7), with no one pathway being notably dominant. However, it is unclear if those clear cell carcinomas whose pathogenesis does involve ARID1A mutations, represents a clinicopathologically distinct group with definable characteristics."

Behind the Headlines - Can endometriosis guide cancer tests? | GPonline.com

abstract: Adjuvant Chemotherapy for Stage I Clear Cell Carcinoma of the Ovary: An Analysis of Fully Staged Patients

Adjuvant Chemotherapy for Stage I Clear Cell Carcinoma of the Ovary: An Analysis of Fully Staged Patients:

Objective: 

Although postoperative adjuvant chemotherapy is generally recommended for early-stage ovarian cancer, it remains unclear whether adjuvant chemotherapy is also effective for clear cell carcinoma (CCC).

Methods: 

Seventy-three patients with stage I CCC of the ovary who had undergone complete surgical staging formed the study population (stage IA, 20 patients; stage IC, 53 patients). Survival and multivariate analyses were retrospectively performed to determine the effectiveness of postoperative chemotherapy in these patients.

Results:

Of the total (73 patients), 30 patients received adjuvant chemotherapy (stage I C-positive), whereas 43 patients did not (stage I C-negative).

The 5-year progression-free survival (PFS) and 5-year overall survival (OS) rates for the stage I C-positive group were 80.1% and 87.4% compared with 73.9% and 81.7% for the stage I C-negative group.

The differences in survival between these groups were not significant (PFS: P = 0.610; OS: P = 0.557). Four of the patients with stage IA CCC underwent chemotherapy, whereas the remaining 16 patients received no additional therapy. No recurrence was observed in either group.

Of the patients with stage IC CCC, 26 patients underwent chemotherapy (stage IC C-positive) and 27 received no additional therapy (stage IC C-negative). There was no statistical difference in PFS and OS between the stage IC C-positive and stage IC C-negative groups.

Of the patients with stage IC without artificial rupture, the 5-year PFS rates of the C-positive and C-negative patients were 69.6% and 34.6%, respectively, but the 5-year OS rates were 75.0% and 70.0%, respectively (not significant).

Multivariate analyses confirmed that the presence or absence of adjuvant chemotherapy was not a prognostic indicator.

Conclusions:

The current study was performed only in fully staged patients, suggesting that postoperative adjuvant chemotherapy is not necessary for stage IA CCC patients.

For patients with stage IC CCC patients, adjuvant chemotherapy suppressed recurrence, but the effectiveness was insufficient in our limited study. Further studies are required to clarify this.

abstract: Prognostic determinants in patients with uterine and ovarian clear carcinoma

Highlights

► OCCC and UCCC have the same rate of localized disease, regional spread and distant metastasis.
► Endometriosis was frequently identified in patients with OCCC, but not in UCCC.
► After controlling for age, tumor extension, optimal cytoreduction, and platinum based chemotherapy; UCCC was not associated with decreased overall survival compared to OCCC.

abstract: Histological Grading of Ovarian Clear Cell Adenocarcinoma: Proposal for a Simple and Reproducible Grouping System - Intl Jnl Gyn Pathology

Blogger's Note: 'interesting' stat ranges between early/advanced clear cell ovarian cancers; read full abstract for more details (full access requires subscription $$$); some details deleted for ease of reading 

Abstract

"In this study, we aimed to develop a histological grading system for ovarian clear cell adenocarcinoma (CCA), based on the tumor growth architectures."

"The interobserver reproducibility and prognostic value of the assigned groups were analyzed for 159 CCAs from 5 institutions."

"In early-stage cases [International Federation of Gynecology and Obstetrics (FIGO) stage I–II], .....(survival rates 56-100%)

"In advanced cases (FIGO stage III–IV),.....(survival rates 16-52%)

"The proposed grouping system could divide patients with CCA into 3 subgroups with distinct prognostic indications, providing a 3-tier histological grading system for ovarian CCA."

abstract: (in mice) MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

Blogger's Note: in research (mice)

Abstract

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model.  
However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR

Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients