Expression of DNA repair genes in ovarian cancer samples: Biological and clinical considerations

Abstract

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas.  


ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis.

With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

Prognostic Significance of Splenectomy as Part of Initial Cytoreductive Surgery in Ovarian Cancer

Note:  a similar paper regarding splenectomy - posted on this blog Sept 6, 2010




PURPOSE: 
 We sought to examine how splenectomy as part of up-front cytoreductive surgery in ovarian cancer influences the postoperative course and affects survival.

CONCLUSIONS: 
 The addition of splenectomy to up-front cytoreductive surgery was feasible and safe. However, it appears to carry with it a shortened survival that is unrelated to postoperative morbidity. Our data raise the questions that splenectomy is needed for optimal cytoreduction in more biologically aggressive disease and that splenectomy may be an independent prognostic factor related to depressed immune function.

full free access (pdf): Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations

OBJECTIVES: Previous studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for "survival bias" by minimizing lead time that may exist between diagnosis and genetic testing.
CONCLUSIONS: This multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the "survival bias" that coincides with genetic testing.

Nuclear P27 (gene) expression in benign, borderline (LMP) and invasive tumors of the ovary and its association with prognosis: A GOG group study

Abstract

Objective

Nuclear p27 expression was examined in non-invasive and invasive ovarian tumors from a cross-sectional study, and clinical relevance of p27 was evaluated in the primary tumors from women participating in two randomized phase III treatment trials.

Methods

An immunohistochemistry assay was used to detect p27 in formalin-fixed paraffin-embedded ovarian tumors from 3 distinct sources.

Research Highlights

► Low p27 expression is associated with malignant transformation of the ovary.
► A cyclin E to p27 ratio > 1.0 may be associated with shorter survival.
► Study required confirming increased recurrences with low p27 in early stage patients.

Health-related quality of life and cancer clinical trials — Therapeutic Advances in Medical Oncology

"...Health-related quality of life has become a more accurate predictor of survival than some other clinical parameters, such as performance status. The overall outlook for the routine assessment of patient-reported outcomes in clinical trials is assured and, eventually, it is likely to become a standard part of clinical practice. ...."

abstract: Role of adjuvant radiotherapy in granulosa cell tumors of the ovary

PURPOSE: To review the role of adjuvant radiotherapy (RT) in the outcome and recurrence patterns of granulosa cell tumors (GCTs) of the ovary.

CONCLUSION: Ovarian GCTs can be indolent, with patients achieving long-term survival. In our series, adjuvant RT resulted in a significantly longer DFS. Ideally, randomized trials with long-term follow-up are needed to define the role of adjuvant RT for ovarian GCTs.

Commentary: Early versus delayed treatment of relapsed ovarian cancer : The Lancet (re: Rustin trial early vs delayed treatments/survival)

free full access: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients — Ann Oncol

Medical News:video (Dr Coleman) Similar Survival with Two Ovarian Cancer Strategies - in Oncology/Hematology, Ovarian Cancer from MedPage Today

"Patients with bulky, advanced ovarian cancer survived just as long whether treated with neoadjuvant chemotherapy and surgery or with primary surgery followed by adjuvant chemotherapy, investigators in a multinational trial reported."

"Subgroup analysis failed to identify any patient or tumor characteristics associated with better outcomes with one treatment strategy or the other. In both treatment groups, the success of cytoreductive surgery was the strongest predictor of survival."

Action Points

* Explain to interested patients that according to a recent randomized study, patients with bulky, advanced ovarian cancer survived just as long whether treated with neoadjuvant chemotherapy and surgery or with primary surgery followed by adjuvant chemotherapy


* Explain that both treatment strategies led to a median overall survival of about 30 months and median progression-free survival of 12 months.


Original Article
Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer - NEJM

The National Cancer Database report on advanced-stage epithelial ovarian cancer: Impact of hospital surgical case volume on overall survival and surgical treatment paradigm (abstract)

Objective

To examine the effect of hospital procedure volume and other prognostic variables on overall survival outcome and likelihood of receiving standard recommended care among patients with advanced-stage epithelial ovarian cancer.

Conclusions

Hospital ovarian cancer surgical volume ≥ 21 cases/year is associated with a higher likelihood of patients with Stage IIIC/IV epithelial ovarian cancer receiving standard treatment (surgery followed by adjuvant chemotherapy). Even after adjusting for treatment paradigm and other factors, hospital volume ≥ 21 cases/year was significantly predictive of improved overall survival outcome.

Prognostic Relevance of Uncommon Ovarian Histology (abstract) multinational study

 Note:   and stage 1/11??;  see abstract for authors

Prognostic Relevance of Uncommon Ovarian Histology in Women With Stage III/IV Epithelial Ovarian Cancer.

BACKGROUND::
The prognostic relevance of uncommon epithelial ovarian cancer (EOC) histological subtypes remains controversial. The Gynecologic Cancer InterGroup (GCIG) initiated this meta-analysis to assess the relative prognosis of women with a diagnosis of rare EOC histologies from completed, prospectively randomized studies performed by cooperative GCIG study groups.

METHODS::
Studies eligible for analysis included first-line treatment of at least 150 patients with stage III/IV EOC treated with a platinum/taxane-based regimen. Collaborating groups were to provide patient-level data. Serous acted as the reference histology, and a proportional hazards model was used to estimate the relative rate of progression or death.

RESULTS::
Data on 8704 women with stage III/IV EOC from 7 randomized trials were included in these analyses. Two hundred twenty-one patients (2.5%) had clear cell carcinoma; 264 (3.0%), mucinous; and 36 (0.4%), transitional cell. The mean age of patients with serous histology was greater than those with mucinous (4.1 years) and clear cell (2.6 years, P < 0.001). Mucinous, clear cell, and transitional cell tumors were more likely to be completely resected than serous (P < 0.05). When controlling for age and residual disease, mucinous and clear cell tumors had shorter times to progression (hazards ratio [HR], 2.1; 95% confidence interval [CI], 1.8-2.4 and HR, 1.6; 95% CI, 1.4-1.9, respectively) and death (HR, 2.7; 95% CI, 2.3-3.1 and HR, 2.2; 95% CI, 1.8-2.6, respectively) compared with serous. The median overall survival for serous, clear cell, mucinous, and endometrioid histologies were 40.8, 21.3, 14.6, and 50.9 months.

CONCLUSIONS:: Mucinous and clear cell carcinomas are independent predictors of poor prognosis in stage III/IV EOC. Studies targeting these rare histological subtypes are warranted and will require significant intergroup collaboration.

Survival benefit from ovarian metastatectomy in colorectal cancer patients with ovarian metastasis: a retrospective analysis

Abstract

PURPOSE: A recent study demonstrated that colorectal cancer (CRC) with ovarian metastases was less responsive to chemotherapy compared with extraovarian metastases. Hence, the ovary may actually represent a "sanctuary" for metastatic cells from CRC. The aim of the study was to investigate the impact of ovarian metastatectomy on survival of CRC patients with ovarian metastasis.

The role of cytoreductive surgery for non-genital tract metastatic tumors to the ovaries.

Abstract


OBJECTIVE: The aim of this study was to investigate prognostic factors of patients with metastases to the ovaries from non-genital organs.
STUDY DESIGN: From September 1994 to December 2006, 158 patients with pathologically confirmed metastatic tumors to the ovaries at Samsung Medical Center (SMC) were included in this study. The data were obtained from the patients' medical records and pathology reports.
RESULTS: The primary tumor origin was mostly stomach (73 cases) and colon (61 cases). Krukenberg tumor (pathologically proven signet ring cell carcinoma) was found in 34 cases: stomach (25), colon (2), appendix (1), and unknown (6). ....However, age, bilateral tumors, chronology of diagnosis and mass size did not affect survival.
CONCLUSION: Cytoreductive surgery and post-operative adjuvant chemotherapy had a beneficial effect on survival in selected patients.

Systematic Lymphadenectomy for Survival in Epithelial Ovarian Cancer: A Meta-Analysis

Note: also see post of Dr Maurie Markman (blogger dat May 4th) for Editorial on this particular subject matter

Conclusions: These findings suggest the possibility that SL can improve OS in advanced-stage EOC. However, the efficacy of SL on OS is still unknown because of the lack of RCTs, which requires more relevant studies for investigating the role of SL in EOC

from the series The Art of Oncology: "Certain Death in Uncertain Time: Informing Hope by Quantifying a Best Case Scenario"

Note: Stephen Gould's writings were extraordinarily popular died in 2002)

"Research informs us that the majority of patients with metastatic cancer desire information about their likely survival duration. The literature also recommends that prognostic information be communicated to those who request it in a manner that is meaningful and realistic, but maintains hope.....The following edited extract from Edward Kennedy’s memoir (and others) conveys the importance of trying to answer these questions....."

"...But I wasn’t willing to accept the doctor’s prognosis for two reasons. The first was my own obstinate will to carry on in the face of adversity, one of the many habits of discipline that my father instilled in me…. The second was the way the message was delivered. Frankly, it made me furious. I am a realist, and I have heard bad news in my life. I don’t expect or need to be treated with kid gloves. But I do believe in hope...."

"....As Stephen Gould published 3 years after reading that his median survival with abdominal mesothelioma was 8 months, “the median isn’t the message.”7 He argued that median survival can be both misleading and discouraging and believed few people have sufficient understanding of statistics to evaluate what the term median
really means....."

Surveillance for the detection of recurrent ovarian cancer: Survival impact or lead-time bias?

Objective

To compare the survival impact of diagnosing recurrent disease by routine surveillance testing versus clinical symptomatology in patients with recurrent epithelial ovarian cancer (EOC) who have achieved a complete response following primary therapy.

Commentary: Estimating cancer survival--which is the right approach? -- Rachet and Coleman 39 (2): 611 -- International Journal of Epidemiology

Note: full paper requires paid subscription
"Cancer survival has become a key metric to assess the performance of health systems in delivering cancer care, both as part of national cancer programmes and in international comparisons. In this context, we need to know the survival of all cancer patients in the population, not just patients treated in a particular hospital or included in a clinical trial. Population-based survival estimates include all patients, including those who are not treated at all, either because their disease is too advanced at diagnosis for treatment of curative intent, or because they do not have access to the health-care system, or, in some countries, because of resource limitations such as the . . ."

Trends in the survival of patients diagnosed with cancer in female genital organs in the Nordic countries 1964-2003 followed up to the end of 2006

Doubling time of serum CA125 is an independent prognostic factor for survival in patients with (early stage) ovarian cancer relapsing after first-line chemotherapy

"There is a lack of data in early-stage ovarian cancer on the pattern of CA-125," said Chan. "Previous studies generally had no comprehensive staging and no central pathology review."
The Gynecologic Oncology Group (GOG) 157 trial provided an opportunity to examine the change in CA-125 and its relationship to outcomes in women with early-stage ovarian cancer. The trial involved 427 women with stage I-II epithelial ovarian cancer. They were randomized to receive three or six cycles of chemotherapy with carboplatin and paclitaxel.
All patients had detailed surgical staging before randomization. Chan said detailed information about CA-125 levels was available for 350 participants in the trial.

Editorial: Diet and Survival after Ovarian Cancer: Where Are We and What's Next?

  Note: pay-per-view

Journal of the American Dietetic Association
Volume 110, Issue 3, March 2010, Pages 366-368

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Research

Diet and Survival after Ovarian Cancer: Where Are We and What's Next?

Cynthia A. Thomson PhD, RD, CSO and David S. Alberts MD

Article Outline

The Problem

Diet and Survival

Weight Gain a Subsequent Risk

Time to Fill the Research Gaps

Acknowledgements

References

Vitae