Saturday, January 28, 2012
abstract: Survival Benefit Associated With Surgical Oophorectomy in Patients With Colorectal Cancer Metastatic to the Ovary.
Best Pract Res Clin Obstet Gynaecol. 2012 Jan 24. [Epub ahead of print]
The incidence of epithelial ovarian cancer in women aged 40 years and younger is 3-17%. The management of these women is challenging and requires balancing the need to treat epithelial ovarian cancer adequately and preserving reproductive potential. Fertility-sparing surgery, especially for early stage epithelial ovarian cancer, seems to be associated with equivalent clinical and cancer outcomes while preserving reproductive potential. A complete staging and cytoreductive procedure retaining the uterus, and at least one grossly normal ovary, is the minimum recommended procedure. Adjuvant chemotherapy with a platinum-taxane combination is recommended as clinically indicated, and is associated with better cancer and survival outcomes. Adjuvant treatment does not seem to increase the risk of congenital anomalies in subsequent pregnancies. Targeted therapy and ovarian cryopreservation are largely experimental and cannot be recommended as part of the clinical standard of care.
Best Pract Res Clin Obstet Gynaecol. 2012 Jan 24. [Epub ahead of print]
AbstractThe overall increase in cancer prevalence and the significant increase in long-term survival have generated worldwide interest in preserving fertility in young women exposed to gonadotoxic chemo- and radiotherapy. Infertility represents one of the main long-term consequences of combination chemotherapy given for lymphoma, leukaemia and other malignancies in young women. The gonadotoxic effect of various chemotherapeutic agents is diverse, may involve a variety of pathophysiologic mechanisms, and is not unequivocally understood. Proliferating cells, such as in tissues with high turnover (i.e. bone marrow, gastrointestinal tract and growing ovarian follicles) are more vulnerable to the toxic effect of alkylating agents. These agents may also be cytotoxic to cells at rest, as they are not cell-cycle specific. Alkylating agents, the most gonadotoxic chemotherapeutic medications, cause dose-dependent, direct destruction of oocytes and follicular depletion, and may bring about cortical fibrosis and ovarian blood-vessel damage. The reported rate of premature ovarian failure after various diseases and chemotherapeutic protocols differ enormously, and depend mainly on the chemotherapeutic protocol used and age range of the woman.
Several options have been proposed for preserving female fertility, despite gonadotoxic chemotherapy: ovarian transposition, cryopreservation of embryos, unfertilised metaphase-II oocytes and ovarian tissue, and administration of gonadotropin-releasing hormone agonistic analogs in an attempt to decrease the gonadotoxic effects of chemotherapy by simulating a prepubertal hormonal milieu.
None of these methods is ideal and none guarantees future fertility in all survivors; therefore, a combination of methods is recommended for maximising women's chances of future fertility.
AbstractThe importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNPs) in inflammation-related genes and risk of ovarian cancer.
In a multi-site case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with p<0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) collaboration.
Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (heterogeneity p=0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk.
Thus, inherited variation in IL1A and ALOX5 appears to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
Correspondence: Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas' (includes stats on serous/endometrioid/clear cell/mucinous)
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Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas':
In a study involving a large series of epithelial ovarian carcinomas (EOCs), McCaughan et al1 reported human epidermal growth factor receptor 2 (HER2) protein overexpression and amplification in all major histological subtypes, an observation consistent with the literature.2 3 Specifically, they document HER2 gene amplification in 3.0% (7/259) of serous papillary carcinomas, 2.1% (2/92) of endometrioid carcinomas, 25.0% (3/12) of mucinous carcinomas, 4.0% (1/25) of clear cell carcinomas and 11.9% (7/60) of mixed type carcinomas. Although their number of mucinous carcinomas was low (n=12), the higher prevalence of HER2 gene amplification relative to the other histological subtypes is also consistent with the literature.4 5
We had previously reported similar findings of primary ovarian mucinous carcinomas having the highest prevalence of HER2 genomic amplification and protein overexpression among the various EOC histological subtypes and had proposed that ovarian mucinous carcinomas represent a...
abstract: Identification of Cancer Patients with Lynch Syndrome: Clinically Significant Discordances and Problems in Tissue-Based Mismatch Repair Testing
"In summary, concordance between immunohistochemistry and MSI was high, particularly for tumors that are microsatellite stable. Greater frequency of test discordance was identified in the tumors that were MSI-high. Thus, a major consequence of the use of immunohistochemistry by itself as a screen is the failure to identify colorectal and endometrial cancer patients who likely have Lynch syndrome. Cancer Prev Res; 5(2); 1–8. ©2011 AACR.
abstract: Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome
Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome:
The hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.
Objective and methods
To perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX and Lynch syndrome.
The morphological features associated with Lynch syndrome, that is, right-sided tumour location, poor differentiation, expansive growth pattern, tumour-infiltrating lymphocytes, peritumorous lymphocytes, Crohn-like reactions, and lack of dirty necrosis, were significantly less often observed in FCCTX tumours.
The less typical morphology in FCCTX implies that family history of cancer needs to be taken into account since these tumours cannot readily be recognised based on histopathological features.
CONCLUSIONS:While breast MRI surveillance did not have a detrimental psychological impact on women with a BRCA1 or BRCA2 mutation, recalling these very high-risk women for further imaging after a false positive MRI scan temporarily increased their global anxiety.
abstract: Prognostic Value of Biomarkers Related to Drug Resistance in Patients with Advanced Epithelial Ovarian Cancer
Prognostic Value of Biomarkers Related to Drug Resistance in Patients with Advanced Epithelial Ovarian Cancer:
We aimed to investigate the prognostic value of biomarkers [Ki-67, adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), adenosine triphosphate-binding cassette sub-family C member 1 (ABCC1), adenosine triphosphate-binding cassette sub-family C member 2 (ABCC2), p53, cyclin E and v-akt murine thymoma viral oncogene homolog 2 (AKT2)] in patients with advanced epithelial ovarian cancer (EOC).
Materials and Methods:
The levels of expression of biomarkers in tumor tissues of 47 patients with stage 3 or 4 EOC were estimated via immunohistochemical staining using tissue microarrays. The associations of biomarker expression with progression-free survival (PFS) and overall survival (OS) were evaluated using a log-rank test and Cox regression analysis.
Based on multivariate analysis, high expression of Ki-67 (p=0.003) and low expression of ABCC2 (p=0.048) were associated with a prolonged PFS. However, other biomarkers were not associated with PFS. Residual tumor <1 cm (p=0.023) and PFS >6 months (p=0.005) were associated with prolonged OS. However, none of the biomarkers were associated with OS.
Conclusion: High expression of Ki-67 and low expression of ABCC2 appear to be useful as markers for prolonged PFS in patients with advanced EOC.
abstract: Tumor Interstitial Fluid as Modulator of Cancer Inflammation, Thrombosis, Immunity and Angiogenesis
Tumor Interstitial Fluid as Modulator of Cancer Inflammation, Thrombosis, Immunity and Angiogenesis:
Tumor interstitial fluid (TIF) is a watery phase that accumulates inside the tumor interstitium. Its genesis and fate depend on various factors, namely tumor type, metabolic state of the tumor, expression of vascular endothelial growth factor, and absence of lymphatic system. For almost 30 years TIF remained a neglected entity until it was demonstrated that TIF, and in particular its high pressure, constitutes an important obstacle to drug delivery and immunotherapy. The present review not only summarizes the abundant literature on the processes of TIF genesis and on its effects on therapy but it also presents data that, in our opinion, point towards what is perhaps the real physiological purpose of TIF: a primitive means of providing nourishment, oxygen, cytokines and matrikines to tumor cells that furthermore promotes the invasion of the normal surrounding tissue and passive metastatization through lymphatics. It is also an inducer of inflammation through increased osmolarity due to albumin loss. Recently, a role for TIF as a possible source of biomarkers has also been suggested.
The Surprise Question
"We turn to the problem of uncertainty and its impact on providing information. Recently, investigators have studied the “surprise” question, an interesting approach to making better survival predictions. The approach is somewhat ironic because although the question is subjective in nature, it tends to produce a good objective response. When physicians are asked to judge survival time, they tend to be inaccurate even when using the best prognostication information, including comorbidities, staging, advance directive status and whether the cancer has metastasized.
However, a recent study revealed that physicians are more accurate when they answer the surprise question: “Would I be surprised if this patient died in the next year?” A negative answer indicates an expectation of death within a year, whereas an affirmative answer indicates the physician’s gut response that the patient is highly likely to be alive within a year.1 In a study of 826 cancer patients, an affirmative answer proved “correct” in 97% of the responses; almost all of the patients with a “yes” response to the question were alive within a year......"
Comparing Poly (ADP–Ribose) Polymerase Inhibitors With Standard Chemotherapy in BRCA-Mutated, Recurrent Ovarian Cancer: Lessons Learned From a Negative Trial (Olaparib)
"...Thus, although the study by Kaye et al11 does not show a clear advantage of olaparib compared with PLD, it is noteworthy for what it teaches us about the difficulties in performing and interpreting the results of randomized trials that involve this promising class of new agents in patients with recurrent EOC."
JCO Editorial: (pdf) + link to original article abstract - Tumor Genetic Testing for Patient Selection in Phase I Clinical Trials (breast, cervical, endometrial, ovarian) : The Case of PI3K Inhibitors
"On the basis of these considerations, with mTOR and pan-PI3K
inhibitors we might need to cast a wider net and study patients with
mutations of the target gene(s) within the pathway, as well as those
without such mutations, until a stronger predictive relationship
emerges. Regardless, the availability of tumor samples should be mandatory,
and, in those cases with demonstrated clinical responses, we
should be ready to embark in deep sequencing analysis in order to
identify potential mutations indicative of sensitivity to the agents
abstract: original article:
PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring PIK3CA Mutations
JCO Editorial: Moving Beyond Anti–Vascular Endothelial Growth Factor Therapy in Ovarian Cancer (Avastin,AMG-386)
"The drugmaker then said that its investigational compound olaparib would not progress into Phase III development for the maintenance treatment of serous ovarian cancer. Additionally, attempts to identify a suitable tablet dose for use in Phase III studies were not successful."