PET in women with high risk for breast or ovarian cancer : The Lancet Oncology

Summary

Data on the use of PET in women with genetic or familial high-risk for breast or ovarian cancer are scarce.

Open issues include the complementary use of dedicated breast-PET scanners in patients at high-risk for breast cancer, the relation between pathological characteristics of cancer diagnosed in BRCA carriers and 18F-fluorodeoxyglucose (18F-FDG)-avidity, and the predictive value of PET in patients at high-risk for ovarian cancer presenting with a pelvic mass or potential chemical markers. Therefore, the use of PET in high-risk patients with unproven malignant disease needs to be investigated in well designed clinical trials.

Once breast or ovarian cancer is diagnosed, indications for 18F-FDG-PET or PET—CT imaging are similar for high-risk patients and patients with sporadic cancer. However, PET can provide data that are beyond tumour detection per se. Future directions of PET in high-risk patients might include monitoring the response of BRCA carriers to new treatments such as poly-ADP ribose polymerase (PARP) inhibitors, personalisation of treatment, and the use of new PET tracers to investigate the tissue changes related to increased risk for breast and ovarian cancer.

full free access: Biomarkers in Medicine - The dire need to develop a clinically validated screening method for the detection of early-stage ovarian

Note:  I remember the LPA very well (breakthrough screening test for ovarian cancer and the resulting media hype extraordinaire)

Key Excerpts:
Multiple initiatives have been undertaken to discover strategies that detect and diagnose early-stage EOC, including the search for novel serum biomarkers and the development of new technologies, such as contrast-enhanced ultrasonography, with a number of them demonstrating hopeful results. The ideal screening test for ovarian cancer would be a simple measurement of biomolecules in bodily fluids, such as blood, serum or urine, whose absolute concentrations could differentiate cancer from noncancer and be organ specific. In the last decade, insights into the EOC microenvironment, as well as technological advances, such as microarrays and proteomics, have triggered the discovery of hundreds of potential clinically valuable biomarkers:


▪ Lysophosphatidic acid (LPA) is a phospholipid derivative consisting of a glycerol backbone, a single fatty acid chain and a free phosphate group. LPA has a variety of isoforms depending on fatty acid-chain variability at the sn-1 position. LPA was found to be elevated in the serum, plasma and malignant effusions of women with ovarian cancer and has known functions in cell proliferation, invasion and angiogenesis [3]. This molecule initially became of interest in 1998 for its reported high sensitivity and specificity to detect early-stage ovarian cancer [3]; however, its utility as a screening biomarker has been limited owing to the difficulty of isolating and detecting the different isoforms in patients’ serum and its specificity for ovarian cancer;


▪ Human epididymal protein (HE)4 is a relatively new biomarker used to monitor disease recurrence and disease progression in patients with ovarian cancer. It is the product of the WFDC2 (HE4) gene, which is overexpressed in ovarian cancer. HE4 has exhibited increased sensitivity to detect stage I disease [4] and has demonstrated promise as a sensitive and specific biomarker when combined with CA125 and other molecules [5]; although, more studies remain to be done to warrant its use as a biomarker for the detection of early-stage EOC;


▪ Osteopontin (OPN) is a glycoprotein involved in cell adhesion, inflammation and tumorigenesis, with elevated levels seen in ovarian cancer [6]. Similar to HE4, OPN has been used in combination assays to identify ovarian cancer [7]; however, OPN is also elevated in other cancers and benign conditions, limiting its specificity to be used as an ovarian cancer biomarker;


▪ Kallikreins (KLKs) are serine proteases that function in cell growth, angiogenesis and invasion. KLKs are elevated in patient serum with ovarian cancer. KLK8 was reported to be associated with early disease, while KLK5, -6, -10 and -13 have been combined with CA125 to improve the accuracy of ovarian cancer detection [8,9];


▪ Claudins are components of tight junctions that create selective barriers and maintain cell polarity. Multiple claudins have been found to be elevated in ovarian cancer; however, their specificity has yet to be determined and verified [10].

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Of particular note, traditional genetic pedigree analysis of ovarian cancer patients may provide information to help identify high-risk populations; for example, inherited BRCA1 and -2 mutations  increase the risk for women to develop ovarian and/or breast cancer [12]. In addition, molecular profiling at the epigenetic level, such as miRNA profiling, may allow for the identification of novel biomarkers for early detection of ovarian cancer, given that these epigenetic changes might be detectable before the development of the physical tumor.
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Despite these advances, at present, no clinically validated screening protocol for the detection of early-stage EOC exists. The discovery of novel biomarkers relies on obtaining a better understanding of the initiation and progression of EOC. Clinical validation and implementation of biomarkers will also benefit from advancements in new molecular and imaging technologies as patient care is optimized. Fortunately, hundreds of biomarkers have been identified; however, their clinical utility remains to be determined. In addition, the enhanced imaging capabilities of the ovary by ultrasound are providing practitioners with the ability to more accurately and precisely identify changes specific to the newly transformed ovary. The combination of these two modalities, biomarker panels and biologically based imaging may be the future. Therefore, we must forge ahead to develop a validated early-detection protocol that will not only decrease the number of advanced-stage diagnoses and deaths attributed to ovarian cancer but, most importantly, positively impact the future of women’s healthcare.

NCI Cancer Bulletin for May 18, 2010 - SPECIAL ISSUE

Additional Clinical Trials Resources

Cancer Clinical Trials at NIH

NCI supports cancer clinical trials across the country (U.S) through its extramural research program. Meanwhile, on NIH’s main campus, the Institute’s intramural researchers in the Center for Cancer Research (CCR) conduct hundreds of trials each year at the NIH Clinical Center in Bethesda, MD, and these trials often differ from those available elsewhere.
While some cancer centers also offer early-stage clinical trials, the difference is that CCR focuses almost exclusively on early-stage trials, said Dr. Bill Dahut, CCR’s clinical director.

NCI’s intramural program is able to pay the transportation costs for patients who are enrolled in Clinical Center trials. This allows CCR to see many more patients with rare cancers, or rare subtypes of common cancers, than other research sites because CCR can fly in patients from around the country to be treated in investigational studies.

One commonly cited barrier to entering clinical trials is the worry among both patients and their physicians of losing control. “An important point about treatment at NCI is that everything we do here for patients is done in close collaboration with their local physicians back home,” Dr. Dahut explained. “Our physicians provide expert clinical care to patients while they are being treated on protocol at NCI, but our physicians can see patients only while they are at the Clinical Center. Thus, continued care by local physicians is incredibly important to allow patients to access standard treatments or other trials not available here. Local physicians must remain closely involved with patients on NCI studies because side effects, from the cancer or the therapy, may occur when the patient is home and far from Bethesda.”

Patients and physicians interested in exploring cancer clinical trials at NIH can visit CCR’s clinical trials Web site. The site includes detailed descriptions of clinical trials currently recruiting patients; information for the general public about clinical trials and participating in trials at NCI; and information for health professionals about referring patients, the Center’s clinical programs and investigators, and ways to keep up to date with CCR research and opportunities.

“We’d really like to encourage physicians to join our mailing list,” said Susan McMullen, patient outreach and recruitment coordinator for CCR’s Office of the Clinical Director.  “One of the barriers to recruiting patients at NIH is that our doctors don’t have a patient base outside of clinical trials to draw from, so we rely on community doctors to refer patients to us.”

Family Cancer Registries

For some families, the tragedy and sorrow of losing a relative to cancer is repeated as family member after family member is diagnosed with the same disease.
To determine what genetic factors may be at work and how environmental influences alter those genetic risks, researchers rely on those affected by familial cancer to participate in family cancer registries.

“Our major goal in studying these families is to identify what are called high-risk susceptibility genes,” explained Dr. Peggy Tucker, director of the Human Genetics Program and chief of the Genetic Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “We then try to understand the function of those genes, how they confer risk, and what other factors within the family modify risk.

“Ultimately, we want to be able to alter the risk of cancer in these families either by identifying susceptibility factors we can modify—for example, avoiding sun exposure in melanoma families—or designing interventions that can affect risk—such as prophylactic oophorectomy for women in families with high risk of both breast and ovarian cancer,” she said.

Family cancer registry studies can also help inform researchers about cancer susceptibility risks in the general population. For example, researchers identified dysplastic nevi as a major risk factor for melanoma by studying families at high risk of melanoma.

Researchers at NCI first began conducting family registry studies in the mid-1960s. These long-term studies follow families through successive generations, and allow researchers to examine the role of inherited high-susceptibility genes and cancer. Today, DCEG researchers are studying families with a number of inherited cancers or cancer-susceptibility syndromes, and researchers in NCI’s Division of Cancer Control and Population Sciences (DCCPS) sponsor the Breast and Colon Cancer Family Registries.

Whereas DCEG’s family registries are conducted at the NIH Clinical Center, the family registries based in DCCPS are found throughout the United States, Australia, and Canada. “Currently, we have about 78,000 men and women from nearly 26,000 families participating in these registries,” said Dr. Sheri Schully, program officer for the DCCPS family registries program. “The main objective of these registries is to identify and characterize cancer susceptibility genes, but the investigators also look at gene–gene and gene–environment interactions as well.”

Although family registry studies do not provide treatment to participating families, investigators often provide test results that can help family members learn which of them may be at higher risk because of certain susceptibility genes, such as mutations in the BRCA1 and BRCA2 genes or those associated with Lynch syndrome, said Dr. Schully.
Additionally, the studies are an opportunity for people who are often desperate for answers to ask questions.

“We like to think it’s a positive experience for them because they have a whole day at NIH to meet with physicians and nurses who know a lot about the disease,” Dr. Tucker explained. “We try to keep them updated with new findings about the diagnosis and management of the cancer that affects their family, and they know they can always come to us for referrals for care of the disorders that we’re studying.”

Learn More About Clinical Trial Enrollment....

A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects -- Gut

Postoperative Pulmonary Embolism Including Asymptomatic Case... : International Journal of Gynecological Cancer

Conclusions: A substantial number of postoperative PEs were occult, and identification of high-risk patients and routine SpO₂ level monitoring would reduce the diagnostic delay of PE after gynecologic surgery. Increasing age, longer operation time, and obesity were risks. The use of a perioperative intermittent pneumatic compression device in multimodal conditions might thus prevent PE. (pulmonary embolism/blood clot)

full free access: Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study

Note: the full access to this publication is available for free; professional comments included CONCLUSION: The risk of deep vein thrombosis and pulmonary embolism after surgery is substantially increased in the first 12 postoperative weeks, and varies considerably by type of surgery.

BRCA1 185delAG mutant protein, BRAt, up-regulates Maspin in ovarian epithelial cells

"Consequently, understanding early genotypic and phenotypic changes in the context of high risk disease may provide a better understanding of the mechanism of mutation-associated ovarian cancer and provide new targets for therapeutic intervention."

Risk factors for reproductive and breast cancers among older lesbians.

Note: the term 'older' in the study was >40 yrs

Abstract/full free access: Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada

excerpts of interest:

Improving the Quality of Colorectal Cancer Screening: Assessment of Familial Risk.

"Many patients reporting a known familial cancer syndrome or a very strong family history did not have that history indicated on the endoscopist's procedure form, and recommended follow-up intervals were beyond guideline recommendations for 60.4% of the very high-risk group."