Frequent, Personalized CA125 Testing May Help Detect Ovarian Cancer In High-Risk Women

Frequent, Personalized CA125 Testing May Help Detect Ovarian Cancer In High-Risk WomenThe combined results of two ovarian cancer screening trials suggest that a personalized strategy involving frequent screening of high-risk women could improve the chance that tumors are detected at early stages when they are easier to treat. As reported in a paper published in Clinical Cancer Research, these trials imply that a protocol involving quarterly blood test to identify significant increases above each patient’s personal baseline in levels of the protein CA125, followed by ultrasound examination when such elevations are detected, could reduce the risk of diagnosis with advanced cancer in high-risk women who choose to delay recommended preventive surgery.

“The standard advice for women at high risk of ovarian cancer, due to either family history or inherited gene mutations, is to have their ovaries and fallopian tubes removed once their families are complete. Some women choose to postpone this surgery,” says Steven Skates, PhD, of the Massachusetts General Hospital (MGH) Cancer Center and the Biostatistics Unit, co-lead and corresponding author of the report. “Our screening protocol increased the proportion of tumors detected at early stages from 10 percent – which is typically seen in high-risk women who are not screened – to 50 percent.”

CA125 levels are known to be raised over the level of 35 in the blood of most women with ovarian cancer. While screening for raised CA125 and/or transvaginal ultrasound may be considered for high-risk women who postpone surgery, that approach has not been shown to improve patient outcomes.

The two trials reported in the current paper utilize the Risk of Ovarian Cancer Algorithm (ROCA) – co-developed by Skates and Ian Jacobs, MD, FRCOG, of the University of New South Wales in Australia and University College London – which tracks CA125 levels over time to identify significant elevations above each patient’s baseline levels, even those that do not exceed the traditional threshold of 35. One trial conducted through the National Cancer Institute’s Cancer Genetics Network (CGN) – with additional patients from two ovarian Specialized Programs of Research Excellence (SPORE) and two Early Detection Research Network sites (EDRN) – was led by Skates. The other, conducted through the Gynecologic Oncology Group (GOG), was led by Mark H. Greene, MD, of the Clinical Genetics Branch at the National Cancer Institute (NCI).

Both trials followed similar protocols, enrolling women at elevated risk for ovarian cancer – based on either a strong family history of ovarian and/or breast cancer or the presence in the patient or in close blood relatives of risk-associated mutations in the BRCA1 or BRCA2 genes – who had not yet had risk-reducing surgery. Participants had CA125 blood tests utilizing ROCA every three months, compared with screening for raised CA125 values every 6 or 12 months as in previous screening studies. The investigators calculated a patient’s ROCA risk by analyzing the results of each new CA125 test, combined with previous results, and factors such as participant’s age and menopausal status.

Women at intermediate ROCA risk were referred for an ultrasound examination, while those at an elevated ROCA risk received both ultrasound and clinical evaluation by either a gynecologic oncologist or the site principal investigator. While the results of those examinations were used to guide decisions about surgical treatment, study participants were free to choose to have their ovaries and fallopian tubes removed at any time during the clinical trials, as is standard practice for women with a BRCA1/2 mutation.

Between 2001 and 2011, the CGN trial enrolled 2,359 women at 25 U.S. sites. The GOG trial enrolled 1,459 women at 112 sites in the U.S. and Australia between 2003 and 2006 and screened them for five years. Among the more than 3,800 participants in both studies, 19 malignant tumors of the ovaries or fallopian tubes were identified during the study periods. Ten cases were diagnosed during screening, and nine were diagnosed by preventive surgery.

Of the ten cases, there was evidence that four were present at the outset of the trial, while six tumors were likely to have developed during the trial period after a CA125 baseline had been measured. While the algorithm can calculate risk without a baseline, ROCA works best when a baseline has been established. The results in these six cases reflect the benefits of a long-term ROCA screening program; all but one were diagnosed by ROCA, giving a sensitivity of over 80 percent ,and 50 percent were detected at early stages.

Another study – the UK Familial Ovarian Cancer Screening Study, led by ROCA co-developer Jacobs and published today in the Journal of Clinical Oncology – found that a similar protocol using ROCA-based testing every four months was also better than current practice at diagnosing early-stage tumors in high-risk women. Skates notes that a formal analysis of the data from all three trials could increase the statistical power of these studies and could lend stronger support to recommending frequent ROCA-based screening for high-risk women who choose to postpone surgery or while waiting for surgery.

While the pattern of cancers detected in these studies supported the potential value of ROCA screening, these studies were not designed to assess whether screening reduced deaths due to ovarian cancer, the authors note. “It is important to note that removal of ovaries and fallopian tubes remains the standard of care when women at increased familial or genetic risk complete their families and reach an age when their risk exceeds that of the general population,” stresses Skates, who is an associate professor of Medicine at Harvard Medical School.

Adds Greene, who is a senior principal investigator at the NCI, “Surgery is the primary and best option for reducing the risk of ovarian cancer, and ROCA should only be considered as a promising but unproven option for patients who decide, against medical advice, to postpone their surgery.” Both investigators note that further research to identify a greater range of ovarian cancer biomarkers and improved imaging technologies is needed to help detect even more tumors at even earlier stages. Skates is leading a program to discover new biomarkers for early detection of ovarian cancer as part of NCI’s Early Detection Research Network.

Skates and Greene are co-lead authors of the Clinical Cancer Research report; and Dianne Finkelstein, PhD, MGH Biostatistics, and Karen Lu, MD, M.D. Anderson Cancer Center, are co-senior authors. Support for the study includes multiple grants from the National Cancer Institute to the Cancer Genetics Network, the Specialized Programs of Research Excellence, and the Early Detection Research Network, and support from the NCI Intramural Research Program.

To read the full press release on EurekAlert!, please click here.

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Antibody-Drug Conjugate Under Study in Platinum-Resistant Ovarian Cancer

Antibody-Drug Conjugate Under Study in Platinum-Resistant Ovarian CancerA novel targeted therapy, mirvetuximab soravtansine (IMGN853), is being investigated as a single-agent treatment for patients with advanced, platinum-resistant epithelial ovarian cancer with medium and high expression levels of folate receptor–alpha (FR-alpha) in an effort to provide an effective option for a population facing a difficult prognosis.

The phase III FORWARD I trial, which is currently enrolling patients, is seeking to randomize 333 women in a 2:1 ratio to either the experimental mirvetuximab soravtansine arm or to chemotherapy consisting of investigator’s choice of paclitaxel, pegylated liposomal doxorubicin, or topotecan (NCT02631876). If successful, the novel drug would offer an alternative to patients who have not responded to platinum therapy and possibly to individuals who have become resistant to chemotherapy.1

“This is a bold initiative to try and bring what we think is a very active drug to market for patients who desperately need therapies,” said Kathleen N. Moore, MD, a co-principal investigator on the study. “It’s an exciting trial, and we’re hoping for it to accrue quickly, so that we can get this drug to people who need it.”

Mirvetuximab soravtansine is an antibody–drug conjugate that targets FR-alpha, a cell-surface glycoprotein found on approximately 80% of epithelial ovarian cancer tumors; overexpression of receptor levels may be associated with negative outcomes in patients treated with chemotherapy.

Mirvetuximab Soravtansine in Ovarian Cancer 
Phase III FORWARD I Trial

The drug consists of a monoclonal antibody that binds to the FR-alpha receptor and is linked to a tubulin-disrupting maytansinoid DM4 chemotherapy that is delivered directly into the tumor cell. Patients with platinum-resistant ovarian cancer, defined as disease progression within 6 months of treatment with a platinum-containing therapy, have a poor prognosis. In the primary setting, the response rate to subsequent therapies is less than 20%, and in the acquired resistance setting, median overall survival is 21.9 months.1

Mirvetuximab soravtansine “would give another option for standard of care, and it would introduce another drug for patients with platinum-resistant disease where there’s not much that works well at this point,” said Moore, who is associate director for clinical research and director of the TSET Phase I Drug Development Unit at the Stephenson Cancer Center in Oklahoma. “It would give another line of therapy that really has a very well-tolerated safety profile.”

Strong Early Phase Findings

The drug has demonstrated encouraging activity in patients with platinum-resistant epithelial ovarian cancer.2 In 1 study, patients with 1 to 3 lines of prior therapy and medium or high FR-alpha expression (n = 16)—the same subset eligible for the FORWARD I study—the objective response rate (ORR) was 44%, with a progression-free survival (PFS) of 6.7 months and a duration of response (DOR) of 26.1 weeks. In a phase I expansion study, mirvetuximab soravtansine demonstrated a confirmed ORR of 26% among 46 patients with FR-alpha–positive platinum- resistant ovarian cancer, including 1 complete and 11 partial responses.

The median PFS was 4.8 months and the median duration of response was 19.1 weeks.1 Notably, patients who had received 3 or fewer prior lines of therapy (n = 23), had an ORR of 39%, a median PFS of 6.7 months, and a median DOR of 19.6 weeks.1

FR-alpha expression was determined by immunohistochemistry (IHC) testing on archival tissue, with samples categorized as: low, 25% to 49% of tumor cells with ≥2+ staining intensity; medium, 50% to 74% of cells with ≥2+ intensity; or high, ≥75% of cells with ≥2+ intensity. Although most patients experienced tumor shrinkage regardless of FR-alpha expression level, participants with medium and high scores were more likely to respond, with median ORR rates of 28.6% (95% CI, 8.4-58.1) and 26.1% (95% CI, 10.2- 48.4), respectively.

Adverse events (AEs) in the phase I trial were generally mild (grade 2 or lower), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed all-grade treatment-related toxicities. Grade 3 fatigue and hypotension were reported in 2 patients each (4%).1 There has been some reported neuropathy, according to Moore, but it has been seen in less than 10% of patients, and there is no reported alopecia compared with standard chemotherapy.

Similar AEs are expected during the FORWARD I trial, and investigators will be counseling patients about diarrhea and administering prophylactic medications. There is also a risk of keratopathy, which surfaced in 12 patients (13%) at grades 1-2 severity in the phase I trial. Keratopathy “is 100% reversible, but we want to prevent it from happening rather than having it reverse,” said Moore. To achieve this, investigators are mandating steroidal eye drops and lubrication in the study protocol.

Looking toward the future, researchers also have opened the 4-arm phase I FORWARD II trial in patients with advanced ovarian cancer, in which mirvetuximab soravtansine is being tested in combination with either bevacizumab, carboplatin, pegylated liposomal doxorubicin or pembrolizumab (NCT0260635).

“The combination would enable the potential to move into earlier lines of therapy while continuing to understand the biomarker,” said Moore. “I also think there’s potentially a role for this drug in other malignancies where FR-alpha is overexpressed, and there are several studies that are launching across the United States that are exploring those questions.”

ImmunoGen, Inc, is developing mirvetuximab soravtansine. The company is working with Ventana Medical Systems to develop an IHC-based FR-alpha assay for use as a companion diagnostic.

References

1. Moore KN, Martin LP, O’Malley DM, et al. Safety and activity of mirvetuximab soravtansine (IMGN853), a folate receptor alpha–targeting antibody–drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a phase I expansion study [published online December 27, 2016]. J Clin Oncol. doi: 10.1200/JCO.2016.69.9538.

2. Moore KN, Martin LP, Matulonis UA, et al. IMGN853 (mirvetuximab soravtansine), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC): single-agent activity in platinum-resistant epithelial ovarian cancer (EOC) patients (pts). Poster presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 5567. meetinglibrary.asco. org/content/169854-176.

To read this full article on Onclive.com, please click here.

UCSD Study Finds New Ovarian Cancer Treatment Possibilities

UCSD Study Finds New Ovarian Cancer Treatment PossibilitiesUsing a new insight into the nature of ovarian cancer, a team of UC San Diego scientists have found potential new drug targets.

The researchers discovered that existing drugs targeting autophagy were effective in drug-resistant human tumors grafted onto mice, in some cases nearly eradicating the cancer. Genes regulating autophagy are often dysfunctional in ovarian cancer.

This raises the possibility that a five-drug cocktail could be effective on otherwise resistant ovarian cancers, according to a study led by Dwayne Stupack and Joe Delaney of UCSD Moores Cancer Center. Moreover, the strategy might work against other cancers.

Drugs in the cocktail are chloroquine, nelfinavir, rapamycin, dasatinib and metformin. The cocktail is called COAST, for Combination of Autophagy Selective Therapeutics.

“COAST therapy should be clinically tested in OV (ovarian cancer), given its strong effects, minimal toxicity, and genetic rationale,” the study stated.

The study was published Feb. 15 in the journal Nature. It can be found at j.mp/ovcancer.

Ovarian cancer is usually responsive to initial treatment, but tends to recur. Each recurrence becomes harder to treat, as the cancer cells develop drug resistance. Developing new drugs to beat resistant tumors has been impeded by a lack of good targets.

Cancers are considered genetic diseases, caused by mutations, chromosomal rearrangement and other changes caused by the instability of the malignancy’s genome. Cancer researchers have traditionally searched for telltale mutations in important genes that drive the cancer’s progression. One of the most famous is p53, which in its normal state suppresses cancer. Such mutated genes are known as oncogenes.

“Interestingly, 48 percent of studied tumors have no mutations in these oncogenes or tumor suppressors, other than p53,” the study stated.

Since mutant p53 can’t cause cancer alone, the researchers decided to look at another effect of genomic instability, the loss or gain of copies of genes. These are called SCNAs, or somatic copy-number alterations.

Genes mostly come in pairs, one inherited from each parent. Often, just one functioning gene is enough to ward off disease. For example, a person carrying one mutation that causes sickle-cell anemia and a normal partner gene is a healthy carrier, but two mutant copies cause the disease.

This might not be the pattern in some cancers, the researchers reasoned. If multiple related genes were lost or duplicated, resulting in just one copy or three copies, the cumulative disruption of molecular pathways might perturb the cell enough to cause cancer.

To investigate this possibility, Delaney and colleagues designed software called HAPTRIG, for Haploinsufficient/Triplosensitive Gene. HAPTRIG searched for molecular pathways significantly disrupted by such omissions or duplications.

Using HAPTRIG, the team homed in on the autophagy system as a promising target for intervention.

“Our study suggests that a roadmap of targetable genetic changes in tumors should not be limited to mutations,” said Stupack, said in a UCSD statement. “HAPTRIG may reveal additional targetable pathways across cancer types. We have provided a free web tool to allow the community to easily perform a HAPTRIG analysis on 21 cancer types.”

The tool can be found at j.mp/haptrig.

Research funders include the National Cancer Institute and the Nine Girls Ask Foundation.

To read this article published online by The San Diego Union Tribune, please click here.

Ovarian Cancer and Genetics

Ovarian Cancer and GeneticsWomen who have a strong family history of breast or ovarian cancer are more likely to be affected by cancer of the ovaries, fallopian tube, or peritoneal cavity. This is thought to be due to a mutation in one of the genes that are involved in the regulation of cell growth and replication in these areas, which can be inherited from the parents.

It is estimated the 10-15% of ovarian, fallopian tube, or peritoneal cancers are associated with an inherited genetic mutation. The remaining majority of cases of cancer are linked to a genetic mutation that is acquired by the individual in their lifetime.

Genes Associated With Ovarian Cancer

The BReast CAncer 1 (BRCA1) and BReast CAncer 2 (BRCA2) genes have been identified as genes that are linked to an increased risk of the development of both breast cancer and ovarian cancer. Everybody possesses these genes in their body because they play an important role in the regulation of cell growth in the breasts and ovaries, but a mutation in one or both of these genes increases the likelihood that an individual will be affected by breast or ovarian cancer.

A woman with a mutation in the BRCA2 gene has a lifetime risk of 10-20% of developing ovarian cancer. This is approximately ten times higher that the risk of an average woman, which is 1-2%.

Other genes that have been linked to an increased risk of ovarian cancer include:

  • CDH1: mutation is linked to a raised risk of ovarian and breast cancer.
  • MLH1 gene: mutation is linked to a raised risk of both Lynch syndrome and ovarian cancer.
  • MLH2 gene: mutation is linked to a raised risk of both Lynch syndrome and ovarian cancer.
  • PALB2 gene
  • PTEN gene: mutation is linked to a raised risk of Cowden syndrome and ovarian cancer.
  • STK11gene: mutation is linked to a raised risk of Peutz-Jeghers syndrome and ovarian cancer.
  • TP53 gene: somatic mutation is present in almost half of all cases of ovarian cancer.

Genetic Conditions Associated With Ovarian Cancer

There are various genetic conditions that are linked to an increased risk of ovarian cancer development. These include:

  • Lynch syndrome: associated with an increased risk of ovarian, uterine, colorectal, and other types of cancer.
  • Peutz-Jeghers syndrome (PJS): associated with an increased risk of ovarian, breast, colorectal, and other types of cancer.
  • Nevoid basal cell carcinoma syndrome (NBCCS): associated with an increased risk of a type of ovarian cancer, known as fibrosarcoma.
  • Li-Fraumeni and Ataxia-Telangiectasia: associated with an increased risk of ovarian cancer.

Risk Reduction for Women With a Family History

For women who have a raised risk of ovarian cancer due to the inheritance of a gene that is linked to causing the condition, there are several steps that can be taken to reduce their risk.

For example, some women may choose to have their ovaries and fallopian tubes to be removed. This helps to reduce the risk of cancer in these areas, as well as the risk of some types of breast cancer due to decreased production of estrogen, which usually occurs in the ovaries. The risk of ovarian cancer can be reduced by 70-96% and the risk of breast cancer by 40-70%.

However, this surgical procedure should not be considered unless a woman is certain that she does not wish to bear any children in the future because the removal of the ovaries will render her infertile.

Genetic testing is available for women with a strong family history of breast or ovarian cancer to detect mutations in the genes that are known to raise the risk of cancer. It is important for patients to be aware of the benefits and negative aspects of being tested before they undergo the examination.

Reviewed by Susha Cheriyedath, MSc

References

  1. http://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/risk-factors-and-prevention
  2. https://ghr.nlm.nih.gov/condition/ovarian-cancer
  3. https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq
  4. https://ocrfa.org/patients/about-ovarian-cancer/risk-factors/
  5. https://ovariancancer.net.au/awareness/genetic-risks/

To read this article on News-Medical.net, please click here.

Hormone Maintenance Tx Benefits Ovarian Ca Subtype

Hormone Maintenance Tx Benefits Ovarian Ca SubtypeWomen with low-grade serous ovarian cancer had significantly better survival if they received hormone maintenance therapy (HMT) after surgery, a 30-year retrospective review showed.

Overall, women who received HMT lived more than twice as long without disease progression compared with women who did not receive hormonal therapy after surgery. Overall survival (OS) was more than a year longer in HMT-treated patients (115.7 versus 102.7 months), reported David Gershenson, MD, of the MD Anderson Cancer Center in Houston, and colleagues.

Patients who had no evidence of disease after surgery derived even greater benefit from HMT, living 7 years longer than similar patients who entered surveillance without HMT, they wrote online in the Journal of Clinical Oncology.

Though compelling, the evidence requires validation in a prospective clinical trial before HMT becomes part of routine care for patients with low-grade serous ovarian cancer, according to Gershenson.

“Some would say that we already have enough evidence from our retrospective study to support the use of hormonal maintenance therapy, but the gold standard is always a prospective, randomized trial,” Gershenson told MedPage Today. “We’ve designed the trial. We’ve gone through several levels of approval with the National Cancer Institute, and we’re meeting with our international partners in June.”

The findings confirmed an initial report at the 2016 American Society of Clinical Oncology annual meeting.

The findings applied only to low-grade serous ovarian cancer, which accounts for about 10% of all newly diagnosed ovarian cancer. In contrast to the more common high-grade disease, low-grade serous ovarian cancer is relatively chemotherapy insensitive. The German gynecologic oncology group (AGO) recently confirmed low-grade disease’s lack of responsiveness to chemotherapy, which accelerated the search for alternatives to chemotherapy.

Similarities between low-grade serous ovarian cancer and hormone receptor-positive breast cancer have stimulated interest in hormonal treatment for the low-grade ovarian disease. A high proportion of low-grade serous cancers exhibit estrogen and progesterone receptor expression, and hormonal therapy had proved beneficial in relapsed disease.

Gershenson’s group said their experience with low-grade serous ovarian cancer led them to conclude that the disease is not completely resistant to platinum-based chemotherapy, and they continue to recommend it as adjuvant therapy following surgical debulking of stage II-IV disease. However, the authors also acknowledged that “others have begun to abandon postoperative chemotherapy in favor of hormonal therapy despite lack of data from prospective clinical trials.”

They sought to examine the benefits of postoperative HMT in a retrospective review of patients treated from 1981 to 2013. MD Anderson established a low-grade serous tumor database in 2007, and a search of patient records initially identified 544 patients. After exclusions because of incomplete data and other factors, 203 patients remained for the analysis, consisting of 133 who had surgery and adjuvant platinum-based chemotherapy followed by observation and 70 who received HMT after surgery and chemotherapy. The most commonly used agent for HMT was letrozole (Femara, 54.3%), followed by tamoxifen (28.6%).

The observation and HMT groups did not differ significantly with respect to clinical or demographic factors. The study population had a median follow-up duration of 70.8 months, 80.3 months in the observation group and 54.9 months in the HMT group. Overall, the patients had a median progression-free survival (PFS) of 32.6 months. However, HMT was associated with significant prolongation of PFS (64.9 versus 26.4 months, P<0.001).

Median OS for all 203 patients was 104 months. Although patients in the HMT group had numerically better survival, the 13-month difference did not achieve statistical significance (P=0.42).

The authors performed a separate analysis of patients who were clinically disease free after adjuvant chemotherapy (n=144). The data showed that patients in the observation group had a median PFS of 30.0 months compared with 81.1 months with HMT. Women with residual or persistent disease also benefited from HMT, reflected in a median PFS of 38.1 months versus 15.2 months with observation. Both differences represented a significant advantage for HMT (P<0.001).

Women who were clinically disease free after chemotherapy had a OS of 191.3 months if they received HMT versus 106.8 months with observation. Those who had persistent disease had a median OS of 83 months with HMT and 44.4 months without. Both differences achieved statistical significance in favor of HMT (P=0.014).

An analysis of survival by estrogen (ER) and progesterone receptor (PR) status showed that PFS was significantly longer with HMT among women who were ER-positive, PR-positive, or PR negative. OS trended in favor of HMT, but did not achieve statistical significance for any of the analyses of hormone receptor status. Only three evaluable patients were ER-negative, precluding meaningful comparisons.

Study limitations included its retrospective nature, long study period, incomplete data, potential referral bias, heterogeneous therapies, and differing follow-up practice patterns.

To read this entire article on MedpageToday.com, please click here.

Study Links Ovarian Cancer Growth to Gene Defects

Study Links Ovarian Cancer Growth to Gene DefectsDefects in a key gene—long thought to drive cancer by turning off the protection afforded by the BRCA genes—spur cancer growth on their own, according to a study led by researchers from NYU Langone Medical Center (Oncotarget 2017; doi: 10.18632/oncotarget.14637).

The study gene, known as EMSY, has some of the same functions as BRCA1 and BRCA2, which are known to protect against ovarian and breast cancer when normal. When defective, BRCA genes block the body’s self-defense against cancer-causing genetic mistakes.

The new data helps explain why some women with healthy BRCA1 and BRCA2 genes develop cancer. The findings may also expand treatment options for the roughly 11 percent of women with ovarian cancer, as well as breast and normal BRCA genes, according to study authors.

“Now that we know exactly how changes in EMSY spur cancer cell growth, we can start to design therapies to specifically target that activity and hopefully stop it,” said senior author Douglas Levine, MD, Director of the Division of Gynecologic Oncology at NYU Langone and its Perlmutter Cancer Center.

“This work also suggests that treatments that work for patients with BRCA1 or BRCA2 mutations might also be effective against EMSY-driven cancers because the disease mechanism is similar,” added first study author Petar Jelinic, PhD, a Research Assistant Professor at NYU Langone. “The best way to go rapidly from bench to bedside is to find new ways to use existing treatments.”

When normal, EMSY, BRCA1, and BRCA2 give the body’s cells instructions to create proteins that help repair DNA damage that can cause cancer. When those genes are altered, the repair process fails and cancer grows. Overly active EMSY, like mutated BRCA1 or BRCA2, changes those instructions, so the DNA damage repair process is blocked.

This new study dispels prior theories that EMSY’s activation merely turned off the cancer suppression function of BRCA2,noted Jelinic.

Earlier work by Levine and others pointed toward EMSY activation as a culprit in breast and ovarian cancer, but had only examined certain parts of the EMSY protein. The new study was the first to evaluate the full-length EMSY protein and to show that it acts independently of BRCA1 or BRCA2.

Furthermore, the research revealed the part of the EMSY protein is changed by an enzyme called protein kinase A. When there is more active EMSY than normal, this enzyme reacts with the EMSY protein to more thoroughly suppress the DNA repair process.

To read this full article on Oncology Times, please click here.

Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors

Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian TumorsInflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

Introduction

Ovarian cancer is the fifth most common cancer among women in developed countries, and it is the most fatal gynecological malignancy.[1] The etiology of ovarian cancer is still not fully clarified, although a number of risk factors have been identified. A reduced risk of ovarian cancer has been observed with increased parity,[2] use of oral contraceptives,[2] hysterectomy,[3] and tubal ligation,[3] whereas family history of ovarian or breast cancer,[2] use of hormone replacement therapy,[2] exposure to talc,[4] and a history of endometriosis[5] have been associated with increased risks.

The 2 dominant hypotheses to explain the development of ovarian cancer relate increased risk to a large number of lifetime ovulatory cycles (the incessant ovulation theory)[6] or exposure to high levels of gonadotropins (the gonadotropin theory).[7] However, inflammation has also been suggested as a potential biological mechanism that may underlie a number of epidemiologic associations not easily explained by either theory,[8,9] including talc exposure, endometriosis, tubal ligation, and hysterectomy. Furthermore, a link between pelvic inflammatory disease (PID) and the risk of ovarian cancer has been suggested, and this potential association may also be explained by the inflammation theory. PID is defined as an upper genital-tract infection and includes diagnoses of endometritis, salpingitis, pelvic peritonitis, and tubo-ovarian abscess caused by microorganisms ascending from the lower genital tract.[10] Approximately 800,000 women are treated for PID annually in the United States,[11] and it is estimated that 6%–20% of all women in the Western world are diagnosed with PID during their lifetimes.[12–14]

Epidemiologic studies investigating the association between PID and the risk of ovarian cancer and borderline ovarian tumors have been inconsistent, revealing increased risks in some studies[15–19] but not in all.[20–23] Moreover, most previous studies have had methodological problems, including limited statistical power due to small numbers of study subjects and/or a short follow-up period. Also, ovarian cancer is a heterogeneous disease consisting of different histotypes with different risk factor profiles.[24]However, few investigators have studied the role of PID separately for borderline tumors[15,18] or for the separate histotypes of ovarian cancer.[18,20]

To examine the association of PID with the risk of ovarian cancer, an international collaborative study was performed, using data from 13 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). To our knowledge, this was the largest study of PID and ovarian cancer risk to date, thereby enabling a more robust estimation of risks among subgroups according to tumor behavior and histotype than has previously been possible.

Participating Studies

OCAC was founded in 2005 as an international forum of investigators conducting ovarian cancer case-control studies. The main aims of the collaboration are to discover associations between genetic polymorphisms and ovarian cancer risk and to identify and confirm epidemiologic risk factors for ovarian cancer.[25]

For the present study, we obtained individual-level data from 13 case-control studies: 12 studies in OCAC[20,26–37] and a parallel study not originally included in OCAC (Southern Ontario Ovarian Cancer Study (SON)).[38] Eight studies were conducted in the United States (Connecticut Ovary Study (CON), Diseases of the Ovary and Their Evaluation (DOV), Hawaii Ovarian Cancer Study (HAW), Hormones and Ovarian Cancer Prediction (HOP), North Carolina Ovarian Cancer Study (NCO), New Jersey Ovarian Cancer Study (NJO), University of California Irvine Ovarian Cancer Study (UCI), and Los Angeles County Case-Control Studies of Ovarian Cancer (USC)),[26,27,31–36] 2 in Canada (Familial Ovarian Tumor Study (TOR) and SON),[37,38] 2 in Europe (Danish Malignant Ovarian Tumor Study (MAL) and Nijmegen Polygene Study and Nijmegen Biomedical Study (NTH)),[28–30] and 1 in Australia (Australian Ovarian Cancer Study and Australian Cancer Study (Ovarian Cancer) (AUS)).[20]

Characteristics of the 13 included studies are presented in Table 1. Data were cleaned and checked for internal consistency, and clarifications were obtained from the initial investigators if needed. Women with nonepithelial ovarian tumors (n = 186) and with missing information on PID status (n = 278) were excluded, leaving 9,162 women with invasive ovarian cancer (hereafter denoted “ovarian cancer”), 2,354 women with borderline ovarian tumors, and 14,736 control participants for analysis. Eleven studies included both women with ovarian cancer and women with borderline ovarian tumors, whereas 2 studies included only women with ovarian cancer (NTH and NJO). Each study had approval from the relevant institutional review board or ethics committee, and all participants gave informed consent.

PID Assessment

Information on PID was self-reported in all studies, through either in-person interviews (n = 10 studies) or self-administered questionnaires (n = 3 studies). Table 1 includes the phrasing of the question regarding PID status used in each study. We aimed to obtain information on the following PID variables: PID status (ever/never had PID), age at first PID episode, time since first PID episode, and number of PID episodes. All studies except for HAW had information on age at first PID episode, and 5 studies (CON, DOV, NJO, SON, and TOR) had data on number of PID episodes.

Statistical Analysis

Associations between the PID variables and ovarian cancer risk were estimated using a 2-stage method.[39] First, study-specific odds ratios were obtained from logistic regression models and were subsequently combined into a pooled odds ratio with 95% confidence intervals. The pooled estimate was computed by weighting each estimate by the inverse of the sum of its variance and the across-studies variance using a random-effects model.[40] Only studies for which the study-specific model converged contributed to the pooled estimate. We used the Cochran Q and I 2 statistics to evaluate statistical heterogeneity between studies. If heterogeneity was present, we explored the potential sources of heterogeneity, including continent of study (North America vs. Europe vs. Australia) and method of data collection (in-person interview vs. self-administered questionnaire).

For analyses, age at first PID episode and time since first PID episode were modeled both as categorical and continuous variables. Each categorical variable was categorized into ordinal groups (age at first PID episode: <20, 20–29, or ≥30 years; time since first PID episode: <10, 10–19, or ≥20 years; number of PID episodes: 1 or ≥2), with women who had never had PID as the referent. Associations between the continuous variables (age at first PID episode and time since first PID episode) and ovarian cancer risk were assessed only among women who had ever been diagnosed with PID. In order to model these associations, we included PID status in the model as a categorical indicator variable together with the continuous PID variable, as suggested by Leffondré et al..[41]

All analyses adjusted for age, parity (nulliparous vs. parous as well as parity as a continuous variable), oral contraceptive use (ever/never use as well as duration of use as a continuous variable), and family history of ovarian or breast cancer in a first-degree relative (yes/no) irrespective of their effect on the association between PID and ovarian cancer risk, because these factors were considered to be potentially important confounders a priori. For studies that used matching (age, race/ethnicity), conditional logistic regression analysis was used to adjust for these variables. In unmatched studies, age was categorized into 5-year age groups and unconditional logistic regression analysis was used (Table 1). When modeling parity and oral contraceptive use, the categorical variable was included as an indicator variable together with the continuous variable.[41] Other potential confounders were considered but were not included in the final model, because none of them fulfilled an inclusion criterion of changing the log of the pooled estimate for ovarian cancer risk by 10% or more; these potential confounders were tubal ligation, hysterectomy, endometriosis, use of hormone replacement therapy, breastfeeding, age at menarche, menopausal status, body mass index, cigarette smoking, and educational level.

We examined interactions between PID status and parity (nulliparous vs. parous), oral contraceptive use (ever use vs. never use), and family history of ovarian or breast cancer in first-degree relatives (yes vs. no). Family history of breast or ovarian cancer was used as a proxy for hereditary ovarian cancer, as we aimed at exploring whether PID was similarly associated with hereditary and sporadic ovarian cancer. Linearity for all quantitative variables was examined by comparison with models with restricted cubic splines, but no appreciable deviations from linearity were found. The significances of the interactions and nonlinear associations were estimated by likelihood ratio tests of the interactions/nonlinearities and then comparison of the distribution of the study-specific P values with a uniform distribution by means of the Kolmogorov-Smirnov test.[42]

All analyses were performed separately for ovarian cancer and for borderline tumors, and subgroup analyses were conducted by histotype. Ovarian cancers were divided into categories of serous, mucinous, endometrioid, clear cell, and other (including mixed cell, undifferentiated, and tumors of unknown epithelial histology). Additionally, serous cancers were divided into low-grade (grade 1) and high-grade (grade 2 or higher) tumors, because these are considered to represent different histotypes.[43]However, 2 studies had no information on grade (SON and TOR) and were therefore not included in these analyses; they were included only in the analyses for serous cancer overall. Subgroup analyses for borderline ovarian tumors included serous and mucinous tumors, because other histotypes of borderline ovarian tumors are rare. All P values were 2-sided, and the nominal level of statistical significance was set at P < 0.05. All statistical analyses were performed using the statistical software R, version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria), including the packages “survival,” “meta,” and “rms.”

Results

A history of PID was reported by 500 of the 9,162 women with ovarian cancers (5.5%), by 201 of the 2,354 women with borderline ovarian tumors (8.5%), and by 944 of the 14,736 control participants (6.4%). The proportion of control participants with PID varied across study sites, from 0.4% to 26.6%. In 11 of the studies, small proportions (less than 6%) of control participants reported PID, whereas in a Canadian study (SON) and in the Danish study (MAL), larger proportions of the control participants reported having had PID (20.2% and 26.6%, respectively). Median age at first PID episode was 28 years (interquartile range, 22–36 years) among women with ovarian cancer, 24 years (interquartile range, 20–30 years) among women with borderline ovarian tumors, and 25 years (interquartile range, 20–33 years) among control participants. Distributions of the various histotypes of ovarian tumors from the included studies are provided in Web Table 1 (available at http://aje.oxfordjournals.org/).

Ovarian Cancer

In the pooled analysis, we found no association between a history of PID and the risk of ovarian cancer (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.83, 1.19) (Web Table 2 and Figure 1). Furthermore, we observed no convincing associations of the age at first PID episode, time since first PID episode, or number of PID episodes with the risk of ovarian cancer (Web Table 2).

The magnitudes of the risk estimates for associations of specific histotypes of ovarian cancer with the individual PID variables did not differ from those observed for ovarian cancer overall, and only a few of the risk estimates reached statistical significance. However, we noted a higher risk of low-grade serous cancer (OR = 1.48, 95% CI: 0.92, 2.38) associated with PID status, although the risk estimate did not reach statistical significance (Web Table 2).

Borderline Ovarian Tumors

A history of PID was associated with a higher risk of borderline ovarian tumors (OR = 1.32, 95% CI: 1.10, 1.58) (Table 2 and Figure 2). Furthermore, women with 2 or more episodes of PID had a more than 2-fold higher risk of borderline ovarian tumors compared with women without a history of PID (OR = 2.14, 95% CI: 1.08, 4.24). We found no consistent trend in the risk of borderline tumors with age at first episode of PID (P-trend = 0.29) or time since first episode of PID (P-trend = 0.44).

As for borderline ovarian tumors overall, the risk of serous borderline ovarian tumors was statistically significantly increased among women with PID (OR = 1.43, 95% CI: 1.14, 1.79). Similarly, PID was also associated with an increased risk of mucinous borderline ovarian tumors, although the risk estimate was not statistically significant (OR = 1.28, 95% CI: 0.97, 1.68). The risks of serous and mucinous borderline ovarian tumors were not convincingly associated with age at or time since first PID episode. In addition, women with multiple episodes of PID had a higher risk of both serous and mucinous borderline ovarian tumors, but none of the risk estimates reached statistical significance (Table 2).

Additional Analyses

To consider the possibility that early cancer symptoms might have been misinterpreted as PID or that an episode of PID might have resulted in further examinations that led to the identification of ovarian cancer, we performed sensitivity analyses of the association between PID status and the risk of ovarian cancer and borderline ovarian tumors by excluding women whose last PID episode was ≤1, ≤2, or ≤3 years before the date of diagnosis of ovarian cancer (for cases) or date of interview (for controls). The risk estimates in these sensitivity analyses were not substantially different from the risk estimates in the main analyses (data not shown).

We performed additional sensitivity analyses by stratifying studies by data collection method (in-person interview vs. self-administered questionnaire), study continent (North America vs. Europe vs. Australia), whether a physician-verified diagnosis of PID was required, study period (before or including 2000 vs. after 2000), proportion of control participants with PID (low (<6%) vs. high (>20%)), body mass index (calculated as weight (kg)/height (m)2; <25 vs. ≥25), age at diagnosis of ovarian cancer (cases) or interview (controls) (<50 years vs. ≥50 years), and level of education (high school or less vs. more than high school). However, in the vast majority of these analyses, the direction and the magnitude of the associations were virtually unchanged compared with the associations obtained in the main analyses (data not shown). Notable exceptions were the observation of apparently statistically significantly increased risks of low-grade serous ovarian cancer (OR = 2.36, 95% CI: 1.24, 4.48) and endometrioid ovarian cancer (OR = 1.42, 95% CI: 1.01, 1.98) among women in the North American studies. However, no associations between PID and these 2 tumor types were found among the European studies or in the Australian study (low-grade serous cancer: pooled OR = 0.98, 95% CI: 0.61, 1.59 for the European studies and OR = 1.49, 95% CI: 0.52, 4.30 for the Australian study; endometrioid ovarian cancer: pooled OR = 0.60, 95% CI: 0.33, 1.10 for the European studies and OR = 1.09, 95% CI: 0.52, 2.26 for the Australian study).

Statistically significant heterogeneity across studies was observed for only a few of the risk estimates (Web Table 2 and Table 2). However, additional analyses showed that neither the method of data collection nor study continent nor proportion of control participants with PID could explain the observed heterogeneity since these additional analyses did not reveal increased consistency among studies of the same type (data not shown). We observed no effect modification between PID status and any of the potential risk factors (parity, oral contraceptive use, and family history of ovarian/breast cancer) for ovarian cancer and borderline ovarian tumors (all P values > 0.05) (data not shown).

Discussion 

To our knowledge, this was the largest study to date to have investigated the association between history of PID and the risk of ovarian cancer. In a pooled analysis of 13 case-control studies, we found no convincing associations between self-reported PID status and the risk of ovarian cancer overall, but suggestions of an increased risk of low-grade serous cancer were noted. For borderline ovarian tumors, an increased risk was observed among women with a history of PID, both overall and for serous and mucinous borderline tumors separately. Furthermore, the risk of borderline tumors increased with the number of PID episodes.

An association between PID and the risk of ovarian tumors is biologically plausible and could be explained by the inflammation hypothesis.[8] Inflammation is characterized by the production of free radicals, cytokines, prostaglandins, and growth factors with the potential for genetic and epigenetic changes to the DNA, resulting in an increased risk of malignant transformation.[44] Until recently, it was believed that all histotypes of ovarian cancer arose from the mesodermal surface epithelium, either on peritoneal surfaces or entrapped within the ovaries, and inflammation of the epithelium was therefore proposed to trigger malignant transformation.[8] Recently, it has been suggested that some serous ovarian tumors originate in the mucosal epithelium of the fallopian tube, and inflammation of the fallopian tubes has been proposed to contribute to the development of these tumors.[45]

The association between PID and the risk of ovarian cancer has been investigated in only 2 cohort studies[17,19] and 7 case-control studies.[15,16,18,20–23] However, 4 of those case-control studies were based on data from study sites (MAL, USC, AUS, and SON) that were included in the present analysis;(15,18,20,23) results from those studies will not be discussed further. We found a 32% higher risk of borderline ovarian tumors associated with a history of PID, and risk estimates above unity were noted for nearly all individual studies. Furthermore, we observed similarly increased risks of serous and mucinous borderline tumors associated with PID status. Our novel finding of a 2-fold higher risk among women with multiple PID episodes may reflect a true association between PID and the risk of borderline ovarian tumors rather than being caused by chance or bias. Only 2 studies (SON and MAL, both included in the present analyses) have previously investigated the association between PID and the risk of borderline tumors.[15,18]

In the present study, the lack of any marked associations between PID and the risk of ovarian cancer overall is consistent with results from 1 case-control study,[22] whereas 2 other studies found an increased risk of ovarian cancer.[16,17] Additionally, 2 studies assessed PID in relation to ovarian cancer risk but provided results only for ovarian cancer and borderline tumors combined, thereby hampering a comparison with the present results;[19,21] Ness et al.[21] reported null findings, and McAlpine et al.,[19] in a Canadian cohort study, reported a 4-fold higher risk of ovarian cancer among women who had had PID. Concerning the histotypes of ovarian cancer, indications of an increased risk of low-grade serous cancer with PID were noted in the main analysis. Conversely, no convincing associations between PID and the risk of high-grade serous, mucinous, clear cell, or endometrioid ovarian cancer were noted in the main analyses. However, sensitivity analyses revealed statistically significantly increased risks of low-grade serous and endometrioid ovarian cancers when using data from the North American studies only. Other than 2 studies already included in the present pooled analysis, no previous studies have assessed the association between PID and the risk of ovarian cancer according to histotype. Although we cannot completely rule out the possibility that these histotype-specific findings may be due to chance, the present study is the first, to our knowledge, to indicate differences in the risk profile of ovarian cancer histotypes with regard to PID. However, the low number of exposed cases for most of the histotypes limited the precision of the risk estimates, and our results must therefore be confirmed by others.

Nevertheless, our results suggest that PID may be differentially associated with the risk of ovarian tumors. Reasons for this difference are not known, but they may be associated with different pathogeneses of the ovarian tumor histotypes. Recently, the so-called dualistic model of ovarian carcinogenesis proposed that borderline tumors are precursors of type 1 (low-grade) ovarian cancers but unrelated to type 2 (high-grade) ovarian cancers.[46] According to this hypothesis, type 1 tumors include low-grade serous and mucinous carcinomas, and these are believed to develop along a continuum of tumor progression from adenoma to borderline tumor to invasive carcinoma.[46] Clear cell and low-grade endometrioid carcinomas are also type 1 cancers and are believed to develop from endometriosis. Our results demonstrated an association between PID and the risk of borderline ovarian tumors and indicated that the risk of low-grade serous cancer might also be increased, which accords well with the theory of a stepwise development from a serous borderline tumor to low-grade serous cancer. In contrast, no associations between PID and high-grade serous ovarian cancer were observed. Therefore, our results suggest that PID is a risk factor for borderline and possibly also low-grade serous ovarian cancer, whereas no marked associations were observed for the other histotypes of ovarian cancer. The possible underlying biological mechanisms responsible for this differential association between PID and ovarian tumor types are unknown and require further investigation in epidemiologic and biological studies.

A strength of the present study is the use of pooled data from 13 case-control studies. The large sample size resulted in increased statistical power and enabled us to estimate risks according to invasiveness and histotype. Moreover, all the studies we included were population-based, and information on PID was obtained through in-person interviews in the majority of them. In addition, we used individual-level data carefully harmonized and entered into a single data set. The use of a 2-stage approach[39] enabled us to account for differences in design and data collection between studies and to control for several potential confounders. Finally, all studies with the relevant exposure data in OCAC were included regardless of their individual results, thus removing the influence of publication bias.

Some limitations should also be mentioned. First, information about PID status was self-reported in all studies, and the proportion of control participants reporting an episode of PID in the individual studies ranged from 0.4% to 27%. Unfortunately, most studies had no data or insufficient data on treatment for PID, which could have added important information in terms of validating the PID diagnoses. The highest frequencies were reported in the Danish study (MAL: 27%) and in a Canadian study (SON: 20%); the remaining 11 studies all had PID proportions below 6%. Reasons for the differences in proportions among the studies may include geographic variation in the prevalence of PID-causing pathogens, different phrasing of the PID-related questions, or differences in the prevalence of high-risk sexual behaviors. However, we believe that underestimation of PID exposure is the most likely cause for the low proportions of women with a history of PID in the majority of studies, because previous studies from Sweden and the United States have estimated lifetime prevalences of PID between 6% and 20%.[12–14] In studies with self-reported data on PID exposure, including the present study, the true proportion of women who have had PID might be underestimated for several reasons—women might have forgotten about a past PID episode, chosen not to report it, or had unrecognized, subclinical PID. Hence, we cannot rule out the possibility that this misclassification of PID status could have influenced our results. Interestingly, investigators in only 2 previous studies did not use self-reported data on PID but instead obtained information on PID from a population-based health insurance database or used evidence of inflammation at surgery for tubal damage as a proxy for previous PID, and both groups reported an increased risk of ovarian cancer associated with PID.[17, 9] Therefore, in future studies, researchers should consider using a more objective measure of PID, such as data obtained from reliable health registries or through serological testing for antibodies to PID-causing pathogens, including Chlamydia trachomatis and Neisseria gonorrhoeae.

Second, misclassification of PID exposure might also result when women mistakenly report bladder or vaginal infections as PID. However, we expect this misclassification to be relatively infrequent, because in the majority of included studies, PID was defined as diagnosed by a physician, or the question specified that bladder or vaginal infections were not included. Furthermore, the majority of studies performed in-person interviews, thus allowing for potential uncertainties to be clarified. Third, the retrospective design of case-control studies introduces the potential for recall bias, in which case patients are more likely than control participants to report past exposures. However, we would not expect such overreporting to be differential with respect to degree of invasiveness of diagnosed ovarian tumors, and we therefore do not believe that this can explain the increased risk we observed for borderline tumors but not for ovarian cancer. Fourth, surveillance bias is potentially of concern, because women with PID symptoms may undergo ultrasonography or laparoscopy during which the ovaries are visualized, leading to coincidental findings of ovarian tumors. However, this potential surveillance bias is probably minimal, because our sensitivity analyses excluding women with PID less than 1–3 years in the past revealed virtually identical results as in the main analyses. Fifth, only 5 studies had information on the number of PID episodes, and the absence of thorough information on this exposure variable limited our ability to fully investigate and interpret any potential dose-response associations between number of PID episodes and the risk of ovarian cancer and borderline ovarian tumors. Finally, despite the large study size, we still had limited statistical power because of small proportions of women with PID in some of the categorical analyses and for some of the rarer histotypes, and we cannot completely rule out the possibility that some of the observed associations may have been be due to the large number of comparisons; thus our results should be interpreted with caution.

In conclusion, in this large, pooled analysis, we observed an increased risk of borderline ovarian tumors among women with a history of PID. These risks increased with the number of PID episodes. Conversely, we found no association between PID and the risk of ovarian cancer overall, but indications of an increased risk of low-grade serous cancer were noted. These findings suggest that PID may be a risk factor for borderline ovarian tumors and possibly for low-grade serous cancer, although no convincing associations were seen for other ovarian cancer histotypes. However, until the specificity of the association is confirmed in additional epidemiologic and biological studies, the association between PID and ovarian cancer risk is still somewhat uncertain.

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