Sunday, March 3, 2013

Chemotherapy and/or radiotherapy in combination with surgery for ovarian carcinosarcoma.

Chemotherapy and/or radiotherapy in combination with surgery for ovarian carcinosarcoma.

2013 Feb


Gynaecological Oncology Division, Department of Surgical Oncology, Tata Memorial Centre, Dr Ernest Borges Marg, Parel, Mumbai, India, 400012.



Ovarian carcinosarcoma, also known as malignant mixed Mullerian tumour, is a rare malignant gynaecological tumour constituting about 1% or less of all ovarian cancers. In over 80% of cases, there is extra-ovarian intra-abdominal spread at diagnosis. The primary treatment has traditionally been surgical cytoreduction followed by radiotherapy and chemotherapy or chemotherapy alone. Regimes have included cisplatin alone; a combination of doxorubicin, ifosfamide, dacarbazine, cyclophosphamide, taxol; and various other combinations. The effectiveness of these various regimens appears to be mixed. Therefore, there is a need to clarify if there is an optimum neoadjuvant or adjuvant therapy after surgical cytoreduction for this rare tumour. Also, it is important to address quality of life (QoL) issues related to treatment, particularly toxicity, as the overall prognosis appears to be poor.


To assess the effectiveness and safety of various adjuvant and neoadjuvant chemotherapy and radiotherapy options or chemotherapy alone in combination with surgery in the management of ovarian carcinosarcoma.


We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to February 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field.


We searched for randomised controlled trials (RCTs) that compared neoadjuvant or adjuvant chemotherapy and radiotherapy, or chemotherapy alone, in women with ovarian carcinosarcoma (malignant mixed Mullerian sarcoma of the ovary). We also reviewed non-randomised studies (NRS) for discussion in the absence of RCTs.


Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed.


The search strategy identified 297 unique references of which all were excluded.


We found no evidence to inform decisions about neoadjuvant and adjuvant chemotherapy and radiotherapy regimens, or chemotherapy alone, for women with ovarian carcinosarcoma. Ideally, an RCT that is multicentre or multinational, or well designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances, are needed to compare treatment modalities and improve current knowledge. Further research in genetic and molecular signalling pathways might improve understanding of this tumour subtype.

Sunday, February 17, 2013

Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium.

Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium.

Feb 2013


C Olsen, Cancer Control Group, Queensland Institute of Medical Research, Brisbane, Australia.


Whilst previous studies have reported that higher body-mass index (BMI) increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum, and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13,548 cases, 17,913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5kg/m2; 95%CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between HRT users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.

Friday, February 8, 2013

Study drug is first to help patients with recurrent low-grade ovarian cancer

Study drug is first to help patients with recurrent low-grade ovarian cancer

Clinical trial shows targeted therapy shrinks tumors; a step toward individualized treatment

Contact: Scott Merville

HOUSTON - Low-grade serous ovarian cancer is less common and aggressive than the high-grade variety, yet exceptionally difficult to treat when frontline therapy fails.

"After surgery, with or without pre-surgical chemotherapy, when low-grade serous ovarian cancer persists or returns, chemotherapy and hormonal therapy are relatively ineffective," said David Gershenson, M.D., professor in The University of Texas MD Anderson Cancer Center Department of Gynecological Oncology and Reproductive Medicine.

Response rates for treatment are measured in single digits. Gershenson and colleagues have spent the greater part of 20 years characterizing the disease, which makes up 10 percent of ovarian cancer cases, and searching for new ways to treat it. Cancer recurs or persists in 80 to 85 percent of patients.
A phase II clinical trial by the National Cancer Institute's Gynecological Oncology Group provides the first evidence of a drug that shows a relatively high response rate for these patients.

Selumetinib halts growth or shrinks tumors

In the first-targeted therapy clinical trial for low-grade serous ovarian cancer, eight of 52 (15 percent) patients had a complete or objective partial response (tumor shrinkage) and 34 (65 percent) had no disease progression during the two-year course of the study. Study results appear in the February edition of The Lancet Oncology.

"These are remarkably encouraging results for what can ultimately be a devastating disease," said Gershenson, the paper's senior author.
These patients have a median overall survival of 80 months, about twice as long as those with high-grade disease, who are typically in their 60s when diagnosed and comprise 90 percent of ovarian cancer patients. The average age of women with low-grade cancer falls in the early 40s, Gershenson said, and it's not uncommon to see women in their 20s, 30s and 40s and the occasional teenager with the disease.

High-grade serous ovarian cancer is susceptible to chemotherapy upon relapse or recurrence.

Median overall survival not reached.

Cancer-causing genetic mutations in BRAF and KRAS genes occur more frequently in low-grade ovarian cancer, so the researchers chose a drug that targets the molecular network that includes those genes.

Selumetinib inhibits MEK1/2, a critical molecule in what's known as the MAPK pathway, which includes BRAF and KRAS.
All 52 patients had received at least one previous therapy, with 30 having had three or more. Clinical trial results with selumetinib include:

  • Median progression-free survival of 11 months and 34 patients (65 percent) went at least six months without their disease worsening.
  • Two-year overall survival of 55 percent.
  • Median overall survival had not been reached, because more than half of patients (61 percent) remained alive at the time of data cutoff for the study.
  • No treatment-related deaths.

Side effects ranged from cardio and gastrointestinal toxicity to pain, fatigue, anemia and dermatological effects. Of the 52 patients, 22 had their doses reduced and 13 ultimately left the study due to side effects.

Researchers obtained tumor samples sufficient for DNA analysis from 34 patients. While 14 patients had KRAS mutations and two had BRAF mutations, there was no connection between having those mutations and whether the patients responded to selumetinib.

Gershenson said researchers will further explore the question of matching drug to mutation during a larger phase 2/3 clinical trial that he will lead with investigators from the NCI Gynecological Oncology Group and the United Kingdom. The study will enroll 250 patients and is likely to begin later this summer.

Phase 2 trials generally do not include a control or comparison group, but the team noted treatment results for 58 women not in the trial who were treated at MD Anderson with current options. Between them, these patients received 108 different chemotherapy regimens, which produced one complete and three partial responses for an overall response rate of 3.7 percent.

A step toward personalized therapy for ovarian cancer

In an accompanying commentary, Sven Mahner, M.D., and Jacobus Pfisterer, M.D., Ph.D., German oncologists who did not participate in the research, note that the study is a step toward individualized treatment for ovarian cancer that reflects important molecular differences between low-grade and high-grade disease.
The response rate and disease stabilization rate are "particularly promising in a setting of heavily pretreated recurrent disease."
"A strength of the study is mandatory reference pathology of recurrent disease to ensure exclusion of patients with progression to high-grade disease, who are likely to benefit from chemotherapy, and recurrent borderline ovarian tumors that have excellent prognosis with salvage surgery alone," Mahner and Pfisterer wrote.

New surgery helps prevent ovarian cancer

New surgery helps prevent ovarian cancer

KGW Staff
Posted on February 7, 2013 at 3:59 PM

PORTLAND, Oregon -- Doctors at a Portland hospital have joined some others across the nation and Canada in following a new recommendation aimed at preventing one of the deadliest forms of cancer in women.
“This is something so simple that could save a lot of lives,” said Dr. Nathalie Johnson, the Medical Director of the Legacy Cancer Institute. Johnson is recommending women who have tubal ligations or hysterectomies have their fallopian tubes removed.
"It’s because researchers have found the tubes attract cancer cells which can eventually encase the ovary," she said. "You could actually find a normal ovary wrapped in cancer and realize the cancer was starting in the fallopian tube and not the ovary."
The recommendation is supported by research on thousands of women. Legacy researcher Dr. Ann Smith-Shedev has studied the connection for more than a decade.
“We think this could cut the most common type of ovarian cancer by up to 70 percent,” Shedev said.
The Legacy Cancer Institute is the first program in Oregon to make the recommendation that women consider the fallopian tube removal if they’re scheduling a tubal ligation or hysterectomy.
“We’d like to raise awareness and hopefully it can become the standard here in Oregon and across the country,” said Johnson.

** I had several massive experimental surgeries in the early 1970's for lymphedema at Good Samaritan Hospital, which is now Legacy. My questions are, "is this really the answer?  Have you also warned your patients about the possibility of leg or abdominal lymphedema from such a surgery?"  Your peers in the 1960's at the Oregon Health Sciences University wrote a very interesting article about abdominal/leg lymphedema from an abdominal surgery. Pat**

Targeted anti-vascular therapies for ovarian cancer: current evidence.

Targeted anti-vascular therapies for ovarian cancer: current evidence.

Feb 2013


Department of Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.
Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis.

Friday, February 1, 2013

Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin.

Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin.

Jan 2013


Women's College Research Institute, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.


Differentiating ovarian tumors based on developmental pathway may further our understanding of the disease. Traditionally,ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (NECC) and two cohort studies (NHS/NHSII) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and non-dominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelialovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid, or clear cell, whereas non-dominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis, and age were more strongly associated with dominant (RRs = 0.60, 0.83, 1.58, 1.37, respectively) than non-dominant tumors (RRs = 1.03, 0.93, 0.84, 1.14 p-difference = 0.0001, 0.01, 0.0003, 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

Roles of bioactive Sphingolipid metabolites in ovarian cancer cell biomechanics.

Roles of bioactive Sphingolipid metabolites in ovarian cancer cell biomechanics.



Bioactive Sphingolipid metabolites have emerged as important lipid second messengers in the regulation of cell growth, death, motility and many other events. These processes are important in cancer development and progression; thus, sphingolipid metabolites have been implicated in both cancer development and cancer prevention. Despite recent considerable progress in understanding the multi-faceted functions of these bioactive metabolites, little is known about their influence on the biomechanical property of cells. The biomechanical properties of cancer cells change during progression with aggressive and invasive cells being softer compared to their benign counterparts. In this paper, we investigated the effects of exogenous sphingolipid metabolites on the Young's modulus and cytoskeletal organization of cells representing aggressive ovarian cancer. Our findings demonstrate that the elasticity of aggressive ovarian cancer cells decreased ∼15% after treatment with ceramide and sphingosine-1-phosphate. In contrast, sphingosine treatment caused a ∼30% increase in the average elasticity which was associated with a more defined actin cytoskeleton organization. This indicates that sphingolipid metabolites differentially modulate the biomechanic properties of cancer cells which may have a critical impact on cancer cell survival and progression, and the use of sphingolipid metabolites as chemopreventive or chemo-therapeutic agents.

Diabetes Drug May Improve Survival in Patients With Ovarian Cancer

Diabetes Drug May Improve Survival in Patients With Ovarian Cancer

Lauren M. Green
Published Online: Wednesday, January 30, 2013 

The oral diabetic medication metformin may help improve survival in patients with ovarian cancer, according to the results of a retrospective case-control study from the Mayo Clinic in Rochester, Minnesota.

Previous studies have shown promise for metformin as an anticancer compound. For this study, researchers used Mayo Clinic hospital records to identify patients with ovarian cancer who also received metformin for a minimum of 1 year at or after their cancer diagnosis (mean duration = 2.3 years; range, 1-11 years). Duration of metformin therapy prior to their cancer diagnosis was unknown.

The study’s ovarian cancer cohort comprised women with ovarian cancer who were also taking metformin (n = 72) and a randomly selected control group of patients with ovarian cancer who did not receive metformin (n = 143). Median disease-specific survival (DSS) for the entire group was 5.5 years. For the control group, the 5-year survival rate was 44%, whereas the survival rate for patients on metformin was 73% (P = .002).

Because epithelial ovarian cancer (EOC) accounts for most ovarian cancer mortality, the researchers identified a subset of patients with EOC from the initial cohort who had received metformin (n = 61) and compared these cases with a control group of patients with ovarian cancer who had not received metformin (n =178). Variables such as age, disease stage, histology, and receipt of platinum- versus non-platinum–based chemotherapy were similar between the two groups, which together comprised the EOC cohort (N = 239).

For the entire EOC cohort, the 5-year DSS rate was 52%. For the subset of EOC cases taking metformin, the DSS rate was significantly better than DSS in the control group: 67% versus 47%, respectively (P = .006). The researchers found that metformin was an independent predictor of survival, even after adjusting for body mass index, tumor grade, histology, surgical cytoreduction, disease stage, and chemotherapy (hazard ratio = 2.2; 95% CI, 1.2-3.8; P = .007).

When the EOC cohort was compared with a diabetic control group of patients with EOC whose diabetes was being treated with insulin or medications other than metformin (n = 103), 5-year DSS was lower for the diabetic control group (40%) as compared with the EOC cohort and nondiabetic controls. In this analysis, researchers also looked at 5-year DSS associated with specific antidiabetic medications. Metformin use was associated with a higher DSS rate (67%) than insulin (43%) and other antidiabetic medications (34%; P = .004).

The researchers noted that their findings are consistent with an earlier University of Chicago study reported in the January 2012 issue of Obstetrics & Gynecology, which found an association between metformin and improved recurrence-free survival in patients with ovarian cancer.

“Our study demonstrated improved survival in women with ovarian cancer who were also taking metformin,” co-lead author Sanjeev Kumar, MBBS, a fellow in Gynecologic Oncology at the Mayo Clinic, said in a statement. “Although causation could not be assessed by our retrospective study, metformin nevertheless is a strong contender for further clinical studies in ovarian cancer,” the researchers concluded.

Wednesday, January 30, 2013

High Calcium may Flag Ovarian Cancer

High Calcium may Flag Ovarian Cancer

Tuesday - January 29, 2013

Nick Tate

In a groundbreaking new study, researchers from Wake Forest Baptist Medical Center have found high blood calcium levels might flag ovarian cancer — the most lethal of the gynecologic cancers.

The finding, published online in the journal Gynecologic Oncology, could point the way to a new way to predict women who may be at greater risk of developing ovarian cancer, which is often diagnosed late when it is harder to treat.

Lead researcher Gary G. Schwartz, a cancer epidemiologist at Wake Forest Baptist, made the connection by examining associations between blood calcium and ovarian cancer in two groups of cancer patients. Schwartz and co-researcher Halcyon G. Skinner, of the University of Wisconsin Carbone Cancer Center, found women who were later diagnosed with ovarian cancer and women who later died of ovarian cancer had higher levels of calcium in their blood than women who did not before their cancer diagnosis.

Schwartz said the idea for this study sprung from earlier research that showed men with high calcium levels were at increased risk of aggressive prostate cancer. That led him to wonder if a similar relationship were true of ovarian cancer.

"One approach to cancer biomarker discovery is to identify a factor that is differentially expressed in individuals with and without cancer and to examine that factor's ability to detect cancer in an independent sample of individuals," Schwartz said.

"Everyone's got calcium and the body regulates it very tightly," Skinner added. "We know that some rare forms of ovarian cancer are associated with very high calcium, so it's worth considering whether more common ovarian cancers are associated with moderately high calcium."

The researchers explained that tumors in many cancers produce increased levels of a protein — known as PTRHrP (parathyroid hormone-related protein) — that raise calcium levels in blood.

The finding could be particularly significant for patients who develop types of cancer, such as ovarian cancer, that have high fatality rates because they are hard to detect early.

Schwartz said the findings could lead to the use of a calcium biomarker to diagnose ovarian cancer early, but noted more research is needed.

"We found the link between serum calcium and ovarian cancer; we confirmed it, and even though the study is small, we're reporting it because it's a very simple thing in theory to test," he said.


Role of heparan sulfatases in ovarian and breast cancer.

Role of heparan sulfatases in ovarian and breast cancer.



Department of Experimental Pathology, Mayo Clinic College of Medicine Rochester, MN, USA.


Endosulfatases HSulf-1 and -2 (also referred to as Sulf1 and -2) represent a family of enzymes that modulate heparin binding growth factor signaling. Heparan sulfatase 1 (HSulf-1) and heparan sulfatase 2 (HSulf-2) are two important 6-O endosulfatases which remove or edit 6-O sulfate residues of N-glucosamine present on highly sulfated HS. Alteration of heparan sulfatases have been identified in the context of several cancer types. Many cancer types either exhibit increased or decreased HSulfs expression at the transcript levels. Specifically, HSulf-1 was found to be downregulated in early-stageovarian tumors, hepatocellular carcinoma, and metastatic breast cancer patients. HSulf-2 was found to be upregulated in ductal carcinoma in situ and invasive ductal carcinoma, whereas limited information is present about HSulf-2 expression in different stages of ovarian cancers. Here, we review the important role of these sulfatases play in ovarian and breast cancers in terms of tumorigenesis such as angiogenesis, chemoresistance, apoptosis, growth factor signaling, hypoxia and metastasis. These recent discoveries have added significant understanding about these sulfate editing enzymes.

Monday, January 21, 2013

The association between MTHFR C677T polymorphism and ovarian cancer risk: a meta-analysis of 18, 628 individuals.

The association between MTHFR C677T polymorphism and ovarian cancer risk: a meta-analysis of 18, 628 individuals.

Jan 2013


Department of Gynecology, Changning Maternity and Infant Health Hospital of Shanghai, 773 Wuyi Road, Shanghai, 200051, China.


Methylenetetrahydrofolate reductase (MTHFR) enzyme plays an important role in folate metabolism and MTHFR polymorphisms have been suggested to be associated with risk of various cancers. MTHFR C677T polymorphism is a common genetic alteration and may affect the host susceptibility to ovarian cancer. The aim of this study was to investigate the association between MTHFR C677T polymorphism and ovarian cancer risk by performing a meta-analysis. Pubmed, Embase, Web of Science and Chinese Biomedical Database (CBM) databases were searched for case-control studies investigating the association between MTHFR C677T polymorphism and ovarian cancer. Odds ratio (OR) and its 95 % confidence interval (95 % CI) was used to assess this possible association. 13 individual case-control studies from 10 publications with a total of 18, 628 subjects (5, 932 cases and 12, 696 controls) were included into this meta-analysis. Meta-analyses showed there was no association between MTHFR C677T polymorphism and ovarian cancer risk in Caucasians under all five genetic models (All P values for the pooled ORs were more than 0.05), whereas there was an obvious association between MTHFR C677T polymorphism and ovarian cancer risk in Asians under four genetic models (for T vs C, OR (95 % CI) = 1.38(1.19-1.61); for TT vs CC, OR (95 % CI) = 2.32(1.63-3.29); for TT vs TC+CC, OR (95 % CI) = 2.04(1.47-2.85); for TT+TC vs CC, OR (95 % CI) = 1.36(1.12-1.65)). Subgroup analyses suggested ethnicity was the major source of heterogeneity. This meta-analysis supports an association between MTHFR C677T polymorphism and ovarian cancer risk, and there might be a race-specific effect in this association. Further studies with large sample size and careful design are needed to identify this association more comprehensively.

Sunday, January 13, 2013

Breastfeeding babies can reduce a mother's risk of Ovarian cancer by two-thirds

Breastfeeding babies can reduce a mother's risk of Ovarian cancer by two-thirds

Breastfeeding her baby can reduce a mother’s risk of ovarian cancer by nearly two-thirds, according to scientists.

And the longer she continues to do it, the greater the protection against the illness.

The research adds to evidence of the benefits of natural feeding as numerous studies  have already shown it cuts the chance of  breast cancer.

More than 6,000 patients a year in the UK are diagnosed with ovarian cancer, and the illness accounts for about 5 per cent of cancer deaths in women.

It is known as the ‘silent killer’ because symptoms for many sufferers, such as feeling bloated, are non-specific and the illness may not be diagnosed until it is fairly advanced.

For the latest study, Australian scientists studied 493 women diagnosed with ovarian cancer and compared them with 472 healthy volunteers of similar age.

Each was asked how many children they had and for how long they breastfed each one.

The results showed those who breastfed a child for at least 13 months were 63 per cent less likely to develop a tumour than those who did so for less than seven months.

The more children they had, the greater the effect, said the findings, published in the American Journal of Clinical Nutrition. Mothers who had three children and breastfed for a total of 31 months or more were found to cut their chances of ovarian tumours by 91 per cent. This was compared to those feeding naturally for a total of under ten months.

Breastfeeding is thought to help as it delays ovulation, when eggs are released and the ovaries are exposed to high levels of oestrogen-rich fluid.

Some researchers believe a higher number of ovulations raises the risk of mutant cells forming, which can trigger the disease.

But surveys have shown the UK has one of the lowest breastfeeding rates in Europe.

Nearly eight in ten mothers start when their baby is born but after six weeks, this is down to half.

After six months – the recommended time for exclusive breastfeeding – it is only 26 per cent.

The main risk factors for ovarian cancer include a family history of the disease, having already had breast cancer, starting periods at a young age and being overweight.

Dr Helga Groll, of Cancer Research UK, said the findings backed up earlier evidence on the benefits of breastfeeding.

But she warned that some mothers may not accurately remember for how long they had breastfed.

Gilda Witte, chief executive of Ovarian Cancer Action, added: ‘It is proven that breastfeeding can reduce the risk of ovarian cancer.

‘It does this because it reduces ovulation for the nursing mother.

‘The risk is further reduced by each child that a woman bears.’