Managing Endometriosis To Prevent Ovarian Cancer

Endometriosis is a common condition, occurring in this country in 1 of 10 women of reproductive age. An association between endometriosis and subsequent ovarian carcinoma has been reported for decades, yet it is only recently that our knowledge has deepened enough to support more rational methods for preventing the malignancy.

Each year, approximately 22,000 new cases of ovarian cancer are diagnosed. The lifetime risk of developing this malignancy is low, but it is the deadliest of the gynecologic malignancies, with diagnosis usually made in advanced stages when prognosis is poor.

Endometriosis shows some characteristics of malignancy, such as the development of local and distant foci, and attachment to and invasion of other tissues with subsequent damage to these tissues. Endometriosis also is characterized by recurrent, unregulated cell proliferation and estrogen-dependent growth.

Our attempts during the past 2 decades to detect ovarian carcinoma at the early stages through a combined screening modality involving transvaginal ultrasound and a test for the serum level of cancer antigen 125 have failed to provide any survival benefit or even any measurable reduction in morbidity. Today, early-stage ovarian carcinoma, which has a 5-year survival rate of more than 90%, is diagnosed in only a minority of women.

There is good news, however. In recent years our insight into the pathophysiology of ovarian cancer has deepened, providing us with a new paradigm for ovarian cancer pathogenesis that divides ovarian epithelial carcinoma into two distinct types with distinct molecular profiles – one which originates largely in the distal portion of the fallopian tube and the other which traces back to endometriosis.

This new paradigm strengthens and helps to explain the reported association between endometriosis and ovarian cancer. It also has important clinical implications for current practice. While we have much more to learn about the etiology of endometriosis and the causes of malignant transformation, our current knowledge provides a strong rationale for identification and close monitoring of some patients with endometriosis deemed at risk for ovarian cancer, risk-reducing medical management, earlier and more meticulous surgical treatment, and close monitoring.

By combining this new approach to endometriosis with consideration of salpingectomy after completion of childbearing, we have an unprecedented opportunity to reduce the incidence of epithelial ovarian cancer.

Dual Pathogenesis

The majority of ovarian cancers are of epithelial origin and fall into four histologic categories: serous, endometrioid, clear cell, and mucinous. In recent years, we have gained a deeper understanding of the pathogenesis of ovarian carcinoma, with an array of epidemiologic, histologic, and molecular data showing us that epithelial ovarian cancers are also of two distinct types (Am J Obstet Gynecol. 2015 Sep;213[3]:262-7).

One of these types, a high-grade serous carcinoma, appears to arise in many cases in the epithelium of the fallopian tube. The other type of tumor is a low-grade carcinoma – particularly of the endometrioid and clear cell histologic subtypes – that originates largely from ovarian endometriotic lesions or from borderline serous tumors in the case of serous histology.

The majority of diagnosed stage 1 ovarian cancers are carcinomas of this low-grade type and not high-grade serous carcinomas. In a study of 76 consecutive stage 1 carcinomas, investigators found that ovarian endometriosis was present in 40 of the 76 cases. More than two-thirds of the 76 cases (71%) were nonserous cancers, and almost all of these cases were associated with endometriosis based on histologic examination (Fertil Steril. 2007 Oct;88[4]:906-10).

This study was among the first to show that the majority of stage 1 ovarian carcinomas are not high-grade serous carcinomas, but rather nonserous, primarily endometrioid and clear cell, cancers. The research demonstrated that endometriosis should be viewed as a potential precursor lesion to specific subtypes of ovarian cancer.

The malignant transformation of endometriosis was first suggested by Dr. J. A. Sampson in 1925, and a number of studies – in addition to the 2007 landmark study – have since described ovarian cancer arising from endometriosis, based on the frequent co-occurrence in surgical specimens.

Most recently, a study from the Ovarian Cancer Association Consortium (OCAC) found that women who reported a history of endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio, 1.46).

Investigators of this critical study pooled data from 13 ovarian cancer case-control studies involving more than 13,226 controls and 7,911 women with invasive epithelial ovarian cancer – 818 (6.2%) and 738 (9.3%) of whom, respectively, reported a history of endometriosis. Specifically, they determined that self-reported endometriosis was associated with a 3.05-fold increased risk for clear cell invasive ovarian cancer and a 2.04-fold increased risk of endometrioid ovarian cancer.

Moreover, a significant association between preexisting endometriosis and low-grade serous invasive ovarian cancer (OR, 2.11) was demonstrated, while no association was found between endometriosis and the risk of high-grade serous invasive ovarian cancer (Lancet Oncol. 2012 Apr;13[4]:385-94).

A second recently published report – a meta-analysis of 20 case-control and 15 cohort studies published between 1990 and 2012 and involving more than 444,000 patients – found that endometriosis increased cancer risk in case-control or two-arm cohort studies by 27% (relative risk, 1.265) and by approximately 80% in single-arm cohort studies (standard incidence ratio, 1.797). Endometrioid and clear cell carcinomas were more common in endometriosis-associated ovarian cancer, while serous carcinoma was less frequent (Br J Cancer. 2014 Apr 2;110[7]:1878-90).

Findings of both of these large studies have served to clarify the association between endometriosis and specific histologic subtypes and suggested that there are important differences in the pathogenesis of low-grade and high-grade serous ovarian carcinomas.

Clinical Implications

It is not clear what causes malignant transformation or what predisposes some patients with endometriosis to develop ovarian cancer, but the risk likely involves genetic and epigenetic influences as well as immunologic, inflammatory, and hormonal factors.

The molecular profiles of the main two types of ovarian cancer are different: While the majority of high-grade serous ovarian tumors are characterized by TP53 mutations, the low-grade carcinomas are characterized by a variety of mutations, including KRAS, BRAF, ERBB2, CTNNB1, and BCL2 mutations.

There currently are not enough data to recommend genetic screening tests in patients with endometriosis, but our hope is that we eventually will be able to screen for “high-risk” endometriotic lesions by testing for genes specific to various histologic subtypes of low-grade ovarian cancer, or by finding and utilizing other biomarkers.

In the meantime, we believe it is important to more thoroughly treat endometriosis and to identify and follow women with a history of the condition, especially those with a long-standing history, those with a history of endometriosis associated with infertility, and those with ovarian endometrioma. Each of these factors predisposes patients to a higher risk of malignant transformation.

Complete surgical resection of all visible endometriosis is the most effective treatment and will afford the best cancer prevention, even in women who are asymptomatic. In a recent Swedish national registry case-control study, women who underwent radical surgical excision of all visible endometriosis were significantly less likely (OR, 0.30) to develop ovarian cancer (Acta Obstet Gynecol Scand. 2013 May;92[5]:546-54).

Suppressive hormonal therapy is another treatment option for patients with no interest in conceiving. Most large endometriomas are functional ovarian cysts that have been invaded by cortical ovarian endometriosis or by small primary endometriomas (J Reprod Med. 1992 Sep;37[9]:771-6).

While hormonal therapy will not always result in complete regression of endometriotic lesions, it will decrease the recurrence rate of endometriomas and can be considered for long-term prevention of potentially premalignant lesions. It is most effective when it follows surgical excision of endometriomas and associated endometriosis.

A patient who has completed childbearing at the time of surgical resection may be offered bilateral salpingectomy, regardless of menopausal status. Salpingectomy in both average and high-risk populations (e.g., BRCA 1/2 carriers) not only prevents high-grade serous carcinoma by eliminating the site of origin, but also may decrease the risk of endometrioid and clear cell carcinoma by blocking the passageway that enables the flow of endometrium and factors that induce inflammation. It is estimated that the procedure reduces the risk of ovarian cancer by 40%.

Interestingly, tubal ligation has historically been shown to decrease the risk of ovarian cancer, and recent data have shown that the risk of endometrioid and clear cell carcinoma is cut even more than the risk of high-grade serous carcinoma (Int J Epidemiol. 2013 Apr;42[2]:579-89).

The Society of Gynecologic Oncology recommends that risk-reducing salpingectomy be considered at the time of hysterectomy or other abdominal or pelvic surgery, and in lieu of tubal ligation. The American College of Obstetricians and Gynecologists similarly has stated that prophylactic salpingectomy may offer clinicians the opportunity to prevent ovarian cancer in their patients. Salpingectomy is an important option for all patients, but is especially important when the fallopian tubes are found to be damaged by endometriosis and/or pelvic inflammatory disease. When imaging studies show that endometriomas are present and resection is not performed, pelvic ultrasound should become part of the patient’s routine examination.

Most endometriomas have a homogeneous appearance; any significant increase in size or a change in the homogeneous cystic characteristics to a more heterogeneous appearance with mural components should raise suspicion about malignant change.

It can be difficult to detect relatively small endocystic components with ultrasound, so if there is any doubt about whether there is some heterogeneous consistency, an MRI should be performed. MRI is showing more promise in detecting malignant change. Hyperdense mural nodules within the ovary and rapid growth of an endometrioma have both been associated with malignant transformation and can be seen on these images.

In a cohort study comparing MRI findings of 10 patients with ovarian adenocarcinoma to 10 patients with benign endometriomas, investigators found mural nodules in all 10 malignancies but in only three of the benign cases (AJR Am J Roentgenol. 2000 Nov;175[5]:1423-30).

Long-term follow-up is necessary to understand the timeline of transformation in patients with mural nodules. This together with increasing knowledge of molecular events underpinning evolution of endometriosis will lead to better screening and preventive strategies.

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

Gene Testing Could Help Predict Ovarian Cancer Patients’ Sensitivity to New Class of Drugs

Testing for a gene commonly mutated in ovarian cancers could pick out patients who will respond well to a promising new class of cancer drugs, a major new study reveals.

Scientists found that defects in a gene called ARID1A caused sensitivity to new drugs targeting the DNA repair process within tumour cells.

The new drugs – called ATR inhibitors – are already being tested in early clinical trials, and the new research could help identify those patients who will benefit most.

Scientists at The Institute of Cancer Research, London, used molecular screening techniques to find that cancers with mutations in ARID1A were particularly sensitive to ATR inhibitors.

ARID1A is mutated in a wide range of hard-to-treat tumour types, including ovarian cancer and stomach cancer, but until now there has been no way of targeting treatment at tumours with this genetic defect.

The research, which is published in the journal Nature Communications, was funded by Cancer Research UK and Breast Cancer Now.

Scientists at The Institute of Cancer Research (ICR) found that ATR inhibitors stopped cancer cells with ARID1A mutations from growing, both in culture dishes and in mice.

They also found that switching off the ARID1A gene in breast and bowel cancer cells greatly increased their sensitivity to ATR inhibitors.

The researchers found the treatment killed cancer cells with ARID1A mutations through a process called ‘synthetic lethality’.

Cancer cells with ARID1A mutations become particularly reliant on the DNA safeguarding activity of the ATR protein to survive – so they are especially sensitive to drugs that block its effects.

Patients on clinical trials of ATR inhibitors could now start to be tested for ARID1A mutations in their tumours – in order to assess whether those with the genetic defects are particularly likely to benefit.

Dr Chris Lord, Leader of the Gene Function Team at The Institute of Cancer Research, London, said: “Our research has opened up a potential way of personalising treatment for cancer by targeting drugs to those patients who will benefit most.

“We found in cell cultures and in mice that cancers with defective versions of the ARID1A gene are particularly sensitive to a new class of drug called ATR inhibitors.”

“Our research could lead to patients with ARID1A mutant tumours being assessed for whether they respond particularly well to this new class of cancer treatment.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “By identifying a potential way to exploit a specific genetic vulnerability in cancer this research could point the way to tailoring treatments to each patient, helping to make them kinder and more effective. The next steps will be to better understand the effects of targeting this weakness, and to find out whether this promising strategy will work in people.”

Katie Goates, Senior Research Communications Officer at Breast Cancer Now, said: “This early finding could bring us a step closer to more ‘personalised’ medicine, targeting treatment to exploit weaknesses in patients’ tumours and hopefully improve their chances of survival.

“It’s particularly exciting to see an idea that was initially tested in breast cancer cells be translated into potential benefit for a number of other cancers. We hope these findings now lay the groundwork for clinical trials to investigate the potential of ATR inhibitors as a targeted cancer treatment in the near future.”

To read this full article on News Medical Life Sciences, please click here.

Liquid Biopsy Monitors Response in Ovarian Cancer

Another study shows that a “liquid biopsy” that measures levels of circulating tumor DNA (ctDNA) can be useful for monitoring cancer patients – this time patients with ovarian cancer.

At a recent cancer research meeting, experts predicted that liquid biopsies are “the future.” Jean-Charles Soria, MD, chair of the scientific committee for the EORTC-NCI-AACR symposium and director of the Site de Recherche Intégrée sur le Cancer (SIRIC) Socrate project at Gustave Roussy Cancer Campus, Paris, said that liquid biopsies are going to “completely change the rules of engagement” for patient management and clinical practice.

Dr Soria continued: “I really think ― and I’m ready to bet ― that this is the most transformational thing that’s going to happen in oncology in terms of how it’s going to impact cancer clinical trials and cancer daily management for the next 5 years.”

The latest study, conducted by researchers from Cancer Research UK Cambridge Institute, was published online December 20 in PLOS Medicine. The researchers found that ctDNA test results correlated with the size of ovarian cancers and was predictive of response to treatment or time to disease progression.

“These findings have strong potential for clinical utility owing to the ease of assaying DNA in plasma and the low cost and speed of ctDNA testing,” write the authors, led by Nitzan Rosenfeld, PhD, and James Brenton, MD, PhD, both of Cancer Research UK. “Having very early information on response would empower patients and physicians to test alternative treatment options and have high utility in trials that link biomarkers to targeted therapy.”

The standard clinical blood test used in ovarian cancer is the serum protein cancer antigen 125 (CA-125), which is sensitive but lacks specificity for detecting ovarian cancer, note the authors. In addition, CA-125 levels do not change quickly enough following treatment to inform decisions regarding changes in chemotherapy after one or two cycles in cases in which the patient is not responding.

Therefore, there is a need for better tumor markers, and ctDNA is a promising candidate, the authors suggest.

Sensitive to Treatment Response

Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). Dr Rosenfeld, Dr Brenton, and colleagues evaluated the use of these mutations as personalized markers to monitor tumor burden, early response to treatment, and time to progression.

They conducted a retrospective analysis using 318 blood samples that had been obtained from 40 HGSOC patients. Patient-specific TP53 assays were designed and used to quantify the amount of ctDNA in the samples that were collected before, during, and after chemotherapy.

Of these samples, 261 were collected during treatment of relapsed disease. Treatment included 54 courses of chemotherapy (n = 32 patients). An additional 57 specimens were collected from 12 patients during first-line treatment with chemotherapy.

The findings showed that the fraction of mutated TP53 in ctDNA (TP53MAF) had a significant correlation with disease volume, as measured by CT scan (Pearson r = 0.59; P < .001). Pretreatment TP53MAF levels correlated with the time to progression.

These findings are consistent with previous studies across a range of tumor types, note the authors, which found that ctDNA levels increase as stage increases.

Patient response to chemotherapy was seen much earlier with ctDNA, with a median time of 37 days, as compared to 84 days with CA-125.

The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04%/cm³) as compared to patients who were untreated (0.0008%/cm³; P = .004).

In 49 treatment courses for relapsed disease, pretreatment TP53MAF concentration, but not CA-125, was associated with time to progression.

Among patients being treated for relapsed disease, a decrease in TP53MAF of >60% was an independent predictor of longer time to progression (hazard ratio, 0.22; P = .008), whereas a decrease in TP53MAF of ≤60% was associated with poor response and could identify patients for whom time to progression was less than 6 months (sensitivity, 71%; specificity, 88%).

“TP53 ctDNA has the potential to be a clinically useful blood test to assess prognosis and response to treatment in women with HGSOC,” they conclude.

These findings need to be confirmed in larger, prospective studies with patients receiving uniform treatment, the authors comment. If the findings do hold up, then “TP53 ctDNA could be used in HGSOC clinical trials and routine practice to identify earlier whether treatment is effective,” the authors add.

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

Drug Combo Promising in Recurrent Ovarian Cancer

Heavily pre-treated patients with recurrent ovarian cancer have limited options when it comes to regimens that can control disease while maintaining a satisfactory quality of life.

Now, a phase II open-label study has demonstrated that a combination of the camptothecin analog irinotecan (Camptosar), and bevacizumab (Avastin) may be a safe and effective alternative in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

In the study population of 29 women with recurrent ovarian cancer and prior exposure to topotecan (37.9%), and bevacizumab (44.6%), median progression-free survival (PFS) was 6.8 months and median overall survival (OS) was 15.4 months, Amy Tiersten, MD, of the Perlmutter Cancer at New York University Langone Medical Center in New York City and colleagues reported online in Gynecologic Oncology.

Twelve of 24 patients with measurable disease had a response lasting longer than 6 months. The most common grade 3/4 toxicity was diarrhea, and there were no treatment-related deaths.

“Our data not only supports the activity of repeated uses of bevacizumab, but also confirms the safety of this strategy in heavily pre-treated patients,” the researchers wrote. “This is very relevant, as insurance companies are increasingly reluctant to support subsequent access to bevacizumab if it has been used earlier in a patient’s disease course.”

A targeted inhibitor of vascular endothelial growth factor A (VEGFA), bevacizumab has been studied extensively in ovarian cancer and shown to improve PFS in both the upfront and recurrent setting, Tiersten and colleagues noted.

A partial response (PR) was documented in eight patients (30%), and at first assessment, 13 patients maintained stable disease (SD). While no complete response (CR) was observed, the objective response rate (ORR) was 27.6%, and the clinical benefit rate — a measure of CR, PR, and SD — was 72.4%.

“This is notable for this patient population with a median of five prior regimens and diminished reserve,” the researchers said.

“It is also notable that 40% of patients in this study had had prior bevacizumab and yet still responded to a regimen with bevacizumab,” another of the co-authors, Stephanie V. Blank, MD, of NYU Langone Medical Center, said via email. “This may make us rethink how we use bevacizumab in treating patients with recurrent ovarian cancer.

“Ovarian cancer is a very heterogeneous disease, and we need to approach it as such. This is not a one-size-fits-all type of condition. Research funding for ovarian cancer needs to happen to improve the management of patients with recurrent ovarian cancer. The more we learn, the more we can tailor therapies to specific patients.”

Despite excellent response rates with platinum-based chemotherapy, most patients present with advanced stage disease relapse, the researchers pointed out. Treatment for women who experience multiple recurrences is limited, particularly in the presence of platinum-resistant disease and diminished reserve.

This study builds on findings from the AURELIA trial, an open-label randomized phase III trial that assessed the safety and efficacy of adding bevacizumab to physician’s choice chemotherapy in 361 platinum-resistant ovarian cancer patients.

Despite the fact that only 7% of patients in that study had received prior bevacizumab, progression-free survival and toxicity findings were comparable.

“Our study expands on the chemotherapy combinations with bevacizumab studied in AURELIA in the treatment of recurrent ovarian cancer and offers a safe and efficacious alternative,” the researchers said. “Further, the preponderance of patients who had repeated treatment with bevacizumab in this study (>40%) provides much needed data to support a rationale for repeated use of bevacizumab later in a patient’s disease course.”

A total of 29 patients with a median age of 62 were enrolled in the study between April 2010 and May 2013. All had ovarian epithelial, fallopian tube, or primary peritoneal carcinoma that was recurrent, refractory, or persistent.

Of the 29 patients, 24 had measurable disease, and five had evaluable disease with two or more CA125 levels ≥ 50 at least one week apart. The median number of prior regimens the patients had received was five.

Patients received the topoisomerase 1 inhibitor irinotecan at 250 mg/m², as per an earlier trial, and the antiangiogenic agent bevacizumab at 15 mg/kg every 21 days until disease progression or toxicity. After dose-related toxicity was observed in the first six enrolled patients, however, the initial dose of irinotecan was lowered to 175 mg/m².

The median number of study cycles was seven. Every two cycles, the response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) or CA-125 criteria.

Ten patients (34.5%) were platinum-sensitive and had disease recurrence 6 months or longer after the last treatment with platinum-containing chemotherapy.

A total of 19 women (65.5%) were platinum-resistant and had recurrences within 6 months of the last platinum-containing regimen.

Limitations of the study include the fact that it was not designed to target a more homogenous population of platinum-resistant patients, the researchers said. “Arguably, [this] would have allowed us to see a stronger signal of activity.”

In addition, the design did not make it possible to compare the drug combination with single-agent irinotecan or to quantify the benefit of added bevacizumab.

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

FDA Grants Priority Review To Niraparib For Gynecologic Cancers

The FDA granted priority review to niraparib for the treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer following response to platinum-based chemotherapy, according to the drug’s manufacturer.

“FDA’s acceptance of the niraparib new drug application with a priority review designation is an important milestone for Tesaro, and represents a significant step in our efforts to bring meaningful therapies to women with ovarian cancer,” Mary Lynne Hedley, PhD, president and chief operation officer of TESARO, said in a press release. “We believe niraparib could become an important new treatment option for patients with recurrent ovarian cancer, and we look forward to working with the FDA during the review process.”

The ENGOT-OV16/NOVA trial — a double blind, placebo-controlled, international phase 3 study of niraparib (formerly MK-4827, Tesaro) in 533 patients — achieved its primary endpoint in both cohorts, which were based upon germline BRCA mutation status.

BRCA mutation carriers who underwent niraparib treatment demonstrated superior PFS compared with the control arm (21 months vs. 5.5 months; HR = 0.27; 95% CI, 0.17-0.41).

The non-germline BRCA mutant cohort who underwent treatment also had superior PFS (9.3 months vs. 3.9 months; HR = 0.45; 95% CI, 0.34-0.61).

Therefore, the proposed indication included the use of niraparib regardless of tumor biomarker status.

The BRACAnalysis CDx (Myriad Genetics) and myChoice HRD (Myriad Genetics) tests are anticipated to be available as complementary diagnostics, according to the release.

The most common grade 3 to grade 4 adverse events included thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%).

An expanded access program for niraparib in the United States is planned to open in January 2017.

The FDA established a target action date of June 30, 2017 to make a decision regarding this application.

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

In Battle Against Ovarian Cancer, A New Focus on Fallopian Tubes

Two thin tubes that connect the ovaries to the uterus have assumed an outsize role in the battle against ovarian cancer.

Research increasingly points to the likelihood that some of the most aggressive ovarian cancers originate in the fallopian tubes. Most doctors now believe there is little to lose by removing the tubes of women who are done bearing children — and potentially much to gain in terms of cancer prevention.

The stakes in this research are high. Ovarian cancer is the deadliest of gynecologic cancers, killing 14,000 women a year in the United States. It is often diagnosed in the late stages, when it is more difficult to treat.

Routine screening tests to identify it early largely have been discredited. Earlier this fall, the U.S. Food and Drug Administration released a statement recommending against their use. For that reason, prevention is particularly important.

“It’s a really interesting topic and it’s practice-changing,” said Dr. Noelle Cloven, a gynecologic oncologist with Texas Oncology in Fort Worth. “Any opportunity to decrease the risk of ovarian cancer or improve our understanding of ovarian cancer, I’m in support of that. It’s a terrible disease.”

The risks associated with the removal of the fallopian tubes — known as salpingectomy — appear to be minimal, according to a study by Kaiser Permanente Northern California, which was published this summer in the journal Obstetrics & Gynecology. (Kaiser Health News is not affiliated with Kaiser Permanente.)

Between June 2013 and May 2014, nearly 73 percent of the women in the study had their fallopian tubes removed while undergoing a routine hysterectomy. Just two years earlier, fewer than 15 percent of a comparable group had. The large increase yielded no difference in surgical outcomes. And operating times and blood loss were slightly improved for patients whose fallopian tubes were removed.

Dr. Bethan Powell, senior author of the study and a gynecologic oncology surgeon with Kaiser Permanente, said the fallopian tubes until recently have been “a neglected region.” As a result, when women were undergoing hysterectomy — the removal of the uterus and cervix — the tubes were often left behind.

“Nobody thought it made any difference which side you put your clamp on,” Powell said. “If there are health benefits to leaving the ovary, we should leave the ovary. But there’s no reason we should leave the tube.”

In recent years, two medical societies have issued statements about the importance of removing the fallopian tubes. In 2013, the Society of Gynecologic Oncology developed a clinical practice statement recommending the removal of both fallopian tubes as “a viable approach to prevent ovarian cancer.”

In 2015, the American College of Obstetricians and Gynecologists recommended that surgeons discuss the potential cancer prevention benefits of the procedure with their patients.

While it’s now recommended that patients have their tubes removed during a routine hysterectomy, doctors are still wrestling with more complicated scenarios.

Jennifer Klute, 35, a speech-language pathologist in Napa, Calif., was diagnosed breast cancer in 2015. She’d first noticed a lump while breastfeeding her daughter, Genevieve, and doctors initially reassured her that the lump was probably related to that.

Then the lumps multiplied. Biopsies were ordered. Klute received the dreaded phone call, and cut short a family vacation to Nebraska.

Klute had a family history of breast cancer and a genetic test revealed a BRCA1 mutation. Women who are positive for the BRCA1 mutation have a 39 percent likelihood of developing ovarian cancer, in addition to a 55 to 65 percent likelihood of developing breast cancer.

Klute faced a difficult decision.

It’s recommended that women with the mutation have their fallopian tubes and ovaries removed between the ages of 35 and 40, as Angelina Jolie did in 2015.  Jolie earlier had a preventive double mastectomy.

Removal of the ovaries has significant cancer prevention benefits—both for ovarian and breast cancer. But it also carries real consequences, particularly for younger women like Klute. The ovaries regulate hormones and their removal plunges women into early menopause and increases their risk of osteoporosis, cardiovascular disease and dementia.

Klute had chemotherapy, radiation and a double mastectomy. Once she recovered, her doctor recommended she have her fallopian tubes and ovaries removed. Klute requested a second opinion and ended up meeting with Powell. Klute told Powell that while she had a family history of breast cancer, she didn’t have one of ovarian cancer.

Klute wondered whether she might delay the removal of her ovaries for a few more years. She didn’t plan to have more children, but she knew keeping her ovaries a little longer could reduce her risk of other health problems.

Powell knew that leaving the ovaries in high-risk women is “not recommended and not standard” at this point. But she was willing to discuss the idea with Klute, who eventually opted to keep her ovaries for a little longer. She knows they’ll eventually need to go.

Not all doctors feel comfortable offering such a choice to their high-risk patients. Dr. Jill Whyte, a gynecologic oncologist at Northwell Health on Long Island, is waiting for more data before she’s willing to recommend it.

Cloven, the gynecologic oncologist  in Texas, also said she would be nervous taking that approach unless the patient was “really motivated” and understood the risks of delays. Even then, Cloven said she would prefer that a patient choose that option only if participating in a clinical trial.

Nevertheless, Lisa Schlager, vice president of community affairs and public policy for Facing Our Risk of Cancer Empowered, a non-profit advocacy group devoted to hereditary ovarian and breast cancers, said she thinks more doctors are recommending the approach as an interim step for high-risk women in their 30s.

“If you want to have children and don’t want to be plunged into surgical menopause, the options are: do nothing, do imperfect screening, or in-between,” she said. “That in-between is salpingectomy.”

In Klute’s case, she said the salpingectomy itself was easy: Powell made a small laparoscopic incision to remove the tubes. Klute had a little nausea after she woke and couldn’t lift Genevieve for a few weeks. But the pain was manageable.

She’s now enrolled in two clinical studies and has submitted her information to the National Salpingectomy Registry.

“I think that’s super important,” Klute said. “The more knowledge we have, the more informed decisions we can make — and the greater the outcomes for individuals with cancer.”

To read this entire article by Kaiser Health News, click here.

A 23-year-old Bodybuilder Is Being Ravaged By Ovarian Cancer — And Instagramming It All

Three weeks before her wedding day, Cheyann Shaw uploaded a video to YouTube, a space the fitness fanatic regularly filled with workout clips and health tips.

But this time was different: She was now using the social video platform for a more emotional and profound purpose.

“I’m going to cry,” she said in the video, “but — I was told that I have cancer.”

Shaw has stage 4 low-grade serous ovarian cancer, a rare and slow-growing but stubborn strain that can be resistant to chemotherapy treatments.

Over the past four months, she started chemo — then realized it wasn’t working. She lost her hair — and filmed the moment she shaved her head.

She has been diagnosed and re-diagnosed, and moved from Florida to Washington state to be closer to her family and specialists. She has undergone surgery to remove her reproductive organs, appendix, spleen and part of her colon, along with a tumor from her abdomen that was the size of a small beach ball.

And, she said, she has learned that the ovarian cancer is still in her lymph nodes.

She has been sharing her swift decline from a 130-pound bodybuilder to a 102-pound cancer patient to show that having cancer “doesn’t mean you stop living.”

“I decided to document everything right after I got diagnosed because I wanted to show people what cancer does to a body,” she told The Washington Post last week.

She also wanted “to show people that with a positive mind, you can beat this.”

Shaw, 23, is a real estate assistant for her husband, Kaleb, an agent in Kissimmee, Fla., outside Orlando. She has always been an athlete, playing basketball, softball and soccer. She once raced BMX. Then, about three years ago, she got into fitness.

She had her first bodybuilding competition last year, she said, and was preparing for more shows over the summer when her ovarian cancer was diagnosed.

Shaw said she had started having symptoms, as early as fall 2015; but in June, she found a lump on her abdomen. Her OB/GYN told her it was probably a cyst or some torn abdominal muscles from working out too hard. But the next month, she was making trips to the emergency room, with sharp pains and an inability to keep anything down.

In August, she said, her doctors found the disease.

“Today, August 3rd, 2016 is the day that has changed my life for the moment,” she wrote on Instagram. “I found out today that I have been diagnosed with cancer. . . . I never in a million years thought this would happen to me, especially since I am only 23, but I know I will win this battle.”

Ever since, Shaw has been posting photos, videos and messages to keep family members, friends and supporters updated on a journey that she warned would be unashamedly raw.

“I’m literally going to show you the good, the bad and the ugly,” she said on YouTube, adding, “I’m literally showing you guys everything just so everybody is more aware of ovarian cancer because they do call it ‘the silent killer.’”

Ovarian cancer is uncommon, with about 20,000 U.S. women diagnosed each year, according to the Centers for Disease Control and Prevention. Most common in postmenopausal women, ovarian cancer begins in the ovaries but can still spread throughout the abdomen. In advanced stages, it is more difficult to treat, according to data from Mayo Clinic.

The CDC reports that “ovarian cancer causes more deaths than any other cancer of the female reproductive system, but it accounts for only about 3% of all cancers in women.”

Shaw’s doctor, Renata Urban, said the bodybuilder has epithelial ovarian cancer, in which cancer cells form from the tissues of the gynecologic tract.

Urban, who treats gynecologic oncology patients through the Seattle Cancer Care Alliance, said there is no routine screening for ovarian cancer. It is often not diagnosed until the disease is in stage 3 or 4. For patients who are in the advanced stages, she said, the five-year survival rate is between 30 and 50 percent. The survival rate for epithelial ovarian cancer “is not high,” Urban told The Post.

But, she said, younger patients have been found to have better outcomes.

“Epithelial ovarian cancers are generally found in older women, so, for her age, it’s uncommon,” Urban said of Shaw. “She’s been extremely courageous and has such a positive attitude.”

Shaw showed her first chemo treatment on social media.

“It wasn’t as scary as I thought,” she wrote on Instagram. She bragged on YouTube about her new high-calorie diet of ice cream and macaroni and cheese to help her keep on the pounds during her treatments.

And she posted a photo of her first day back in the gym.

In other posts, she has aimed to shed a tragic but truthful light on cancer.

“I’m human, I cry and I’m scared,” she wrote in one post, adding: “Cancer has taken so much from me already and on nights like tonight, I try to remember that it is okay to cry; it’s good to cry. I don’t have to be strong all the time, but I will not let cancer take my light and my smile.”

In September, she posted a video showing the moment she walked into a hair salon to have her head shaved because, she said, “it just bums me out to see my hair falling out.”

“It’s the moment of truth — I’m getting my hair cut, er not cut, I’m getting my head shaved,” said Shaw, with her long, beach-blond hair.

The following month, she appeared in a video from her bedroom in Seattle, saying she had moved there from Florida. She had learned that hers was a rare form of ovarian cancer, she said, and that it was not responding to chemotherapy treatments, which had taken a harsh toll on the body she had worked so hard to sculpt.

At her lowest, she weighed 102 pounds, and her body had started eating its own muscles for nutrients, she said. She’s now 107.

“I’m skin and bones,” the 5-foot-5 Shaw said.

On Halloween, she went for surgery — filming the moment she went to the hospital, and posting photos after it was done.

“Surgery was 5.5 hours,” she wrote after the operation. “I did have to get a blood transfusion because I did lose a lot of blood. They got all the cancer they could see out, took my spleen, appendix, full hysterectomy, and part of my colon out. I am not cancer free however. There is cancer is a couple lymph nodes. This doesn’t mean I am going to die, it just means I have to fight a lot harder. Scared is an understatement, but I know GOD is with me and I will be fine.”

“Some people may see the cancer being in my lymph nodes a step backwards,” she added, “but I just see it as just another bump in the road. I will never question GOD because I know he is at work to heal me and the devil will try whatever he can to get me to turn my back on the Lord; which will never happen. I will beat this, just have a little longer and harder road to travel on.”

A week later, she posted a picture showing her surgery scar on her now-gaunt stomach.

“When they were in surgery they did find out I’m actually Stage 4 because the cancer was in my spleen and I do have cancer in my lymph nodes, but I’m not worried,” she wrote. “Just another bump to get over and with GOD by my side I’m not scared. I’ll be fine and GOD will get me through this. I have a story to tell and I’m not done telling it and GOD knows that.”

Shaw has started a more targeted form of chemo to attack the cancer in her lymph nodes.

“My life has been turned upside down,” she told The Post. “It’s been hard.”

Shaw said her cancer is not terminal, but “there is a chance it may be terminal if some of the methods we have in place don’t work.”

In her most recent video, she sat at the foot of her bed, answering questions about her struggles and her future plans.

She said that if and when her doctors clear her, she wants to get back to bodybuilding, repairing and restoring herself after her body was ravaged by disease.

“After cancer, I definitely plan on doing more competitions and continuing to build my body because, obviously, I don’t like where it’s at now,” she said. “But I love myself and I love my body because I truly believe that if my body wasn’t where it was when I first began, I truly believe I’d be a lot weaker than I am now. So definitely, bodybuilding has saved me.”

To read this full article on The Washington Post, please click here.

Fallopian Tubes May Have Big Role In Ovarian Cancer Fight

Two thin tubes that connect the ovaries to the uterus have assumed an outsize role in the battle against ovarian cancer.

Research increasingly points to the likelihood that some of the most aggressive ovarian cancers originate in the fallopian tubes. Most doctors now believe there is little to lose by removing the tubes of women who are done bearing children — and potentially much to gain in terms of cancer prevention.

The stakes in this research are high. Ovarian cancer is the deadliest of gynecologic cancers, killing 14,000 women a year in the United States. It is often diagnosed in the late stages, when it is more difficult to treat.

Routine screening tests to identify it early largely have been discredited. Earlier this fall, the U.S. Food and Drug Administration released a statement recommending against their use. For that reason, prevention is particularly important.

“It’s a really interesting topic and it’s practice-changing,” said Dr. Noelle Cloven, a gynecologic oncologist with Texas Oncology in Fort Worth. “Any opportunity to decrease the risk of ovarian cancer or improve our understanding of ovarian cancer, I’m in support of that. It’s a terrible disease.”

The risks associated with the removal of the fallopian tubes — known as salpingectomy — appear to be minimal, according to a study by Kaiser Permanente Northern California, which was published this summer in the journal Obstetrics & Gynecology. (Kaiser Health News is not affiliated with Kaiser Permanente.)

Between June 2013 and May 2014, nearly 73 percent of the women in the study had their fallopian tubes removed while undergoing a routine hysterectomy. Just two years earlier, fewer than 15 percent of a comparable group had. The large increase yielded no difference in surgical outcomes. And operating times and blood loss were slightly improved for patients whose fallopian tubes were removed.

Dr. Bethan Powell, senior author of the study and a gynecologic oncology surgeon with Kaiser Permanente, said the fallopian tubes until recently have been “a neglected region.” As a result, when women were undergoing hysterectomy — the removal of the uterus and cervix — the tubes were often left behind.

“Nobody thought it made any difference which side you put your clamp on,” Powell said. “If there are health benefits to leaving the ovary, we should leave the ovary. But there’s no reason we should leave the tube.”

In recent years, two medical societies have issued statements about the importance of removing the fallopian tubes. In 2013, the Society of Gynecologic Oncology developed a clinical practice statement recommending the removal of both fallopian tubes as “a viable approach to prevent ovarian cancer.”

In 2015, the American College of Obstetricians and Gynecologists recommended that surgeons discuss the potential cancer prevention benefits of the procedure with their patients.

While it’s now recommended that patients have their tubes removed during a routine hysterectomy, doctors are still wrestling with more complicated scenarios.

Jennifer Klute, 35, a speech-language pathologist in Napa, Calif., was diagnosed breast cancer in 2015. She’d first noticed a lump while breastfeeding her daughter, Genevieve, and doctors initially reassured her that the lump was probably related to that.

Then the lumps multiplied. Biopsies were ordered. Klute received the dreaded phone call, and cut short a family vacation to Nebraska.

Klute had a family history of breast cancer and a genetic test revealed a BRCA1 mutation. Women who are positive for the BRCA1 mutation have a 39 percent likelihood of developing ovarian cancer, in addition to a 55 to 65 percent likelihood of developing breast cancer.

Klute faced a difficult decision. It’s recommended that women with the mutation have their fallopian tubes and ovaries removed between the ages of 35 and 40, as actress Angelina Jolie did in 2015. Jolie earlier had a preventive double mastectomy.

Removal of the ovaries has significant cancer prevention benefits — both for ovarian and breast cancer. But it also carries real consequences, particularly for younger women like Klute. The ovaries regulate hormones and their removal plunges women into early menopause and increases their risk of osteoporosis, cardiovascular disease and dementia.

Klute had chemotherapy, radiation and a double mastectomy. Once she recovered, her doctor recommended she have her fallopian tubes and ovaries removed. Klute requested a second opinion and ended up meeting with Powell. Klute told Powell that while she had a family history of breast cancer, she didn’t have one of ovarian cancer.

Klute wondered whether she might delay the removal of her ovaries for a few more years. She didn’t plan to have more children, but she knew keeping her ovaries a little longer could reduce her risk of other health problems.

Powell knew that leaving the ovaries in high-risk women is “not recommended and not standard” at this point. But she was willing to discuss the idea with Klute, who eventually opted to keep her ovaries for a little longer. She knows they’ll eventually need to go.

Not all doctors feel comfortable offering such a choice to their high-risk patients. Dr. Jill Whyte, a gynecologic oncologist at Northwell Health on Long Island, is waiting for more data before she’s willing to recommend it.

Cloven, the gynecologic oncologist in Texas, also said she would be nervous taking that approach unless the patient was “really motivated” and understood the risks of delays. Even then, Cloven said she would prefer that a patient choose that option only if participating in a clinical trial.

Nevertheless, Lisa Schlager, vice president of community affairs and public policy for Facing Our Risk of Cancer Empowered, a non-profit advocacy group devoted to hereditary ovarian and breast cancers, said she thinks more doctors are recommending the approach as an interim step for high-risk women in their 30s.

“If you want to have children and don’t want to be plunged into surgical menopause, the options are: do nothing, do imperfect screening, or in-between,” she said. “That in-between is salpingectomy.”

In Klute’s case, she said the salpingectomy itself was easy: Powell made a small laparoscopic incision to remove the tubes. Klute had a little nausea after she woke and couldn’t lift Genevieve for a few weeks. But the pain was manageable.

She’s now enrolled in two clinical studies and has submitted her information to the National Salpingectomy Registry.

“I think that’s super important,” Klute said. “The more knowledge we have, the more informed decisions we can make — and the greater the outcomes for individuals with cancer.”

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

FDA Approves Rucaparib and Companion Genetic Test in Advanced Deleterious BRCA-Mutated Ovarian Cancer

The U.S. Food and Drug Administration (FDA) today granted accelerated approval to rucaparib (Rubraca) to treat women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test. Today, the FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with rucaparib, which is the first next-generation sequencing–based companion diagnostic approved by the agency. The next-generation sequencing test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with rucaparib.

Targeted-Agent Trend

“Today’s approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient’s genes,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and Acting Director of the FDA’s Oncology Center of Excellence. “Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option.”

The National Cancer Institute estimates that 22,280 women will be diagnosed with ovarian cancer in 2016, and an estimated 14,240 will die of this disease. Approximately 15% to 20% of patients with ovarian cancer have a BRCA gene mutation.

BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rucaparib is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slowdown or stoppage of tumor growth.

Trial Findings

The safety and efficacy of rucaparib were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with 2 or more chemotherapy regimens. BRCA gene mutations were confirmed in 96% of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic.

The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (ie, overall response rate). Fifty-four percent of the participants who received rucaparib in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

Common side effects of rucaparib include nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Rucaparib is also associated with serious risks, such as myelodysplastic syndromes, acute myeloid leukemia, and fetal harm.

To read this entire article on The Asco Post, please click here.

Enzyme That Regulates DNA Repair May Offer New Precision Treatments For Breast And Ovarian Cancer

Researchers at Mayo Clinic have identified an enzyme called UCHL3 that regulates the BRCA2 pathway, which is important for DNA repair. Results of this research are published online in Genes & Development.

“DNA encodes the blueprints for our body, and DNA repair is a fundamental mechanism to prevent the accumulation of mutations in DNA and human disease,” says senior author Zhenkun Lou, Ph.D., a molecular pharmacologist at Mayo Clinic.

“The BRCA2 pathway is important for DNA repair, and mutation of the BRCA2 gene is linked to increased cancer risk, especially breast cancer and ovarian cancer.”

Dr. Lou says UCHL3 is highly expressed in some cancers, and mutated or deleted in other cancers. Cancer cells with high UCHL3 expression are resistant to chemotherapy; whereas, cancer cells with low UCHL3 are more sensitive to chemotherapy. Therefore, the expression of UCHL3 could be a guide to develop more precise cancer therapy.

“UCHL3 could be a potential therapeutic target to overcome resistance to chemotherapy in cancer cells that have a high level of UCHL3,” Dr. Lou says. He says UCHL3 gene also could be developed into a biomarker in the clinic to guide precision medicine.

“While more research is needed, our studies may provide a novel therapeutic venue to treat women’s cancer and thereby contribute to the health and welfare of women,” says Dr. Lou.

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