Ovarian Cancer: Testing for BRCA Mutations

Ovarian Cancer: Testing for BRCA MutationsBradley J. Monk, MD, FACOG, FACS: So, I’d like to discuss a case with you, a typical scenario, a woman unfortunately diagnosed with an advanced ovarian cancer, now over 3 years ago. She presented when she was 40 years old, which is unusually young. The median age of advanced ovarian cancer is in the mid-50s. This woman was 40, and she had no past medical or surgical history except that her mother had breast cancer, and she went to her doctor with some abdominal complaints, which led to a sequence of diagnostic events including an ultrasound, a CT scan, and a CA-125. And, unfortunately, the ultrasound showed a mass. Ultrasonographically, we can pretty much tell benign from malignant masses. This mass was solid. Solid masses are more likely to be malignant. The CT scan showed intraperitoneal disease, which we call carcinomatosis, and the CA-125 was just under 1000. So, the chance of this being an ovarian cancer is virtually 100%. However, in the interim between the time that the patient was seen by her primary care physician and the gynecologic oncologist, a biopsy was performed and showed a high-grade serous cancer.

So, the first point is that we don’t have screening for ovarian cancer, but every patient should be referred to a gynecologic oncologist to be evaluated for the opportunity to do a surgery, with the goal of the surgery being complete resection. We used to say that optimal cytoreduction was less than a centimeter. It’s not. There’s nothing optimal about leaving cancer behind. She was evaluated by a gynecologic oncologist. The goal was clear, complete resection, all macroscopic disease. She had a vertical laparotomy incision, a hysterectomy, omentectomy, and debulking operation. Now, unfortunately, there was some residual disease left behind, so maybe one could have argued that they should have started with neoadjuvant chemotherapy. I get it, it’s a hard decision. They decided to go for it. They did an operation. She recovered well and then was considered for adjuvant therapy.

And, at that time in 2014, we had a fascination with intraperitoneal chemotherapy. Quite frankly, we don’t anymore. We now have a recent trial not yet published, GOG 252, that showed that intraperitoneal chemotherapy is not valid. In the olden days, we were engaged by a New England Journal of Medicine paper that looked at intraperitoneal chemotherapy, but it also was dose intense and weekly. So, it didn’t just ask 1 question. She was treated with intraperitoneal chemotherapy and did well. And as per the guidelines from the American Society of Clinical Oncology, the Society of Gynecologic Oncology, and the National Comprehensive Cancer Network—ASCO, SGO, and NCCN—she was tested for BRCA germline mutations. And I get it, her mother had breast cancer, she was young, but age and family history are not enough to determine which patient should be tested for a germline mutation. All patients should be tested, and indeed she was, and she had a germline BRCA mutation. And germline BRCA-mutated ovarian cancers respond exquisitely well because that’s what BRCA does. It repairs double-stranded DNA breaks, and that’s what platinum does, it breaks the DNA. So, she couldn’t repair the double-stranded platinum-induced breaks, had a complete response, and did well.

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


Clinical Trials Offer Promising New Treatments For Ovarian Cancer

By: Deborah Zajchowski, PhD – Scientific Director, The Clearity Foundation

Clinical Trials Offer Promising New Treatments For Ovarian Cancer In the past three years, new hope has come to many women with ovarian cancer because of four new drugs that were approved for the treatment of this disease. These drugs are therapies designed to target specific cellular processes that cancer cells use to create their own blood vessels (called angiogenesis; Avastin) or repair damage to the genetic material or DNA (PARP or the poly-ADP ribose polymerase enzyme; Lynparza, Rubraca, Zejula). They are the first targeted therapies for treating ovarian cancer.

Importantly, some women have benefited from these same drugs for longer than three years because they participated in the clinical trials that proved their safety and effectiveness. While it is not possible to foresee the future and there are risks associated with taking new drugs that have not yet been used by hundreds of people, it can be wise to enroll in a clinical trial -even with a new diagnosis of ovarian cancer. There are science-based reasons to expect that adding a PARP inhibitor (to enhance the effectiveness of cytotoxic chemotherapy) or an immunotherapy (to boost your immune system’s ability to eliminate cancer cells) to the standard first-line chemotherapy treatment of carboplatin and paclitaxel which may increase the chances for a cure. And for women with cancer that has come back or progressed, drugs in clinical trials can have equal or better effectiveness than cytotoxic chemotherapies – oftentimes with less side effects. We think these trials should be considered by each woman and their oncologist.

Despite the potential advantages of clinical trials, the number of cancer patients who enroll in these studies is reported to be very low – around 5-10%. This may be related to many factors, including not knowing that an appropriate trial exists or that the trial site is too far away from home. In addition, there are unfortunate misperceptions that drugs in trials are a last resort or even worse – that one might be given a placebo (e.g., sugar pill) and not receive treatment at all – both of which are false. Sometimes women are not eligible for a desired trial because they have had too many prior treatments or have decided to look for a trial at a time when they need to start a new treatment very soon and there is no time to find, learn about, and complete the steps involved in the application process. This latter scenario happens much too often and as a result, women miss out on opportunities to obtain some of the most promising options to treat this disease.

The Clearity Foundation is here to help make this process easier, and over 25% of the women who have come to us for assistance over the years have enrolled in clinical trials – including women who benefited by receiving those PARP inhibitors before they were approved! In past newsletters, we have explained the basics tenets of clinical trials – what clinical trials are, what the different phases mean, and how to know if you should enroll in a trial.

Please visit our Clinical Trials and Clinical Trials Basics pages to learn more.

Find Clinical Trials That Match Your Precise Clinical Situation and Preferences

From our conversations with women who have ovarian cancer and their supportive spouses, families, and friends, we have learned that it is not easy to search for trials or decide which ones are appropriate, so today, we announce the launching of a beta version of a new Guided Trial Finder. With it, we take you through a step-by-step question-and-answer process that will help narrow down your options for clinical trials-and provide only those that match your precise clinical situation (e.g. newly diagnosed, recurred) and any other parameters (e.g., location, trial phase) that you think are important. Indeed, our new trial finder will help you find trials that are difficult to identify using other search methods.

You can find trials that could enroll you even if you do not have “measurable disease” [which can sometimes be the case when you have an elevated CA125 marker and fluid build-up in your abdomen (ascites) or lungs (pleural effusion) but no appropriately sized mass or nodule that is seen on an imaging scan] – or if you have had multiple prior therapies and don’t want a phase 1 trial – or if you have previously had a different cancer than ovarian that is in remission (many trials exclude you from participating but others will permit you to enroll).

The new trial finder will make it easier to locate such trials. We recognize that finding the trials is only the first step and provide a means for you to download and save a list of those trials to bring to your doctor for discussion. We can also help you do this search or understand how some of the drugs in the trials may benefit you. You can learn more about some of the drugs by visiting our Clinical Trial Results pages or by calling us at 858-675-0282.

Please let us know what you think and of any suggestions for our next version of this Finder.

Prexasertib in Pretreated BRCA Wild-Type High-Grade Serous Ovarian Cancer

Prexasertib in Pretreated BRCA Wild-Type High-Grade Serous Ovarian CancerIn a phase II study reported in The Lancet Oncology by Lee et al, the investigational cell-cycle checkpoint kinase 1 and 2 inhibitor prexasertib produced responses in women with recurrent BRCA wild-type high-grade serous ovarian cancer.

In the study, 28 women with measureable disease enrolled between January 2015 and November 2016 were treated with intravenous prexasertib at 105 mg/m² given over 1 hour every 14 days in 28-day cycles. Patients had a median age of 64 years and had received a median of 5 systemic therapies; 79% had platinum-resistant or -refractory disease.

Response Rates and Adverse Events

All patients received at least one dose of prexasertib; four (14%) were not assessable for Response Evaluation Criteria in Solid Tumors (RECIST) response. A partial response was observed in 8 (33%) of 24 assessable patients (29% of the total population). Response was observed in 6 (32%) of 19 assessable patients with platinum-resistant or -refractory disease, with an additional 5 (26%) of these patients having stable disease for ≥ 6 months. Median progression-free survival in the 24 assessable patients was 7.4 months.

The most common grade 3 or 4 adverse events were neutropenia (93%), leukopenia (82%), thrombocytopenia (25%), and anemia in (11%). Grade 4 neutropenia occurred in 79% patients after the first dose of prexasertib; neutropenia in these cases was transient (median duration = 6 days and resolved without growth-factor support). Treatment-related febrile neutropenia occurred in 7% of patients.

The investigators concluded, “Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.”

The study was funded by the Intramural Research Program of the National Institutes of Health and National Cancer Institute.

To read this entire article by The ASCO Post, please click here.

Screening For Ovarian Cancer Not Recommended

Screening For Ovarian Cancer Not RecommendedThe U.S. Preventive Services Task Force (USPSTF) recommends against screening for ovarian cancer in women without symptoms and who are not known to be at high risk (such as those who have certain hereditary cancer syndromes that increase the risk for ovarian cancer).

The USPSTF routinely makes recommendations about the effectiveness of preventive care services. This latest recommendation statement on screening for ovarian cancer is an update from 2012. Ovarian cancer is the fifth most common cause of cancer death among U.S. women, with approximately 14,000 deaths per year.

The USPSTF recommendation statement follows a review of evidence on the benefits and harms of screening for ovarian cancer in asymptomatic women not known to be at high risk for ovarian cancer.

The USPSTF found adequate evidence that screening for ovarian cancer does not reduce ovarian cancer mortality. The USPSTF found adequate evidence that the harms from screening for ovarian cancer are at least moderate and may be substantial in some cases, and include unnecessary surgery for women who do not have cancer. Given the lack of mortality benefit of screening, and the moderate to substantial harms that could result from false-positive screeningtest results and subsequent surgery, the USPSTF concludes with moderate certainty that the harms of screening for ovarian cancer outweigh the benefit, and the net balance of the benefit and harms of screening is negative.

To read this full article on Science Daily, please click here.

Fathers May Pass Ovarian Cancer Risk to Daughters

Fathers May Pass Ovarian Cancer Risk to DaughtersUS scientists believe they have identified a new gene mutation that can raise the risk of ovarian cancer, and is passed from father to daughter.

It is inherited through the X-chromosome and is independent of other known susceptibility genes that women can already be tested for.

Experts say more studies are needed to confirm the identity and function of the gene.

The latest findings appear in the journal PLoS Genetics.

Family Risk

Currently, women with a strong family history of cancer can be tested for the BRCA gene, which greatly increases a woman’s chance of developing breast cancer and ovarian cancer.

Angelina Jolie inherited BRCA1 from her mother – she had preventative surgery after her doctors estimated she had an 87% risk of breast cancer and a 50% risk of ovarian cancer.

But researchers believe there may be many other cases of seemingly sporadic ovarian cancer that are actually inherited – some via the X chromosome girls get from their father.

Men pass on one X chromosome to their daughters.

Dr Kevin Eng and colleagues at the Roswell Park Cancer Institute honed in on one suspect gene, called MAGEC3, located on the X chromosome from fathers.

Ovarian cancers linked to genes inherited from the father (and paternal grandmother) had an earlier age-of-onset than ones linked to maternal genes, and were also associated with higher rates of prostate cancer in fathers and sons.

Lead author Kevin Eng from the Roswell Park Comprehensive Cancer Centre in Buffalo, New York said: “What we have to do next is make sure we have the right gene by sequencing more families. This finding has sparked a lot of discussion within our group about how to find these X-linked families.

“It’s an all-or-none kind of pattern: A family with three daughters who all have ovarian cancer is more likely to be driven by inherited X mutations than by BRCA mutations.”

Dr Catherine Pickworth from Cancer Research UK said: “This research suggests that some women’s risk of ovarian cancer could be passed down through their father’s family, as well as their mother’s, due to newly discovered faulty genes.

“In future, this could help women with a family history of ovarian cancer better understand their risk of developing the disease. This is important because ovarian cancer is often diagnosed at a late stage when it’s harder to treat. Further work is now needed to get a clearer picture of how the genetic faults uncovered in this research might affect inherited risk of ovarian cancer.”

Annwen Jones, Chief Executive of Target Ovarian Cancer, said: “These findings, if borne out by further research, would represent a significant step forward in ovarian cancer prevention, saving thousands of lives.”

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

A Cancer Researcher Takes Cancer Personally

By: Susan Gubar

A Cancer Researcher Takes Cancer PersonallyOngoing breakthroughs in cancer care involve personalized medicine, we are often informed. Because every malignancy is unique in terms of its genetics and genomics, one size (or protocol) cannot fit all.

A diagnosis of multiple myeloma, cancer of the plasma cells, motivated Dr. C. Anthony Blau of the University of Washington to come up with an innovative approach to his disease. He combined his research in hematology, his physician wife’s clinical expertise and crowdsourcing to develop an individualized treatment plan.

As a cancer patient whose life has been extended by an experimental drug, I was curious about Dr. Blau’s approach. By what methods can medical practices be tailor-made? And how do scientists find the ways and means to extend analyses of individual cases to a significant aggregate of patients?

Whereas patients conventionally receive treatment options from an oncologist, Dr. Blau’s strategy is to help patients learn about treatment decisions and consequences from other patients and from a number of experts whose ideas could then be explored with an oncologist.

Let’s begin Dr. Blau’s story with a romantic encounter over a pencil. In 2000, Dr. Blau, who goes by Tony, met a woman named Sibel (who had trained in Istanbul and then in Cleveland) at Seattle’s Fred Hutchinson Cancer Research Center, specifically on the stem cell transplant ward. He was an attending physician; she a senior fellow. His pencil rolled under one patient’s closed door; a few seconds later it rolled back out: Sibel and Tony fell in love. She became an oncologist, he a cancer researcher, and they lived so happily ever after that eventually they joined forces to investigate one of the most recalcitrant types of breast cancer.

With some dismay, Dr. Blau had observed that he was better equipped to analyze the condition of his lab mice than his wife was to comprehend the state of her patients with metastatic triple negative breast cancer, an incurable condition.

In the lab, he had the time and expertise to analyze the data of every mouse’s cancer and compare it to that of all the other mice he has studied. With human subjects, most oncologists don’t have data on the evolving tumors of each individual patient and of a cohort group. Dr. Blau wanted a way to characterize the effect of various treatments on malignancies in humans at a molecular level.

To address the problem, he helped create the Center for Cancer Innovation at the University of Washington in 2013 and the next year he helped design a new type of clinical trial.

It brought together clinicians and researchers with nurses, geneticists, specialists in information technology, computational biologists and statisticians, not only at one hospital but globally. Each breast cancer patient would be closely monitored. There would be multiple biopsies of tumors from multiple sites on each patient — many enrolled as a last-ditch effort to help themselves and future patients — as well as DNA and RNA sequencing to produce huge databases. Hypotheses about treatment were put on the cloud; experts around the world could provide input and feedback. Dr. Blau said he discovered that most scientists appreciated the opportunity to offer their arcane knowledge to aid people in dire straits.

After Dr. Blau’s myeloma was diagnosed in 2015, he decided to apply this approach to himself. “I had 22 biopsies of the tumor in my left pelvis, as well as bone marrow biopsies,” he said, “and we compared the genomic profile of the myeloma cells in my pelvic tumor with that of myeloma cells in my bone marrow.” In the process, he learned about a molecular feature that kicked him out of the most favorable prognostic category.

Because he still had a tiny percentage of myeloma cells in his bone marrow after an arduous autologous stem cell transplant, which uses the patient’s own cells, he rejected the advice of specialists and underwent an allogeneic stem cell transplantation, using cells from a genetically matched person. His donor, a brother and a Methodist minister, believes that he infused Dr. Blau with the Holy Spirit.

With (possibly related) zeal, Dr. Blau soon started All4Cure, a knowledge-sharing platform for clinicians, researchers and myeloma patients who register (without cost) to allow their medical records to be accessed. Once names are replaced by numbers, these files can be tapped to create “a personalized dashboard”: a graph depicting all treatments, tests and responses as well as tumor sequencing. Beneath the graph, a discussion panel enables participants to comment on the particular patient’s situation. To date, about 150 myeloma patients, 30 clinicians and 20 researchers have enrolled.

Personalized medicine depends upon information technology and knowledge sharing. Since every cancer contains a singular collection of mutations that can vary significantly across patients or over time within a single patient, computational analysts map how mutations interact within a specific individual, Dr. Blau explains. When a physician reviews data about a faraway patient, that doctor may draw upon her experience — for example, with the synergy of combining three drugs in a similar case — to propose an alternative approach.

Such global networking has the capacity to break down geographic and institutional barriers to communication. It also enables patients to report outcomes immediately so that protocols with deleterious side effects can be quickly changed. Patients can compare their treatment with those of others; researchers can broadcast breakthroughs. The growing database should help predict which regimens might be most effective for a particular person.

Of course maintaining and extending the platform could be expensive. When I asked Dr. Blau how his for-profit company was financed, he said that the initial investment came from a house he and his wife sold three years ago. He hopes that future revenue might come from pharmaceutical companies. All4Cure could accelerate the approval of investigational drugs and provide feedback on approved drugs.

Dr. Blau’s enthusiasm sparks my realization that the sort of networking available to myeloma patients through All4Cure would transform the lives of the women in my gynecological cancer support group. Most of us feel only tenuously connected to an oncologist who often does not specialize in ovarian or uterine disease.

It is paradoxical that personalized medicine involves crowdsourcing. You need not understand all that Dr. Blau knows about cancer to revel in his survival and to thrill at the promise of the maxim underscoring the work it makes possible: “All for one and one for all.”

To read this entire article by The New York Times, please click here.

Ovarian Cancer: How Your Father’s Genes Can Affect Your Risk

Ovarian Cancer: How Your Father's Genes Can Affect Your RiskScientists studying ovarian cancer have revealed a new genetic mutation that increases a woman’s risk of ovarian cancer — and it can be passed to her by her father.

Recently, Medical News Today covered a study that looked into whether or not all women should get screened for ovarian cancer.

In that article, we looked at the results of a review published in JAMA that assessed the findings of more than 1,000 research papers published between 2003 and 2017 in order to establish whether screening reduces mortality risk for women who do not have a hereditary risk for ovarian cancer.

The authors of that study paper concluded that the harms of ovarian cancer screening outweighed the benefits for woman in the average risk category. But who is more at risk of ovarian cancer?

Now, research published in the journal PLOS Genetics identifies a new mutation associated with early-onset ovarian and prostate cancer that is passed down the paternal line through the X chromosome.

Previous studies have observed that the sisters of ovarian cancer patients seem to have a higher risk of developing this cancer than their mother, and it was this fact that led the researchers — at Roswell Park Comprehensive Cancer Center in Buffalo, NY — to explore whether or not genes passed down by the father of ovarian cancer patients increase their risk of cancer.

Cases ‘Develop 6 Years Earlier Than Average’

The researchers examined data on pairs of granddaughters and grandmothers using the donor-funded Familial Ovarian Cancer Registry resource, which is based at Roswell Park.

Their results demonstrate that cases of ovarian cancer linked with genes passed down from the paternal grandmother were more strongly associated with early-onset cancer than cases linked with genes passed to patients from their mother.

The team also sequenced portions of the X chromosome from 186 people with ovarian cancer and discovered that a previously unidentified mutation is associated with an increased risk of ovarian cancer.

Cases of ovarian cancer that are linked to the newly identified mutation develop more than 6 years earlier than the average age of onset for ovarian cancer. The study also uncovered an association between this mutation and increased risk of prostate cancer among male family members.

However, the study has not confirmed the identity and function of the specific gene at play in this association, so the researchers acknowledge that further studies are needed.

Many Ovarian Cancer Cases ‘May Be Inherited’

Commenting on the findings, study author Kevin H. Eng says, “Our study may explain why we find families with multiple affected daughters: because a dad’s chromosomes determine the sex of his children, all of his daughters have to carry the same X chromosome genes.”

“What we have to do next,” he adds, “is make sure we have the right gene by sequencing more families. This finding has sparked a lot of discussion within our group about how to find these X-linked families.

Eng and his colleagues believe that many cases of ovarian cancer that appear to be sporadic might actually be inherited. Identifying the gene responsible will therefore contribute to improved ovarian cancer screening.

To read this article by Medical News Today, please click here.