New Research Results

New Research from the Society of Gynecologic Oncology

by Lisa Rezende, PhD

03/29/13

The annual meeting of the Society of Gynecologic Oncology (SGO) was held March 9-12 in Los Angeles. Several research studies relevant to the hereditary breast and ovarian cancer (HBOC) community were presented. You can view abstracts from the presentations here.

• A study from Dr. Lu and colleagues at MD Anderson Cancer Center in Houston examined ovarian, fallopian tube, and primary peritoneal cancers from women with known mutations in either BRCA1 or BRCA2. Experts classify invasive epithelial ovarian cancer into subtypes based on their appearance. Most common is serous ovarian cancer that is often seen in hereditary breast and ovarian cancers that run in families. Other types include mucinous, endometrioid, and clear cell ovarian cancers. Some cancers, which don’t resemble any of these, are called undifferentiated. Using this method of classification, previous studies showed that the majority of ovarian, fallopian tube, and peritoneal cancers from BRCA1 or BRCA2 mutation carriers are categorized as serous carcinomas. In this new study of 180 patients with confirmed BRCA1 or BRCA2 mutations, the authors reported that approximately 10% of the ovarian, fallopian tube, or primary peritoneal cancers were not serous cancers. Based on these results, the authors caution that BRCA testing should not be limited to patients with the serous cancer subtype.
• Removal of the fallopian tubes and ovaries, known as risk-reducing salpingo-oophorectomy, has been shown to reduce not only the risk of gynecological cancers, but also the risk of breast cancer in women with mutations in BRCA1 or BRCA2 genes when the procedure is performed prior to menopause. A new study by Dr. Kauff at Memorial Sloan-Kettering Cancer Center in New York reported that risk-reducing salpingo-oophorectomy may also reduce the risk of breast cancer in BRCA1 or BRCA2 mutation carriers who have already undergone menopause. The study followed 199 post-menopausal BRCA mutation carriers and found that risk-reducing salpingo-oophorectomy appeared to confer a 57% reduction in breast cancer risk in women who had undergone menopause before surgery —although the ovaries stop producing estrogen and progesterone after natural menopause, they continue to produce some hormones, including testosterone. This could explain why RRSO after menopause still has protective effects against breast cancer.
• Recent evidence that many BRCA-associated ovarian cancers actually originate in the fallopian tubes has piqued interest for prophylactic removal of fallopian tubes only (salpingectomy) in premenopausal BRCA1 or BRCA2 mutation carriers. FORCE conducted an online survey of 204 premenopausal women with BRCA mutations who had neither ovarian cancer or a risk-reducing removal of fallopian tubes and ovaries (salpingo-oophorectomy). Thirty-four percent of women surveyed said they would definitely be interested in a study of salpingectomy; approximately 83% of these women cited the possibility of reducing ovarian cancer risk without menopause as their motivation to participate. On the other hand, approximately 30% of women said they would not be interested in such a study, citing concerns about surgical complications, the possibility of ovarian damage, and potential cost. Notably, 68% of respondents indicated that the possibility that the experimental surgery might not lower their risk for ovarian cancer would be acceptable when they considered whether or not to participate in such a study. Based on these findings, study authors suggest that there would be enough patient interest in the HBOC community to begin a clinical trial of risk-reducing salpingectomy.

Research on Fallopian Tube Surgery to Lower Risk

by Sue Friedman and Helen Smith

02/20/13

Emerging research suggests that many ovarian cancers in BRCA gene mutation carriers may actually start in the distal fallopian tube (part of the tube closest to the ovary), causing researchers to question whether preemptively removing the tubes might reduce cancer risk. Although experts agree this important issue deserves more research, identifying the best approach is the subject of debate. At our annual conference in 2012, gynecologic oncology experts Dr. Illana Cass and Dr. Douglas Levine presented the history of hereditary ovarian cancer research and the pros and cons of further research on salpingectomy to lower the risk in high-risk women.

Since the discovery of BRCA mutations and the availability of commercial BRCA testing, experts have recommended that women with mutations remove their ovaries between the ages of 35 - 40 or after childbearing is completed. In the early years after the discovery of BRCA, little data backed up these recommendations, but common sense seemed to dictate that removing the ovaries at a young age would also remove much of the risk. Subsequent research proved that removing the ovaries and tubes lowers the risk for ovarian cancer; more recent research shows that it also lowers the risk of death from breast cancer and ovarian cancer. Some women, however, still develop primary peritoneal cancer, a gynecologic cancer that behaves like ovarian cancer but may occur even after the ovaries are removed.

As hereditary gynecologic cancer research evolved, a new hypothesis about the origin of ovarian cancers in mutation carriers emerged. Previously, all ovarian cancers were believed to develop in the lining of the ovary as a result of the constant rupture and repair process during ovulation. Researchers established early on that fallopian tube cancer—which is rare in the general population—is more common in women with BRCA mutations. This discovery led to recommendations favoring bilateral salpingo-oophorectomy (BSO)—removal of the ovaries and the fallopian tubes—to greatly lower the risk of these cancers in high-risk women. The discovery of unexpected, or “occult” fallopian tube cancers during prophylactic surgery led to recommendations of “serial sectioning” of the fallopian tubes by pathologists, a procedure involving more intensive evaluation of the fallopian tubes to find hidden cancers that might require further surgery or treatment.

Careful examination of the fallopian tubes from research studies such as GOG-0199 led to the discovery of precancerous fallopian tube changes called “serous tubal intraepithelial carcinoma “ (STIC) lesions. No similar lesions have been found in ovaries of high-risk women. This discovery is good news for the high-risk community because it is the first time that precancerous changes have been identified as part of the process of normal tubal or ovarian tissue becoming cancer. This establishes the opportunity to study these STIC lesions further to identify how early changes progress into cancer, and to develop better prevention and treatment options. Based on the discovery of these precancerous lesions and other findings, some researchers have theorized that perhaps all high-grade serous ovarian cancers may actually originate in the fallopian tubes

Arguments that support tubal origins of BRCA ovarian cancers include:

• STIC lesions found in fallopian tubes appear to be “precursor” lesions that will develop into ovarian cancers. No similar lesions have been found in the ovaries of high-risk women
• STIC lesions have similar gene profiles as serous ovarian cancers.
• As many as 50% of women with BRCA mutations who have ovarian cancer also have lesions in their fallopian tube.
• Preliminary studies in cancer-prone mice show that removal of fallopian tubes prevents high-grade serous carcinoma of the ovaries—the type that women with BRCA mutations are most likely to get.

 These arguments led some gynecologic oncologists to propose that interval salpingectomy—removing the fallopian tubes and leaving the ovaries intact until after natural menopause—might lower risk for ovarian cancer in high-risk women while avoiding the negative side effects and long-term health consequences associated with oophorectomy at a young age. After menopause women would then undergo a second procedure to remove their ovaries. But before the medical community can accept salpingectomy as a risk-reducing option, we need evidence that it is safe and effective. This requires a research study, optimally one that follows out hundreds to thousands of high-risk women for more than a decade, and compares outcomes of women who have salpingectomy, women who have BSO, and those who choose surveillance. The design of such a study faces several challenges. Some experts are reluctant to support such a study based on some valid concerns:

• Although many cancers in high-risk women may start in the fallopian tube, we have no proof that the tubes are the source for all ovarian cancers. Pathology shows that some women with BRCA mutations who have ovarian cancer also have clear fallopian tubes. Researchers are concerned that salpingectomy will represent a partial and inferior surgical option to BSO.
• The benefits of salpingectomy are unknown. Even if the procedure lowers the risk for ovarian-type cancers, it’s unlikely to impact breast cancer risk. Meanwhile, well-documented benefits of BSO for mutation carriers include:
• reduction of ovarian cancer and fallopian tube cancer risk
• reduction of breast cancer risk
• reduction in breast cancer-associated mortality, ovarian cancer-associated mortality, and overall mortality
• Concern that women who remove their tubes only to avoid menopause will not return for additional surgery to remove their ovaries after they undergo natural menopause.
• Worry that removal of tubes could disrupt ovarian blood supply, thereby leading to menopause and negating a potential benefit of the surgery over BSO.
• Concern that offering salpingectomy, even in a research study with consent forms that clearly outline the risks, might be perceived by patients as an endorsement or suggestion that the surgery prevents ovarian cancer.
• Women can avoid menopausal symptoms and other unwanted health effects with BSO followed by hormone replacement. (Studies indicate that hormone replacement after BSO is safe for previvors.)
• Designing such a study would require a large, costly cooperative research effort that would take over a decade, thousands of high-risk women participating, and massive recruitment and follow-up effort.

Despite these valid concerns, other experts make cogent arguments in favor of studying salpingectomy as a risk-reducing option for high-risk women, including:

• A growing and compelling body of research suggests that many so-called ovarian cancers in mutation carriers begin in the fallopian tubes.
• Even if all ovarian-type cancers don’t start in the fallopian tubes, some do. Salpingectomy might serve as an “interval surgery” to manage and lower risk in high-risk women who are not ready for BSO and would otherwise opt for surveillance only, which the gynecologic oncology community recognizes as an ineffective strategy to reduce risk. Women in this category could benefit from salpingectomy surgery.
• Women who undergo salpingectomy can maintain their ovaries longer and avoid long-term medical consequences of surgical menopause.
• This type of large-scale study could provide information about development and prevention of ovarian cancer that could help to propel more research into better options for both women with BRCA mutations and those without.

Although our conference presentation on salpingectomy was set as a debate format, both presenters agreed on one important conclusion: the time is right for additional study of salpingectomy as a valid risk-reducing option. Still, questions remain about the feasibility of conducting such a study. Recently the Gynecologic Oncology Group, part of the National Cancer Institute’s Clinical Trials Cooperative Group Program approved further development of a study on salpingectomy. Development of study design could take months, and it may be more than a year before the study would open at GOG sites around the country. The purpose of this pilot study would be to further examine the fallopian tubes of high-risk women who undergo the procedure and to assess:

• immediate and long term complications of the procedure
• impact of the procedure on ovarian function
• the proportion of women who ultimately undergo completion oophorectomy
• feasibility of conducting a larger trial to determine impact of the procedure on cancer risk.

Preliminary results of a FORCE-conducted survey on attitudes of high-risk women towards participating in ovarian cancer risk-reduction research were presented at our 2011 annual conference. Almost one-third of the 333 respondents indicated interest in participating in a prophylactic salpingectomy study. The final results from our survey will be presented by researchers from MD Anderson Cancer Center as a poster at the Society for Gynecologic Oncology annual meeting in Los Angeles next month.

Stay tuned for further updates on salpingectomy research.

If you are a woman at high-risk for ovarian cancer and you have had your fallopian tubes removed but retained one or both ovaries, please consider participating in our salpingectomy research registry.

References:

Domchek, SM et. al., Association of Risk- Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers with Cancer Risk and Mortality. Journal of the American Medical Association; 304:967-975, September, 2010.

Carlson, JW, et. al., Serous Tubal Intraepithelial Carcinoma: Its Potential Role in Primary Peritoneal Serous Carcinoma and Serous Cancer Prevention. Journal of Clinical Oncology; vol. 26 no. 25: 4160-4165, September 2008.

Callahan, MJ, Crum, CP et. al., Primary Fallopian Tube Malignancies in BRCA-Positive Women Undergoing Surgery for Ovarian Cancer Risk Reduction. Journal of Clinical Oncology; vol. 25 no. 25: 3985-3990, September 2007.

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Weighing the Risks and Benefits of Screening Mammography

by Sue Friedman

12/03/12

A recent research article has questioned the benefits while highlighting the potential harms of mammogram screening in women of average risk for breast cancer. The study raises some valid concerns; more research is needed to refine breast-screening guidelines to improve outcomes. But it does not provide the definitive answers needed to dismiss mammography as a screening tool.

The research report looked at large population-based statistics over three decades to determine if mammograms are leading to a decrease in later-stage cancers by detecting more early-stage cancers. The study found that although mammograms found more early cancers, they did not lead to a similar reduction in cancers diagnosed at a late stage. The authors conclude that while mammograms find more cancers, for most women, they do not improve survival or outcomes. The authors cite the concern that mammograms find breast changes that are precancers that may never actually develop into cancer or threaten a woman’s life. The authors go on to state that as many as one-third of breast cancers may be overdiagnosed and treated, leading to side effects and consequences that can impact women’s quality of life.

The study authors conclude:

• The increase in early cancers due to mammogram screening is not leading to a similar decrease in later stage diagnoses. Therefore mammograms are not improving survival or outcomes for the women whose cancers they are detecting.
• The increase in early cancers being found on mammograms is leading to the overdiagnosis and treatment of cancer in 1/3 of these women.

Based on these conclusions, the authors question the benefit of screening mammograms for the general population. A closer look at the full research paper raises important concerns about the study and the authors’ conclusions:

• The study divides breast cancer diagnoses into two categories: “late stage” which includes stages II, III and IV and “early stage” which includes DCIS and stage I breast cancers. Yet the risks and consequences of overtreatment are different for DCIS compared to stage I breast cancer. Although DCIS is a very early type of cancer that may never lead to invasive or life-threatening disease, stage I cancers are invasive, and without treatment are capable of spreading and becoming life-threatening.
• The study looked at breast cancer incidence but was not designed to look at the outcomes of women who underwent screening mammograms. We do not know from the study if women diagnosed at stage I were less likely to have distant recurrence later than those diagnosed at later stages.
• Although the authors account for the rise in breast cancer incidence due to hormone replacement therapy, they do not account for other factors that may contribute to changes in breast cancer incidence over the last three decades.
• The authors imply that earlier diagnosis equals overtreatment. However, this is not necessarily an accurate assumption. The study didn’t account for tests like Oncotype DX and Mammaprint that analyze tumor genetics and characteristics to better determine which early-stage cancers are more likely to behave aggressively. These tools can shift the balance in favor of mammograms, allowing us to better determine which women would benefit from further treatment. It is difficult to detect the cancers that are most likely to behave aggressively if we don’t screen for them.
• The study looked at breast cancer incidence but was not designed to look at the age of women who underwent screening mammograms. Breast cancer detected in a premenopausal woman is more likely to behave aggressively and impact survival and outcome than breast cancer detected in a 70 year-old woman.
• The authors conclude that as many as 1/3 of early-stage breast cancer patients are being overdiagnosed. This means that 2/3 of patients are being diagnosed appropriately. Changing screening practices to lower the number of women that are overdiagnosed could lead to an increase in women being diagnosed at a stage requiring more extensive treatment.

In an opinion piece in the New York Times, one of the study authors made these recommendations:

“We must redesign screening protocols to reduce overdiagnosis or stop population-wide screening completely. Screening could be targeted instead to those at the highest risk of dying from breast cancer—women with strong family histories or genetic predispositions to the disease. These are the women who are most likely to benefit and least likely to be overdiagnosed.”

Personalizing screening recommendations based on risk makes sense. Identifying those in the highest risk category for breast cancer who are most likely to benefit can help remedy the potential harms of screening. But before we dismiss population-based screening mammograms in favor of only screening high-risk women, we need to do a better job at risk assessment. Research shows that the health care community underutilizes genetics experts and risk-assessment tools, and importantly, that high-risk women do benefit from breast cancer screening. Additionally, women who inherit a mutation from the paternal side, and women with a small family, and/or limited family history of breast cancer are less likely to be identified as high risk until they are diagnosed with breast cancer, often based on a screening mammogram. Changing screening guidelines will disproportionately hurt these women in our community.

The author also suggests:

“What should be done? First and foremost, tell the truth: women really do have a choice. While no one can dismiss the possibility that screening may help a tiny number of women, there’s no doubt that it leads many, many more to be treated for breast cancer unnecessarily. Women have to decide for themselves about the benefit and harms.”

It is important for women to make informed decisions about screening. In order to do so, women must be educated about all the factors, tools, and consequences that can influence their decisions when weighing benefit and harm from mammograms. The author cites the importance of educating women about the possible harms of mammograms and overtreatment. A balanced discussion should also include information about the possible consequences of a delayed diagnosis, the additional treatment that might be required for later-stage diagnosis, and the existence of decision-support tools such as Oncotype DX and Mammaprint and other personalized medicine technologies that can help determine which early stage cancers, once found, are more likely to behave aggressively and thus avoid overtreatment.

The author goes on to state the following:

“But health care providers can also do better. They can look less hard for tiny cancers and precancers and put more effort into differentiating between consequential and inconsequential cancers.”

Research is ongoing to determine which cancers are more or less likely to behave aggressively. Currently we have the technology to test breast tumors for markers of aggressive behavior. But these tests require detecting the tumors and sampling them through biopsy. If we pass up the opportunity to find them with mammograms and sample them, we deprive women of critical information on which to base their health care decisions.

Although imperfect, mammography does save lives, and we must apply all the means we have to save as many lives as we can. For high-risk women, experts all agree that the benefits of breast screening outweigh the risks. For women of average risk the jury is still out. It is risky to draw conclusions about outcomes from population-based screening in all women based on a study with this design. More research is needed to determine if the harms of diagnosis and treatment outweigh the consequences of missing cancers, and to provide a clearer understanding of how many more lives will be lost if screening guidelines and recommendations are changed. Women should be educated about all the factors that mayinfluence their outcomes in order to help them make informed decision.

References:

Bleyer, A, and Welch, HG. Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence. New England Journal of Medicine. 367:1998-2005. 2012 November.

Welch, HG. Cancer Survivor or Victim of Overdiagnosis? New York Times, Op-Ed. November 12, 2012.

Granader E, Dwamena B, Carlos R. MRI and mammography surveillance of women at increased risk for breast cancer: recommendations using an evidence-based approach. Acad Radiol. 2008 Dec.

Samphao S, Wheeler A, Rafferty E, Michaelson J, Specht M, GaddM, Hughes K, Smith B, Diagnosis of Breast Cancer in Women Age 40 and Younger: Delays in Diagnosis Are Common Due to Underutilization of Genetic Testing and Breast Imaging. American Society of Breast Surgeons, presented at ASBS annual meeting, April 2009.

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Breast Surveillance, Radiation, and Young Previvors

by Clayton Boldt and Sue Friedman

12/03/12

The National Comprehensive Cancer Network (NCCN) outlines screening guidelines for women with BRCA1/2 gene mutations. These guidelines include annual MRI and mammograms beginning at age 25. Although Radiation is minimal from individual mammograms, repeated exposure can add up over the course of a woman’s lifetime. There is evidence that radiation can be a risk factor for breast cancer, particularly when it occurs early in life. Additionally, since the BRCA genes are involved with DNA damage repair, there has been speculation about whether x-ray exposure from mammograms may put BRCA1/2 mutation carriers at additional risk compared to individuals without mutations.

A small number of studies have sought to quantify the risk posed to BRCA1/2 mutation carriers by radiation imaging, with inconclusive results. However, the findings of a recent study on the subject published in the September 2012 issue of the British Medical Journal raised quite a bit of interest and received a lot of mainstream media attention that has alarmed many of our members. This retrospective study included 1,993 BRCA1/2-positive women from the European research project GENE-RAD-RISK. Each participant completed an in-depth questionnaire regarding her history of exposure to diagnostic radiation; the answers were used to estimate the dose of ionizing radiation that each patient had received. Researchers then compared approximate doses and breast cancer diagnoses across the group to identify potential correlations between exposure and cancer incidence.

The researchers concluded that exposure to ionizing radiation before the age of 30 is associated with an increased risk of breast cancer and argued for the use of non-ionizing radiation techniques, such as magnetic resonance imaging (MRI) as the main tool for diagnostic imaging in BRCA1/2 carriers. Closer review of the article, however, highlights areas that warrant more examination before we completely eliminate mammograms as screening tools for young previvors. Here are some of the considerations that have been raised by members of our Scientific Advisory Board:

• In the article, the increased breast cancer incidence when comparing those with no radiation exposure to those with any exposure between ages 20-39 was not statistically significant. A statistically significant but very small risk increase is evident only when cases of exposure before the age of 20 are included. Normally, mammograms in BRCA mutation carriers aren’t recommended until age 25, so it’s unclear how relevant that data may be.
• The estimated radiation doses used in this paper were self-reported by each participant which could sway results. This approach is a less accurate way to measure exposure than reviewing actual medical records for this information. “Recall bias” where some groups of participants may be more likely to remember radiation exposure than others can impact findings in studies with this type of design. An example would be if women who were diagnosed with cancer are more likely to remember exposure than women who were not diagnosed with cancer.
• It is unclear from the article whether radiation exposure from mammograms used to diagnose the participants’ breast cancer was excluded. Once a lump or abnormality is identified it often leads to more imaging and radiation to confirm the diagnosis and stage the cancer. However, radiation exposure at the time of diagnosis of cancer would not have contributed to the development of that cancer.
• Although MRIs are very sensitive for finding abnormalities in the breast, mammograms find microcalcifications, small changes that can indicate an early cancer which are sometimes missed by MRIs. The ability to distinguish small cancers on MRI can be related to the quality of equipment used and the experience of the radiologist interpreting the images. There is concern that in eliminating mammograms, some of early cancers might be missed until they are more advanced. Alternating MRIs and mammograms every six months ensures that mutation carriers are seen and screened every six months rather than once annually.

Currently, diagnostic imaging approaches for BRCA1/2 mutation carriers under age 30 vary among the top cancer centers and other facilities. Some offer patients an informed choice between MRI and mammogram before the age of 30. New screening tools are being studied, including advanced, 3-dimensional ultrasound, and micro-dose mammograms, which lower the amount of radiation exposure. Members of the FORCE Scientific Advisory Board agree that this is a critical question that must be answered, but generally feel that the results of the current study are not conclusive. More research is needed to clarify the possible link between radiation exposure and increased cancer risk in BRCA1/2 carriers, and expert panels will continue to update screening guidelines based on those future results.

References:

Pijpe A, Andrieu N, Easton DF, Kesminiene A, Cardis E, Noguès C, Gauthier-Villars M, Lasset C, Fricker JP, Peock S, Frost D, Evans DG, Eeles RA, Paterson J, Manders P, van Asperen CJ, Ausems MG, Meijers-Heijboer H, Thierry-Chef I, Hauptmann M, Goldgar D, Rookus MA, van Leeuwen FE. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). British Medical Journal. 2012 Sept.

 

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