NCCN: Continuing Education
Accreditation Statement
This activity has been designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-16-002-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/78021; and 4) view/print certificate.
Release date: February 10, 2016; Expiration date: February 10, 2017.
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 2; 10.6004/jnccn.2016.0018
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Family studies have long documented an increased risk of several forms of cancer among first- and second-degree relatives of affected individuals. These individuals may have an increased susceptibility to cancer as the result of one or more genetic mutations present in parental germline cells; cancers developing in these individuals may be classified as hereditary or familial cancers. Hereditary cancers are often characterized by mutations associated with a high probability of cancer development, vertical transmission through a parent, and an association with other types of tumors.1,2 They often have an early age of onset and exhibit an autosomal dominant inheritance pattern. Advances in molecular genetics have allowed researchers to identify a number of genes associated with inherited susceptibility to breast and/or ovarian cancers (eg, BRCA1/2, PTEN, TP53).
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 2; 10.6004/jnccn.2016.0018
Genetic Evaluation and Testing
Genetic testing is a complex process involving several phases. First, an initial risk assessment is performed to determine whether genetic assessment should be undertaken. Next, a patient would undergo a formal risk assessment, including a detailed family history, a personal medical and surgical history, a focused physical examination, and an evaluation of the patient's needs and concerns. Testing may be offered; counseling should be performed both before and after testing. Before the 2015 update, recommendations regarding testing and counseling principles (eg, consideration of cancer risk in relatives) were scattered throughout the guidelines, often as footnotes. For the 2015 guidelines update, much of this information was consolidated
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 2; 10.6004/jnccn.2016.0018
For the most recent guidelines update, the panel revised recommendations regarding multigene testing. Minor modifications were also made to testing criteria for genetic mutations, including clarification regarding ovarian cancer histology and revision of BRCA1/2 testing criteria for those with a personal history of pancreatic cancer and with Ashkenazi Jewish ancestry.
Multigene Testing
Next-generation sequencing allows for the sequencing of multiple genes simultaneously. In this approach, referred to as multigene testing, a set of genes that are associated with a specific family cancer phenotype or multiple phenotypes are simultaneously analyzed. The recent introduction of multigene testing for hereditary forms of cancer has rapidly altered the clinical approach to testing at-risk patients and their families. This approach may detect mutations not found in single-gene testing. Multigene testing could include only high-penetrance genes associated with a specific cancer, or both high- and moderate-penetrance genes. Comprehensive cancer risk panels, which include a large number of genes associated with a variety of cancer types, are also available.3
The NCCN Guidelines panel had added information regarding multigene testing for the 2014 update. This new section included a list of advantages and disadvantages of multigene testing, examples of when this testing may be particularly advantageous and cost-effective, and issues to consider (eg, clinical
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 2; 10.6004/jnccn.2016.0018
Multigene testing should ideally be offered in the context of professional genetic expertise.
Multigene testing may be more efficient and/or cost-effective for patients who have a family history suggestive of an inherited cancer syndrome and in the setting of clinical features common to more than one hereditary syndrome or more than one gene.
Multigene testing may also be warranted in those who have tested negative (indeterminate) for a single inherited syndrome but whose personal or family history remains strongly suggestive of an inherited susceptibility.
Both the laboratory and test panel should be chosen carefully and limitations understood.
The panel also noted that multigene testing may include moderate-penetrance genes. Currently, there are limited data and no specific guidelines regarding degree of cancer risk associated with some moderate-penetrance genes and management for gene carriers.4–6 These issues are compounded by the low incidence rates of hereditary disease, making it difficult to conduct adequately powered studies.4 The approach to risk management after detection of a mutation in a moderate-risk gene and how best to communicate risk to relatives are currently unknown.7 Ideally, testing should only be performed for genes that are clinically actionable. The panel now provides recommendations regarding risk management
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015
Version 2.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 2; 10.6004/jnccn.2016.0018
Finally, the panel noted that multigene tests increase the likelihood of detecting a variant of unknown significance (VUS).3,5–9 The considerable possibility of detecting a VUS adds to the complexity of counseling for multigene testing.
Ovarian Cancer Histology and Genetic Mutations
During the meeting for the 2015 guidelines update, the panel debated whether the criteria for genetic risk evaluation should be more specific regarding ovarian cancer histology. The histology of ovarian cancers in carriers of a BRCA1/2 mutation is more likely to be characterized as serous adenocarcinoma and high grade compared with ovarian cancers in nonmutation carriers. However, endometrioid and clear cell ovarian cancers have also been reported in BRCA1/2 carriers.10–15 Mutations are also associated with nonmucinous ovarian carcinoma as opposed to mucinous.16,17 Mucinous epithelial ovarian carcinomas may be associated with other gene mutations, such as KRAS and TP53 mutations.18 Nonepithelial ovarian carcinomas (eg, germ cell and sex cord stromal tumors) are not significantly associated with BRCA1/2 mutations,19 but they may be associated with other cancer genetic syndromes, such as Peutz-Jeghers syndrome.20–23 Current data indicate that ovarian low-malignant-potential tumors (ie, borderline epithelial ovarian tumors) are also not associated with BRCA1/2 mutations.16
Based on these study findings, the following modifications were made to the genetic risk evaluation guidelines (BR/OV-1, page 155):
“Epithelial ovarian cancer” was replaced with “invasive ovarian cancer.”
The footnote was modified to indicate that BRCA-related ovarian cancers are associated with epithelial nonmucinous histology, although other cancer genetic syndromes may be associated with ovarian cancer that is mucinous or nonepithelial.
Pancreatic Cancer Risk and BRCA1/2 Mutations
BRCA1/2 mutations are associated with an increased propensity for developing pancreatic cancer.24–28 In an analysis of samples from patients with familial pancreatic cancer (kindreds in which ≥3 family members had pancreatic cancer, at least 2 of whom were first-degree relatives), BRCA2 mutations were detected in 17% of patient samples.27 Patients with pancreatic cancer who also have Ashkenazi Jewish ancestry may have a greater likelihood of testing positive for a BRCA1/2 mutation, with prevalence of detected mutations in this group ranging from 5.5% to 19%, and with mutations in BRCA2 (4%–11%) being more common than BRCA1 (1%–8%).29–31 In 211 Ashkenazi Jewish patients with breast cancer who had a family history of pancreatic cancer, 6.6% had a BRCA1 mutation and 7.6% had a BRCA2 mutation.32
Regarding testing criteria for BRCA1/2 mutations, the panel previously recommended that criteria for those with a personal history of pancreatic cancer would be the same as for those with a personal history of prostate cancer; specifically, a personal history of pancreatic or prostate cancer, with at least 1 close relative with breast cancer diagnosed at age 50 years or younger and/or invasive ovarian cancer and/or pancreatic or prostate cancer diagnosed at any age. Given the elevated risk for pancreatic cancer in BRCA1/2 carriers24,25,27,28,33 relative to the risk for prostate cancer,28,33 and the short survival of most patients with pancreatic cancer (which limits the ability to perform genetic testing in these individuals in the future), the panel argued that less stringent criteria are warranted for testing in those with a personal history of pancreatic cancer. Based on concerns raised by 2 panel members, the panel now recommends that a family history of prostate cancer is no longer a criterion for testing in those with a personal history of pancreatic cancer. Furthermore, a personal history of pancreatic cancer combined with Ashkenazi Jewish ancestry warrants testing, given the considerable rates of BRCA1/2 mutations in Ashkenazi Jewish patients with pancreatic cancer (HBOC-1, page 156).29–31
Risk Management Recommendations
The panel's recommendations regarding screening and risk reduction for those found to have a genetic mutation associated with hereditary cancer are based on existing evidence. Changes made for the 2015 update include refinement of risk management recommendations for less common genetic mutations associated with breast and/or ovarian cancer, and recommendations regarding ovarian cancer risk-reducing surgery in BRCA1/2 mutation carriers.
Less Common Genetic Mutations Associated With Breast/Ovarian Cancer
In these NCCN Guidelines, the panel focuses specifically on assessment of known high-penetrance mutations (ie, BRCA1/2, TP53, PTEN). In the 2014 update, the panel added CDH1, STK11/LKB1, and Lynch syndrome to the guidelines as other genes associated with increased breast and/or ovarian cancer risk. Although evidence is limited, other genes have been shown to be associated with increased cancer risk, including ATM, CHEK2, PALB2, BARD1, BRIP1, RAD51C, and RAD51D.
During the 2015 guidelines update meeting, the panel debated the possibility of including information and recommendations for these less common genes, including population frequency, estimated cancer risks, and management strategies. The panel ultimately decided that providing this amount of detailed information in the guidelines for all of the rare genes noted would be premature, given the current state of the evidence. Risk management recommendations should be evidence-based and matched to cancer risk and should only be made for genes that are clinically actionable. Because risk may differ between breast and ovarian cancers, different recommendations may need to be made for these 2 cancer types.
Based on this logic, the panel created a new table summarizing which gene mutations are associated with breast and/or ovarian cancer risk, and when breast MRI, risk-reducing mastectomy (RRM), and risk-reducing salpingo-oophorectomy (RRSO) should be recommended or considered (ADDIT-2, page 159). Breast MRI is recommended when the gene mutation is associated with at least a 20% lifetime risk of breast cancer. This threshold was identified in breast cancer risk models dependent on family history (see NCCN Guidelines for Breast Cancer Screening and Diagnosis and for Breast Cancer Risk Reduction for more information; available at NCCN.org).34,35 Most of the recommendations in this new table are extrapolated from BRCA studies, because no strong evidence exists regarding risk management recommendations for the other genes. Genes for which there is little to no existing evidence suggesting an association with breast and/or ovarian cancer risk are noted in a row titled “Insufficient evidence for intervention.” Intervention may be warranted based on family history or other clinical factors. The recommendations in this table can be used to inform which genes may be included in multigene testing (see earlier discussion).
Salpingectomy in BRCA1/2 Mutation Carriers
Salpingectomy (surgical removal of the fallopian tube) has recently gained attention as a potential procedure to reduce the risk of ovarian cancer. Salpingectomy rates are increasing, especially in women younger than 50 years.36 Its use is supported by the finding that high-grade serous carcinomas may originate in the fallopian tube.37–39 This procedure allows patients to avoid the disadvantages of oophorectomy, such as lack of ovarian preservation and onset of early menopause.40 Salpingectomy has been shown to be a safe and feasible procedure when performed at the same time as hysterectomy.36,41
Despite evidence regarding the safety and feasibility of salpingectomy, more data are needed regarding its efficacy in reducing the risk of ovarian cancer.37,42 Furthermore, BRCA1/2 carriers who undergo salpingectomy without oophorectomy may not get the 50% reduction in breast cancer risk associated with oophorectomy. During the 2015 update meeting, a panel member presented data showing that, although ovarian carcinomas often originate in the fallopian tube, a significant minority (>20%) originates in the ovary.43–46 For these reasons, the panel included a statement that salpingectomy is not the standard of care, and risk-reducing salpingectomy alone or outside the context of a clinical trial is not recommended (HBOC-A, page 157).
Summary and Conclusions
In summary, the panel discussed several pertinent issues this year, including multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also made the following changes to the 2015 recommendations:
Consolidated recommendations regarding testing and counseling principles into a new set of pages, titled “Principles of Cancer Risk Assessment and Counseling,”
Added more specific language regarding ovarian cancer histology criteria for genetic risk evaluation, and
Revised testing criteria for BRCA1/2 mutations for those with a personal history of pancreatic cancer and who have Ashkenazi Jewish ancestry.
The evidence base for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes is rapidly evolving. It is essential for recommendations to reflect the current state of the evidence.
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