National Medical Policy

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1 National Medical Policy Subject: Policy Number: Prophylactic Mastectomy NMP21 Effective Date*: September 2003 Updated: May 2016 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. Prophylactic Mastectomy May 16 1

2 If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Please refer to the HN NMP on Genetic Testing for BRCA1 and BRCA2 Health Net, Inc. considers prophylactic mastectomy medically necessary for patients with a high risk of hereditary breast cancer when they meet the following criteria. These criteria are based on a position statement on Prophylactic Mastectomy developed by the Society of Surgical Oncology. Health Net, Inc. considers reduction mammoplasty, as an alternative to prophylactic mastectomy for women at high risk of developing breast cancer for the primary purpose of reducing cancer risk, not medically necessary due to lack of evidence from peer reviewed randomized control trials comparing the efficacy of reduction mammoplasty to other recommended options for the prevention of breast cancer in these individuals. Bilateral Prophylactic Mastectomy Bilateral prophylactic mastectomy is medically necessary in patients with no cancer diagnosis in any of the following clinical scenerios that portend a high risk of cancer: 1. Atypical hyperplasia of lobular or ductal origin confirmed on biopsy by a qualified pathologist. This diagnosis takes on added significance if atypical hyperplasia is present in multiple sites in a breast and/or if it is bilateral; or 2. Family history of breast and /or ovarian cancer in a first-degree relative, (especially a mother or sister) who is premenopausal and has had bilateral breast cancer (family cancer syndrome), with no demonstrative mutation or a genetic mutation conferring a high risk of breast cancer *; or 3. Dense, fibronodular breasts that are mammographically or clinically difficult to evaluate in a patient with either (or both) of the above clinical presentations. The combination of atypical hyperplasia with a family history of breast cancer implies significant risk (8-l0x) in excess of that of index populations; or 4. Family history of multiple family members with bilateral and/or premenopausal and/or male breast cancer may be associated with a familial breast cancer syndrome. Genetic counseling should be strongly considered, although prophylactic surgery is appropriate in women with a family history consistent with genetic predisposition and no demonstrative genetic mutation*; or 5. Prior thoracic radiation therapy <30 y of age. *Note - Per NCCN (Version ) on Guidelines for Breast Cancer Risk Reduction; Genetic/Familial High-Risk Assessment: Breast and Ovarian, The option of risk-reduction mastectomy (RRM) is warranted based on gene and/or risk level (i.e., BRCA1, BRCA2, CDH1, PTEN, TP53 and PALB2). There is insufficient evidence for RRM for ATM, CHEK2, and STK11 genetic mutations, however, intervention may be warranted based on family history or other clinical factors. The value of risk reducing mastectomy in women with deleterious mutations in other genes associated with a 2-fold or greater risk of breast cancer (based on Prophylactic Mastectomy May 16 2

3 large epidemiologic studies) in the absence of a compelling family history of breast cancer is unknown. (NCCN v1.2016, Breast Cancer Risk Reduction) Unilateral Prophylactic Mastectomy Unilateral prophylactic mastectomy is medically necessary in patients with a diagnosis of cancer in the ipsilateral breast in any of the following clinical scenerios that portend a high risk of cancer: 1. Diffuse microcalcifications in the remaining breast, especially when ductal carcinoma in situ has been diagnosed in the ipsilateral breast. In this individual, there is a 30-40% probability that these microcalcifications will harbor carcinoma; or 2. Lobular carcinoma in situ (LCIS) in the remaining breast. This diagnosis is a marker of risk for the development of invasive cancer and carries special significance when the previously treated breast had either invasive or in situ lobular disease. The tissue diagnosis has a bilateral incidence approaching 80% in many instances; or 3. Development of either invasive lobular or ductal carcinoma in a patient who elected surveillance for lobular carcinoma in situ. This patient is at significant risk (8-10x) for the development of cancer in the intact breast; or 4. The large, breast and/or ptotic, dense, or disproportionately-sized breast that is difficult to evaluate mammographically and clinically. This presentation has added significance when any of the qualifiers listed below are present: Atypical hyperplasia Multicentric primary tumor Family history of breast or ovarian cancer in a first-degree relative (mother, sister, etc.) Young age (<40 years) Presence of a BRCA1 or BRCA2 breast cancer susceptibility gene mutation Multiple breast biopsies resulting in difficulty performing or interpreting diagnostic breast exams; or 5. Previous cancer in one breast as recommended by the American Cancer Society (9/18/2006), for women at high risk of breast cancer. Individuals with known mutations in BRCA1 and BRCA2. or who potentially meet criteria for an inherited syndrome, should also be offered counseling about the risks, benefits, and limitations of other management options including intensive surveillance and chemoprevention. Ideally, the patient should be informed of the breast cancer risk reduction that can be achieved with tamoxifen alone (~50%). Patients undergoing prophylactic mastectomy for suspected hereditary disease should also consider ovarian screening or prophylactic removal, as well as colon screening. Prophylactic mastectomy in men is medically necessary for those men who have been diagnosed with breast cancer. Prophylactic Mastectomy May 16 3

4 Definitions LCIS Lobular carcinoma in situ PM Prophylactic mastectomy BPM Bilateral prophylactic mastectomy CPM Contralateral prophylactic mastectomy BCT Breast conservation therapy UM Unilateral mastectomy TM Therapeutic mastectomy MRI Magnetic resonance imaging CBC Contralateral breast cancer DFS Disease-free survival RRM Risk reduction mastecomy Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes V16.3 Family history of malignant neoplasm-breast V16.9 Unspecified malignant neoplasm V50.41 Prophylactic organ removal, breast V84.01 Genetic susceptibility to malignant neoplasm of breast 174 Malignant neoplasm of female breast Nipple and areola Central portion Upper-inner quadrant Lower-inner quadrant Upper-outer quadrant Lower-outer quadrant Axillary tail Other specified sites of female breast Breast (female) unspecified 175 Malignant neoplasm of male breast Nipple and areola Other and unspecified sites of male breast ICD-10 Codes C C Malignant neoplasm of breast Z15.01 Genetic susceptibility to malignant neoplasm of breast Z40.01 Encounter for prophylactic removal of breast Z80.3 Family history of malignant neoplasm of breast Z80.9 Family history of malignant neoplasm, unspecified Prophylactic Mastectomy May 16 4

5 CPT Codes Mastectomy, partial;(eg, lumpectomy, tylectomy, quadrantectomy, segmentectomy); Mastectomy, partial; with axillary lymphadenectomy Mastectomy, simple, complete Mastectomy, subcutaneous Mastectomy, radical, including pectoral muscles, axillary lymph nodes Mastectomy, radical, including pectoral muscles, axillary and internal mammary lymph nodes (Urban type operation) Mastectomy, modified radical, including axillary lymph nodes, with or without pectoralis minor muscle, but excluding pectoralis major muscle BRCA 1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants (i.e., exon 13 del 3.835kb, exon 13 dup6kb, exon14-20 del26kb, exon 22del 510bp, exon8-9 del 7.1kb) BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant BRCA 2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis BRCA 2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant HCPCS Codes N/A Scientific Rationale Update May 2016 Per the NCCN Guidelines, (Version ) on Genetic / Familial High Risk Assessment: Breast or Ovarian, it notes the following: Breast and Ovarian Management Based on Genetic Tests Results Recommended Breast MRI Intervention warranted based on gene &/risk level Insufficient evidence for intervention ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53 BRIP1 Discuss Option of Risk Reducing Mastectomy (RRM) BRCA1, BRCA2, CDH1, PTEN, TP53, PALB2 ATM, CHEK2, STK11 Recommendation/Consider Risk-Reducing Salpingooopherectomy (RRSO) BRCA1, BRCA2, Lynch Syndrome, BRIP1, RAD51C, RAD51D PALB1 Per the same NCCN Guidelines as noted above, it also states: The panel specifically focuses on assessment of known high-penetrance mutations (i.e., BRCA 1/2, TP53, PTEN) and recommendations for genetic testing, counseling and management strategies in individuals with these mutations. There are additional gene mutations that the NCCN panel feels warrant additional screening beyond what is recommended in the general population (i.e., those without the specific gene mutation). These include mutations for CDH1, CHEK2, PALB2, STK11, BRIP1, RAD51C, and RAD51D. Prophylactic Mastectomy May 16 5

6 A retrospective analysis of 337 patients who met NCCN criteria for BRCA 1 /2 mutation testing and had multigene testing showed that showed that 25 patients (7.4%) had non-brca mutations. The most common of these mutations were PALB (23%), CHEK2 (15%), and ATM (15%). Another breast cancer susceptibility gene that has been identified is CHEK2. Walsh et al. (2006) completed a study of breast cancer patients in the U.S. with a strong family history of breast or ovarian cancer but who tested negative for a BRCA 1 /2 mutation, 5% had CHEK2 mutations. Deleterious CHEK2 mutations have been reported to occur with a higher frequency in Northern and Eastern European countries compared with North America. The cumulative lifetime risk for breast cancer in women with CHEK2 mutations and familial breast cancer has been estimated to range from approximately 28% to 37%, and is higher in women with this gene mutation. Kurian et al. (2014) completed a study of 198 women who were referred for BRCA 1 / 2 testing and underwent multi-gene testing which showed 16 deleterious mutations out of 141 women who tested negative for BRCA 1 / 2 (11.4%, 95% Cl= ). The discovery of these mutations led to recommendations for further screening. Therefore, findings from multigene testing may have the potential to alter clinical management. The NCCN Guidelines, (Version ) on Genetic / Familial High Risk Assessment: Breast or Ovarian, has a section on the overview of multi-gene testing which notes: 1. The recent introduction of multi-gene testing for hereditary forms of cancer has rapidly altered the clinical approach to testing at-risk patients and their families. Based on next-generation sequencing technology, these tests simultaneously analyze a set of genes that are associated with a specific family cancer phenotype or multiple phenotypes. 2. Patients who have a personal or family history suggestive of a single inherited cancer syndrome are most appropriately managed by genetic testing for that specific syndrome. When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/or cost-effective. 3. There is a role for multi-gene testing in individuals who have tested negative (indeterminate) for a single syndrome, but whose personal or family history remains strongly suggestive of an inherited susceptibility. 4. As commercially available tests differ in the specific genes analyzed (as well as classification of variants and many other factors), choosing the specific laboratory and test panel is important. 5. Multi-gene testing can include intermediate penetrant (moderate-risk) genes. For many of these genes, there are limited data on the degree of cancer risk and there are no clear guidelines on risk management for carriers of mutations. Not all genes included on available multi-gene tests are necessarily clinically actionable. 6. As is the case with high-risk genes, it is possible that the risks associated with moderate risk genes may not be entirely due to that gene alone, but may be influenced by gene/gene or gene/environment interactions. In addition, certain mutations in a gene may pose higher or lower risk than other mutations in that same gene. Therefore. It may be difficult to use a known mutation alone to assign risk for relatives. 7. In many cases the information from testing for moderate penetrance genes does not change risk management compared to that based on family history alone. 8. Mutations in many breast cancer susceptibility genes involved in DNA repair may be associated with the rare autosomal recessive condition, Fanconi anemia. 9. It is for these and other reasons that multi-gene testing is ideally offered in the context of professional genetic expertise for pre-and post-test counseling. Prophylactic Mastectomy May 16 6

7 Wang et al. (2015) Certain predisposition factors such as BRCA1/2 and CHEK2 mutations cause familial breast cancers that occur early. In China, breast cancers are diagnosed at relatively younger age, and higher percentage of patients are diagnosed before 40 years, than that in Caucasians. However, the prevalence for BRCA1/2 mutations and reported. CHEK2 germline mutations is much lower or absent in Chinese population, arguing for the need to study other novel risk alleles among Chinese breast cancer patients. In this study, we searched for CHEK2 mutations in young, high-risk breast cancer patients in China and detected a missense variant Y390C (1169A>G) in 12 of 150 patients (8.0%) and 2 in 250 healthy controls (0.8%, P=0.0002). Four of the Y390C carriers have family history of breast and/or ovarian cancer. In patients without family history, Y390C carriers tend to develop breast cancer early, before 35 years of age. The codon change at Y390, a highly conserved residue located in CHEK2's kinase domain, appeared to significantly impair CHEK2 activity. Functional analysis suggested that the CHEK2 Y390C mutation is deleterious as judged by the mutant protein's inability to inactivate CDC25A or to activate p53 after DNA damage. Cells expressing the CHEK2 Y390C variant showed impaired p21 and Puma expression after DNA damage, and the deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumorigeneisis. Taken together, our results not only identified a novel CHEK2 allele that is associated with cancer families and confers increased breast cancer risk, but also showed that this allele significantly impairs CHEK2 function during DNA damage response. Our results provide further insight on how the function of such an important cancer gene may be impaired by existing mutations to facilitate tumorigenesis. It also offers a new subject for breast cancer monitoring, prevention and management. Easton et al. (2015) completed an article in the New England Journal of Medicine that reported that the magnitude of relative risk of breast cancer associated with CHEK2 truncating mutations is likely to be moderate and unlikely to be high. On the basis of two large case-control analyses, the authors calculated an estimated relative risk of breast cancer associated with CHEK2 mutations of 3.0 (90% confidence interval [CI], 2.6 to 3.5), and an absolute risk of 29% by age 80 years. Kuusisto et al. (2011) completed a study in which 82 well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. Three previously reported breast cancer-associated variants, BRCA1 c.5095c > T, CHEK2 c.470t > C, and CHEK2 c.1100delc, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470t > C and/or c.1100delc. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72a > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA). In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470t > C and c.1100delc, Prophylactic Mastectomy May 16 7

8 make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool. Scientific Rationale Update October 2015 Per the NCCN Guidelines, (Version ) on Breast Cancer Risk Reduction, under (BRISK)-6 Footnotes, the following modifications are noted: Risk-reduction mastectomy should generally be considered only in women with a genetic mutation conferring a high risk for breast cancer (see NCCN Guidelines for Genetic/Familial High-Risk assessment; Breast and Ovarian- Table on GENE-2), compelling family history, or possible with LCIS or prior thoracic radiation therapy<30 years of age. The value of risk-reducing mastectomy in women with deleterious mutations in other genes associated with a 2-fold or greater risk for breast cancer (based on large epidemiologic studies) in the absence of a compelling family history of breast cancer is unknown. Breast and Ovarian Management Based on Genetic Testing Results Discuss Option of Risk Reduction Mastectomy Intervention Warranted based on gene and/or risk level Insufficient evidence for intervention* BRCA1 BRCA2 CDH1 PTEN TP53 ATM BARD1 CHEK2 PALB2 STK11 *Intervention may still be warranted based on family history or other clinical factors **NCCN Guidelines Genetic/Familial High-Risk Assessment: Breast and Ovarian (2.2015) King et al (2015) reviewed 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk. Patients participating in surveillance after an LCIS diagnosis were observed in a prospectively maintained database. Comparisons were made among women choosing surveillance, with or without chemoprevention, and those undergoing bilateral prophylactic mastectomies between 1980 and One thousand sixty patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27 to 83 years). Fifty-six patients (5%) underwent bilateral prophylactic mastectomy; 1,004 chose surveillance with (n = 173) or without (n = 831) chemoprevention. At a median follow-up of 81 months (range, 6 to 368 months), 150 patients developed 168 breast cancers (63% ipsilateral, 25% contralateral, 12% bilateral), with no dominant histology (ductal carcinoma in situ, 35%; infiltrating ductal carcinoma, 29%; infiltrating lobular carcinoma, 27%; other, 9%). Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% Prophylactic Mastectomy May 16 8

9 with chemoprevention; 21% with no chemoprevention; P <.001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P =.008). The authors concluded they observed a 2% annual incidence of breast cancer among women with LCIS. Common clinical factors used for risk prediction, including age and family history, were not associated with breast cancer risk. The lower breast cancer incidence in women opting for chemoprevention highlights the potential for risk reduction in this population. DeFelice et al (2015) sought to clarify the role of bilateral risk-reducing mastectomy (BRRM) in reducing breast cancer risk in women carriers of BRCA1 and BRCA2 mutations. The Pubmed, MEDLINE and Scopus databases were searched to retrieve articles written in the English language. Two investigators independently extracted the characteristics and results of the selected studies. Only prospective trials with available absolute numbers of breast cancer and death events were included. Pooled hazard ratio (HR) with 95 % confidence interval (CI) was calculated using fixed or random effects model. Meta-analysis of four prospective studies, including 2635 patients, demonstrated a significant risk reduction of breast cancer incidence in BRCA1 and BRCA2 mutation carriers receiving BRRM (HR 0.07; 95 % CI ; p = 0.004). Among patients without previous risk-reducing salpingo-oophorectomy, a significant benefit was similarly recorded (HR 0.06; 95 % CI ; p = 0.005). The reviewers concluded performing BRRM may lead to highly significant risk reduction of breast cancer in BRCA1 and BRCA2 mutation carriers. These data allow clinicians to discuss more in-depth with patients all the available options in order to design better management strategies. Scientific Rationale Update October 2014 Per the NCCN Guidelines, Version on Breast Cancer Risk Reduction, under (BRISK)-6 Footnotes, the following modifications are noted: Risk reduction mastectomy should generally be considered only in women with a genetic mutation conferring a high risk for breast cancer (BRCA1/2, PTEN, TP53, CDH1, STK11), compelling family history, or possibly with LCIS or prior thoracic radiation therapy at <30 Yrs of age. The value of risk reducing mastectomy in women with deleterious mutations in other genes associated with a 2-fold or greater risk for breast cancer (based on large epidemiologic studies) in the absense of a compelling family history of breast cancer is unknown. Axillary node assessment has limited indication at the time of risk reduction procedure surgery. Scientific Rationale Update October 2013 Peled et al (2013) reported total skin-sparing mastectomy (TSSM) with preservation of the nipple-areolar complex skin has become increasingly accepted as an oncologically safe procedure. Oncologic outcomes after TSSM in BRCA mutation carriers have not been well-studied. The authors identified 53 BRCA-positive patients who underwent bilateral TSSM for prophylactic (26 patients) or therapeutic indications (27 patients) from 2001 to Cases were age-matched (for prophylactic cases) or age- and Prophylactic Mastectomy May 16 9

10 stage-matched (for therapeutic cases) with non-brca-positive patients. Outcomes included tumor involvement of resected nipple tissue, the development of new breast cancers in patients who underwent risk-reducing TSSM, and local-regional recurrence in patients who underwent therapeutic TSSM. Outcomes from 212 TSSM procedures in 53 cases and 53 controls were analyzed. In patients undergoing TSSM for prophylactic indications, in situ cancer was found in one (1.9 %) nipple specimen in BRCA-positive patients versus two specimens (3.8 %) in the non-brca-positive cohort (p = 1). At a mean follow-up of 51 months, no new cancers developed in either cohort. In patients undergoing TSSM for therapeutic indications, in situ or invasive cancer was found in zero of the nipple specimens in BRCA-positive patients versus two specimens (3.7 %) in the non-brca-positive cohort (p = 0.49). At a mean follow-up of 37 months, there were no local-regional recurrences in the BRCA-positive cohort and 1 (3.7 %) in the non-brca-positive cohort. Investigators concluded TSSM is an oncologically safe procedure in BRCA-positive patients. In patients undergoing TSSM as a risk-reducing strategy, 4-year follow-up demonstrates no increased risk of developing new breast cancers; longer-term follow-up is ongoing. Singh et al (2013) reported that despite substantial survival benefits of risk-reducing mastectomy (RRM) and risk-reducing bilateral salpingo-oophorectomy (RRBSO) among BRCA mutation carriers, only a minority elect to undergo these procedures. This study investigated factors that might influence decision making regarding prophylactic surgeries among women with BRCA mutations. Unaffected BRCA mutation carriers who were counseled at a single center and either underwent prophylactic surgery or participated in a high-risk surveillance program at our institution from 1998 through 2010 were included in the study. Medical records were reviewed and data collected included age, family history, parity, mutation type, history of breast biopsy or cosmetic surgery, and uptake of prophylactic surgeries. Among 136 unaffected women with BRCA mutations, uptake of RRM was 42% and uptake of RRBSO was 52%. Family history of first- and second-degree relatives being deceased from breast cancer was predictive of uptake of RRM and of RRBSO (odds ratio [OR], 11.0; P =.005; and OR, 15.8; P =.023, respectively), and history of a mother lost to pelvic cancer was predictive of uptake of RRBSO (OR, 7.9; P =.001). Parity also predicted both RRM and RRBSO uptake (OR, 4.2; P =.001; and OR, 5.4; P =.003, respectively). Age at the time of genetic testing and history of breast biopsy or cosmetic surgery were not predictive of RRM uptake. The authors concluded perceptions of cancer risk are heavily influenced by particular features of an individual's family history and may be motivators in preventive surgery more than actual cancer risk estimations themselves. Awareness of subtle factors beyond the statistical risk for cancers is relevant when counseling at-risk women. Dražan et al (2012) sought to verify if prophylactic mastectomy with immediate breast reconstruction can prevent breast cancer in BRCA positive patients. There were 100 BRCA positive women in which prophylactic mastectomy with immediate reconstruction, 75 dieps, 25 with implants, performed in period Group A was composed of healthy, non-affected 41 patients, group B of 59 patients in remission after breast cancer treatment. These groups were compared to group C that consisted of 219 healthy carriers of BRCA1/2, non-operated, from registry of genetic department of a single center from Follow-up for oncology status was done in September 2011 for all 3 groups. Average follow-up of 21 months revealed that in group A there was no breast cancer, in group B 4 patients died and 2 had treatment for metastases. In group C, there were 16 new cases of breast cancer. Authors concluded bilateral prophylactic mastectomy with immediate reconstruction can be an effective way in breast cancer prevention in healthy carriers of BRCA1/2 Prophylactic Mastectomy May 16 10

11 mutation. In BRCA positive patients treated for breast cancer, the effect of prophylactic mastectomy is unclear. Their survival is more influenced by their previous disease than by a new tumor in the breast. This et al (2012) described the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingooophorectomy was observed. The authors reported this study confirms the high breast cancer risk in these women. Scientific Rationale October 2012 According to the NCCN, the lifetime risk of breast cancer in BRCA 1/2 mutation carriers has been estimated to be 56%-84%. Per the NCCN guidelines on breast cancer risk reduction: Risk reduction mastectomy should generally be considered only in women with BRAC 1/2 or other strongly predisposing gene mutations, compelling family history or possibly women with lobular carcinoma in situ (LCIS) or prior thoracic radiation therapy <30 y of age (e.g., to treat Hodgkins Disease). Evaluation should include consultation with surgery and reconstructive surgery. Psychological consultation may also be considered. Discussion regarding the risk of breast or ovarian cancer and the option of risk reduction bilateral ovarian salpingo-oophorectomy. Dražan et al (2012) sought to verify if prophylactic mastectomy with immediate breast reconstruction can prevent breast cancer in BRCA positive patients. There were 100 BRCA positive women in which prophylactic mastectomy with immediate reconstruction, 75 dieps, 25 with implants, performed in period Group A was composed of healthy, non-affected 41 patients, group B of 59 patients in remission after breast cancer treatment. These groups were compared to group C that consisted of 219 healthy carriers of BRCA1/2, non-operated, from registry of genetic department of the Masaryk Memorial Cancer in Brno, from Average follow-up of 21 months revealed that in group A there was no breast cancer, in group B 4 patients died and 2 had treatment for metastases. In group C, there were 16 new cases of breast cancer. Investigators concluded bilateral prophylactic mastectomy with immediate reconstruction can be an effective way in breast cancer prevention in healthy carriers of BRCA1/2 mutation. In BRCA positive patients treated for breast cancer, the effect of prophylactic mastectomy is unclear. Their survival is more influenced by their previous disease than by a new tumor in the breast. Prophylactic Mastectomy May 16 11

12 Scientific Rationale Update February 2011 Lostumbo et al (2010) performed a Cochrane data base review to determine whether prophylactic mastectomy (PM) reduces death rates from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast, and also examined the effect of prophylactic mastectomy on other endpoints, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. The study included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer. At least two authors independently abstracted data. Data were summarized descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. Data were analyzed separately for bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM). All 39 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 7,384 women with a wide range of risk factors for breast cancer who underwent PM. BPM studies on the incidence of breast cancer and/or disease-specific mortality reported reductions after BPM particularly for those with BRCA1/2 mutations. For CPM, studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups and this study showed no overall survival advantage for CPM at 15 years. Another study showed significantly improved survival following CPM but after adjusting for bilateral prophylactic oophorectomy, the CPM effect on all-cause mortality was no longer significant. Sixteen studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have PM but more variable satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM. Case series reporting on adverse events from PM with or without reconstruction reported rates of unanticipated re-operations from 4% in those without reconstruction to 49% in patients with reconstruction. The reviewers concluded while published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. BPM should be considered only among those at very high risk of disease. There is insufficient evidence that CPM improves survival and studies that control for multiple confounding variables are needed. Stucky et al (2010) investigated factors associated with CPM. A breast cancer database collected from 2000 through 2008 was retrospectively reviewed. Treatment groups analyzed included breast conservation therapy (BCT), unilateral mastectomy (UM) with or without reconstruction (± R), and CPM ± R. Variables were compared using ANOVA F-tests and chi-square tests. Multivariate analysis was performed using logistic regression. A total of 1,391 patients underwent surgery for invasive breast cancer: 69% BCT, 21% UM, and 10% bilateral mastectomy. Of those undergoing bilateral mastectomy, 30% had bilateral cancer and were excluded from analysis. The rate of CPM increased significantly from 0 to 20%, whereas the rate of UM remained relatively stable. Factors associated with CPM included younger age, significant family history, genetic testing, positive BRCA gene mutation, and preoperative magnetic resonance imaging (MRI). Tumor characteristics associated with CPM included positive axillary lymph node metastases and triple-negative disease (ER-/PR-/HER2 normal). Breast reconstruction was more common among women who underwent CPM. On multivariate regression comparing BCT with CPM, younger age, larger tumors, multifocal disease, and MRI significantly predicted CPM. Comparing UM with CPM, only Prophylactic Mastectomy May 16 12

13 age and genetic testing significantly predicted CPM. The reviewers concluded the rate of bilateral mastectomy for unilateral breast cancer is increasing. This is particularly true for younger patients with strong family history. The availability of breast reconstruction may play a role and the effects of stage and multifocal disease needs further exploration. Boughey et al (2010) investigated whether CPM in addition to therapeutic mastectomy (TM) is associated with a survival advantage in high-risk women with breast cancer. A total of 385 women with stage I or II breast cancer and a family history of breast cancer who underwent TM and CPM between 1971 and 1993 were evaluated and compared to 385 patients matched on age at diagnosis, tumor stage, nodal status, and year of diagnosis who underwent TM-only. Contralateral breast cancer (CBC) events and survival outcomes were compared. At a median follow-up of 17.3 years, 2 CBCs (0.5%) developed in the CPM cohort and 31 (8.1%) in the TM-only cohort, representing a 95% decreased risk of CBC. One hundred twenty-eight women in the CPM group and 162 women in the TM-only group have died, resulting in 10-year overall survival estimates of 83 and 74%, respectively. This difference in overall survival persisted in multivariate analysis. Disease-free survival (DFS) was better in the CPM cohort than the TM-only group and remained significant in multivariate analysis. In this retrospective cohort study, the authors concluded CPM was associated with decreased CBC event and improved overall survival and disease free survival. Scientific Rationale June 2009 It has been suggested that breast reduction surgery may be an alternative preventative option to prophylactic mastectomy for women at high risk of developing breast cancer. For women who have a genetic mutation that predisposes them to breast and ovarian cancer, the currently accepted options include prophylactic surgery, intensified surveillance, and chemoprevention. There is no clear "best" choice among these alternatives and the choice usually depends on patient preference. Prophylactic bilateral mastectomy has been demonstrated to reduce breast cancer incidence in women with a high inherited susceptibility to breast cancer. In both retrospective and prospective studies, prophylactic mastectomy decreases the incidence of breast cancer by 90 percent or more in women at high risk. A prospective study (Rebbeck et al 2004) of 105 healthy BRCA1/2 carriers who underwent prophylactic mastectomy demonstrated two cases of breast cancer after an average of 6.4 years of follow-up, compared with 184 cases of breast cancer among 378 mutation carriers matched for specific gene, center, and age who did not undergo the procedure. The two cases of breast cancer in women undergoing prophylactic surgery occurred after subcutaneous rather than total mastectomy. Among mutation carriers undergoing bilateral mastectomy, the risk of subsequent breast cancer was reduced by 95 percent in women who had undergone prior or concurrent bilateral oophorectomy and by 90 percent in those with intact ovaries. Total (or simple) mastectomy is recommended for prophylaxis because subcutaneous mastectomy leaves behind more glandular tissue that remains at risk for future cancers. Tarone et al (2004) reported that that several epidemiological follow-up studies have indicated that there may be a substantial reduction in breast cancer risk among women who have undergone breast reduction surgery. The authors note that although such observational studies cannot demonstrate definitively that reduction mammaplasty reduces the risk of breast cancer, the evidence from these studies is Prophylactic Mastectomy May 16 13

14 sufficiently strong to warrant the evaluation of breast reduction surgery as an option for primary prevention in clinical studies of women at increased risk of breast cancer. The authors suggest that the availability of a more acceptable surgical option for primary prevention of breast cancer could increase the number of women willing to choose risk reduction surgery and thus may result in an overall reduction in breast cancer mortality among high-risk women. Brinton et al (2001) investigated whether the reduction in breast cancer risk was related directly to the amount of breast tissue removed. Medical record retrieval was attempted for 161 breast cancer patients in a Swedish cohort of 31,910 women who had had breast reduction surgery and for 483 women who had not developed breast cancer. Information on amount of breast tissue removed was abstracted along with other factors that influence breast cancer risk. Odds ratios of developing breast cancer were calculated based on amount of breast tissue removed. The amount of tissue removed was a significant predictor of risk, as subjects in the highest quartile of tissue removal had a significantly lower risk than those in the lowest quartile. Considering the total amount of tissue removed (both breasts), subjects with > 1600 versus < 800 grams removed had an odds ratio (OR) of This relation persisted after adjustment for other breast cancer risk factors and was apparent within every subgroup examined. Fryzek et al (2006) extended the above study yielding an average of nearly 16 years of follow-up. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated comparing women who underwent breast reduction surgery with women in the general Swedish population. Breast cancer was observed in 443 women versus 624 expected for a statistically significant reduced SIR of 0.71 (95% CI= ). Analyses by age at surgery, time since surgery or calendar year of surgery revealed similar reductions in risk. The investigators concluded the study offers further evidence that women undergoing breast reduction surgery have reduced breast cancer risk. They recommend direct testing of this reduction in risk through clinical trials should be considered. According to the American Society of Breast Surgeons, the National Comprehensive Cancer Network (NCCN), National Cancer Institute, American College of Obstetricians and Gynecologists and the American Cancer Society, risk reduction interventions for those at high risk include bilateral total mastectomy, bilateral salpingo-oophorectomy and/or chemoprevention. None of these societies make any recommendations for breast reduction surgery as a risk reducer for breast cancer in the average or high-risk individuals. At this time, there is a lack of evidence from peer reviewed randomized control trials comparing the efficacy of reduction mammoplasty to other recommended options for the prevention of breast cancer in high risk individuals. Scientific Rationale June 2007 In September 2005, the U.S. Preventive Services Task Force (USPSTF) published recommendations for genetic counseling and BRCA mutation testing for women with family history patterns associated with an increased risk for mutations in BRCA1 or BRCA2 genes because of an increased risk for developing breast or ovarian cancer. The USPSTF does not endorse routine genetic testing in the general female population. The USPSTF recommended that high risk women seek genetic counseling to allow for informed decision making about testing and to determine if further prophylactic Prophylactic Mastectomy May 16 14

15 treatment is advised. There is insufficient evidence to determine the benefits of chemoprevention or intensive screening in improving health outcomes in these women if they test positive for BRCA1 or BRCA2 mutations. However, there is fair evidence that prophylactic surgery for these women significantly decreases breast and ovarian cancer incidence. In addition, the USPSTF has recommended genetic testing for the BRCA gene for women who are not of Ashkenazi (Eastern European) Jewish heritage and possess any of the following criteria: 1. Two first-degree relatives with breast cancer, one of whom was diagnosed when they were younger than 50; or 2. Three or more first or second degree relatives diagnosed with breast cancer at any age; or 3. A first degree relative diagnosed with cancer in both breasts; or 4. Two or more first or second degree relatives diagnosed at any age; or 5. A male relative with breast cancer. Women of Ashkenazi (Eastern European) Jewish heritage should be referred for genetic evaluation if they have either of the following criteria: 1. A first degree relative with breast or ovarian cancer at any age or 2. Two second degree relatives on the same side of the family with breast or ovarian cancer at any age. (2006) The American Cancer Society Board of Directors has stated that "only very strong clinical and/or pathologic indications warrant doing this type of preventive operation (prophylactic mastectomy)." Nonetheless, after careful consideration, this might be the right choice for some women. Per the National Cancer Institute, the estimated new cases and deaths from breast cancer in the United States in 2007 are 178,480 (female) and 2,030 (male). The estimated deaths in 2007 are 40,460 (female) and 450 (male). In March 2007, the Society of Surgical Oncology, developed a position statement in favor of prophylactic mastecomy. This relates to patients without a cancer diagnosis but are high risk with any of the following factors: BRCA mutations or any other susceptibility genes; (eg. A known mutation of BRCA 1 or BRCA 2 genes or other stongly predisposing breast cancer susceptibility genes) or Strong family history with no demonstrative mutation; (eg. A family history of breast cancer in multiple first-degree relatives and/or multiple successive generations of family members with breast and/or ovarian cancer (family cancer syndrome). Additionally a family history of multiple family members with bilateral and/or pre-menopausal and/or male breast cancer may be associated with a familial breast cancer syndrome. Genetic counseling should be strongly considered, although prophylactic surgery is appropriate in women Prophylactic Mastectomy May 16 15

16 with a family history consistent with genetic predisposition and no demonstrive genetic mutation) or Histologic risk factors. (eg. Atypical ductal or lobular hyperplasia or lobular carcinoma insitu confirmed on biopsy. These changes are especially significant if present with a strong family history of breast cancer.) It is important for women with a BRCA 1 or BRCA 2 mutation to recognize that they have a high risk of developing ovarian cancer, as well as breast cancer. They should be given the option of prophylactic oopherectomy to be done once child bearing is complete. (See Health Net s National Medical Policy on Prophylactic Oopherectomy). In addition, women who have the BRCA1 mutation and who have their ovaries surgically removed after child bearing is complete, appear to have a reduced risk of breast cancer. Per the peer-reviewed medical literature, prophylactic mastectomy is indicated as an effective treatment in reducing the occurrence of breast cancer for individuals in highrisk categories. It is important that affected individuals receive counseling regarding all available options, in addition to the risks and benefits of this procedure. It is also imperative that the patient understand that the surgery will not eliminate the risk of developing cancer. However, for patients who carry the BRCA mutation, prophylactic mastectomy can minimize the additional risk conferred by genetics. Scientific Rationale - Initial For women at high risk for hereditary breast cancer, there are three general approaches to the development of intervention/prevention strategies: intensified surveillance, chemoprevention, and prophylactic mastectomy. Intensified Surveillance An alternative to prophylactic mastectomy includes a regular annual schedule of clinical breast exams (CBE) starting at age 25-35, annual mammography starting at age 25-35, and self breast exams (SBE) starting at age Intensified screening may identify disease at a favorable stage, but it does not prevent cancer. Chemoprevention - Tamoxifen and Other SERMs Tamoxifen is known as a selective estrogen-receptor modulator (SERM) and is FDA approved for women at high risk of developing breast cancer, and reducing the risk for recurring cancer. It has also been shown to improve survival rates in women who have estrogen-receptor positive breast cancer. Research has shown that tamoxifen can reduce the chances of developing breast cancer by 49% in high-risk women, and is particularly protective in women over 60. Tamoxifen is the most widely used chemoprevention agent for the prevention of breast cancer, although there are other antiestrogens currently being tested. Investigative Agents Raloxifene is another SERM that is also proving to be protective against breast cancer and has a lower risk than tamoxifen of causing uterine cancer. In 2001, a major on-going study on raloxifene reported a reduced risk for breast cancer of 72% over a four-year period and an 84% reduced risk for hormone receptivepositive breast cancer. More research is warranted. Aromatase inhibitors are proving to be effective treatments for hormone-receptor positive breast cancer. Like tamoxifen, they are also being investigated for protection in high-risk women. Prophylactic Mastectomy May 16 16

17 COX-2 inhibitors, which include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra), are newer anti-inflammatory agents normally used for pain relief. They also have anti-cancer properties, and, in fact, celecoxib has been approved for preventing an inherited form of colon cancer. Researchers hope these agents may also help reduce the risk for breast cancer, although there is currently no firm evidence that these agents can do so. Retinoids. Analogues of vitamin A called retinoids are being studied for protection against breast cancer. One retinoid, fenretinide, appears to offer some protection against a second breast cancer in previously diagnosed, premenopausal women (but not in postmenopausal women, who in fact may do worse). Prophylactic mastectomy According to the American Cancer Society (2003), recent studies have shown that about 10% of breast cancer cases are hereditary as a result of genetic changes (mutations). The most common genetic changes are those of the BRCA1 and BRCA2 genes. Normally, these genes help to prevent cancer by making proteins that keep cells from growing abnormally. However, if a genetic mutation is inherited from either parent, the risk for developing breast cancer increases in relation to the general population. The availability of genetic markers such as BRCA1 and BRCA2 can help to quantify the cancer risks for some individuals suspected as having a dominantly inherited susceptibility to breast and/or ovarian cancer. The results of these tests are used for estimation of risk for the disease. It is important to note however that, in women, breast cancer risk is based on the combination of many heterogeneous risk factors including family history, menstrual history, pregnancy as well as the presence or absence of a BRCA1 or BRCA2 mutation. Also, although both men and women can inherit and pass on defective BRCA genes, genetic screening for breast cancer in men with no symptoms is not recommended. Alterations in BRCA1 and BRCA2 explain a majority, but not all, of the inherited forms of breast and ovarian cancers. According to lifetime risk estimates for women in the general population, about 12% (1 in 8 women) will develop breast cancer, compared with an estimated 50 to 85% of women with mutations in the BRCA1 or BRCA2 genes. Women with these inherited mutations also have an increased risk for developing ovarian cancer. Lifetime risk estimates for women in the general population predict that 1.5% (1 in 70 women) will develop ovarian cancer, compared with an estimated 40-60% of women with mutations in BRCA1 and 10-15% of women with mutations in BRCA2. Breast cancer risk is higher among women whose close blood relatives have this disease. Blood relatives can be from either the mother s or father's side of the family. Having one first-degree relative (mother, sister, or daughter) with breast cancer approximately doubles a woman's risk, and having two first-degree relatives increases her risk 5-fold. Although the exact risk is not known, women with a family history of breast cancer in male family members also have an increased risk of breast cancer. Though extremely rare, male breast cancer does occur. Males who have had breast cancer, particularly those with a family history of the disease (in either male or female relatives), may want to consider prophylactic treatment of the ipsilateral breast. With respect to breast cancer, it is important to note that BRCA1 and BRCA2 gene mutations are only associated with hereditary forms of the disease-and only about 5 Prophylactic Mastectomy May 16 17

18 percent of all breast cancers are inherited. The remaining 95 percent are nonhereditary or of unknown cause. Breast cancer is common enough that random, non-inherited breast tumors may appear in more than one member of a single family. However, that does not necessarily mean family members have inherited an abnormal gene which predisposes them to breast cancer, especially if the disease occurs late in life. Families in which breast cancer is inherited typically demonstrate the following characteristics: Breast cancer in two or more close relatives, such as a mother and sister; Early onset of breast cancer in family members, often before age 50; History of breast cancer in more than one generation; Cancer in both breasts in other family members; Frequent occurrence of ovarian cancer; Ashkenazi (Eastern and Central European) Jewish ancestry, with a family history of breast and/or ovarian cancer; Male breast cancer Prophylactic mastectomy is the surgical removal of one or both breasts to try to prevent or reduce the risk of breast cancer. Prophylactic mastectomy can be performed either as a subcutaneous or a total simple mastectomy. Subcutaneous mastectomy removes the majority of glandular breast tissue while sparing the skin, lymphatic drainage system, and nipple-areolar complex. Simple total mastectomy removes the vast majority of the glandular breast tissue extended to include a layer of pectoralis major fascia and the lower-level axilla along with the axillary nodes, and is the procedure of choice. Prophylactic mastectomy is often considered by women who have a strong family history of breast cancer, especially among close relatives who develop the disease before age 50. Although having a preventive mastectomy can reduce the risk, no one can be certain that this procedure will protect a woman from breast cancer. Because it is impossible to remove all breast tissue, breast cancer can still develop in the small amount of remaining tissue. However, according to a study supported by the Agency for Health Care Policy and Research (NRSA Training Grant HS00020), for young women with BRCA gene mutations, prophylactic mastectomy may substantially improve life expectancy. Still, the decision is not easy. Having the genes does not mean that cancer will always occur, meaning that mastectomy might not be necessary in all such women. Nevertheless, in one 2000 study, 70% of women were satisfied with their decision to have prophylactic breast removal. Women should discuss all options with their physician, including oophorectomy and close monitoring. Review History August 2003 September 2003 August 2005 March 2007 June 2007 Medical Advisory Council Review Medical Advisory Council Review Coding Updates Update. Unilateral prophylactic mastectomy added as medically necessary, per recommendation of A.C.S., for patients with a high risk of hereditary breast cancer who have had previous cancer in one breast. Additional guidelines from the Society of Prophylactic Mastectomy May 16 18

19 June 2009 February 2011 November 2011 October 2012 October 2013 October 2014 October 2015 May 2016 Surgical Oncology, have been added under bilateral prophylactic mastectomy, #2&4. Added reduction mammoplasty for the primary purpose of reducing breast cancer risk as investigational and therefore not medically necessary. Update no revisions Update no revisions Added Prior thoracic radiation therapy <30 y of age as a medically necessary indication for prophylactic mastectomy based on NCCN recommendations. Update no revisions. Code Updates Update Added genetic mutation conferring a high risk of breast cancer (i.e., PTEN, TP53, CDH1, STK11), per NCCN V1.2014, on Breast Cancer Risk Reduction. Codes reviewed. Update Under section on Bilateral Prophylactic Mastectomy, revised criteria #2, removing specific genetic mutations (BRCA 1 or BRCA2, PTEN, TP53, CDH1, STK11) and adding note The option of riskreduction mastectomy is warranted based on gene and/or risk level (i.e., BRCA1, BRCA2, CDH1, PTEN and TP53). There is insufficient evidence for intervention for the ATM, BARD1, CHEK2, PALB2 and STK11 genetic mutation, however, intervention may be warranted based on family history or other clinical factors as per recommendations from NCCN on Breast cancer risk reduction (2.2015). Code updates. Per NCCN (V2.2016) on Genetic Familial High Risk Assessment: Breast or Ovarian: genetic mutation, added PALB2 as an option for risk reduction mastectomy, based on gene &/risk level. Codes updated. This policy is based on the following evidence-based guidelines: 1. National Cancer Institute. Breast Cancer. Available at: 2. National Guideline Clearinghouse. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005 Sep 6;143(5): National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Breast Cancer Risk Reduction. V Updated v Updated V Updated V Updated V Updated V.I Updated version V Updated Version Update Updated Version The American Society of Breast Surgeons. BRCA Genetic Testing for Patients With and Without Breast Cancer. Available at: 5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. No April Reaffirmed Hereditary Breast and Ovarian Cancer Syndrome. Prophylactic Mastectomy May 16 19

20 6. Society of Surgical Oncology (SSO) Position Statement on Prophylactic Mastectomy. March Updated Available at: 7. National Cancer Institute. Preventive Mastectomy. July Available at: 8. Hayes. Medical Technology Directory. Risk-Reducing (Prophylactic) Mastectomy. December 9, Update Dec Updated November 16, National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Genetic/Familial High Risk Assessment: Breast and Ovarian. Version Update Updated Version National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Breast Cancer. Version Updated Version Hayes. GTE Report. CHEK2-Related Susceptibility to Breast Cancer. April 26, Updated April 3, References Update May Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. The New England journal of medicine Jun 4;372(23): PMID: Kriege M, Hollestelle A, Jager A, et al. Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy. Br J Cancer Aug 26;111(5): doi: /bjc Epub 2014 Jun Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol Jul 1;32(19): doi: /JCO Epub 2014 Apr Kuusisto KM1, Bebel A, Vihinen M, et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res Feb 28;13(1):R20. doi: /bcr Pfeifer W, Sokolenko AP, Potapova ON, et al. Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers. Breast Cancer Res Treat Dec;148(3): doi: /s Epub 2014 Nov Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295 (12): Wang N, Ding H, Liu C, et al. A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk. Oncogene Jan 26. doi: /onc [Epub ahead of print]. References Update October Ashfaq A, McGhan LJ, Pockaj BA, et al. Impact of breast reconstruction on the decision to undergo contralateral prophylactic mastectomy. Ann Surg Oncol Sep;21(9): Basu NN, Ingham S, Hodson J, et al. Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis. Fam Cancer Aug Chai X, Friebel TM, Singer CF, et al. Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat Nov;148(2): Prophylactic Mastectomy May 16 20