Since BRCA1/2 mutations were identified in the early 1990s, the concept of prophylactic breast and ovarian surgery in cases of deleterious mutation has been accepted to help prevent breast and ovarian cancer.1–7 It is known that women with BRCA1 or BRCA2 mutations have a risk of breast cancer approximately five times (70 to 80 percent) baseline, and the risk of ovarian cancer is increased 10- to 30-fold.6,8,9 The impact of genetic mutations on medical decision making may be profound; Lokich et al. demonstrated that over 70 percent of patients found to harbor BRCA mutations choose surgery different from that initially planned.6,8–12 Failure to diagnose pathogenic mutations puts individuals at risk for future breast and ovarian cancers, and also has implications for family members.9,13,14
Whereas testing was originally offered for BRCA1/2 only, now extended panels are performed that include additional genes such as ATM1, CHEK2, and BRIP1 among others.15,16 A mutation can be classified as either (1) normovariant or benign, (2) pathogenic or deleterious, or (3) a variant of uncertain significance.17 A variant of uncertain significance may later be reclassified as benign or pathogenic, and patients may be notified of such a change.8,9,13,18 Using expanded panel testing, a recent study at our institution showed that 10.7 percent of patients with stage I to III breast cancer were found to harbor pathogenic mutations.1
Stratification of breast cancer patients into low-risk and high-risk groups for genetic mutations according to clinical and family histories is now the standard of care.2,19,20 Guidelines for patient screening are published by the National Comprehensive Cancer Network, and others.7,21–24 Unfortunately, not all potential carriers are identified by existing criteria for BRCA testing.8,18,25 In fact, 80 percent of the mutation carriers younger than 50 years do not have usual characteristics associated with BRCA mutation carriers (i.e., personal/family history of breast and/or ovarian cancer or Ashkenazi Jewish ancestry).15,23,24,26,27 Because guidelines for testing are imperfect, some women with breast cancer and pathogenic mutations will fail to be identified before diagnosis and treatment.11,19,24 In addition, some patients who do meet criteria for genetic testing decline testing or fail to pursue it.2,28 Insurance companies may also refuse coverage for genetic testing for breast cancer.29 Therefore, not all patients who qualify for genetic testing undergo it, and those who do not meet testing criteria may harbor a pathogenic mutation.7,27,30
From a reconstructive standpoint, an unidentified pathogenic mutation at the time of unilateral mastectomy is especially problematic for patients opting for abdominally based free flap breast reconstruction, as this donor site can be used only once. If a deleterious mutation is discovered later and contralateral prophylactic mastectomy is recommended, the patient must undergo additional procedures and the abdomen is no longer an option as a donor site. Alternatives, such as implant-based reconstruction or nonabdominal donor sites, may be available but problematic for various reasons.31–35 The purpose of this study was to determine (1) the frequency of genetic testing before unilateral abdominally based free flap breast reconstruction, (2) the frequency of mutations detected in patients undergoing unilateral abdominally based free flap breast reconstruction, and (3) the cost-effectiveness of expanding genetic testing in this patient population.
PATIENTS AND METHODS
After obtaining approval from the Institutional Review Board of Brigham and Women’s Hospital/Dana-Farber Cancer Institute, we performed a retrospective review to identify all breast cancer patients who underwent unilateral abdominally based free flap breast reconstruction at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between September of 2007 and April of 2016. Patients who underwent either deep inferior epigastric perforator (DIEP), muscle-sparing free transverse rectus abdominis musculocutaneous, free transverse rectus abdominis musculocutaneous, or superficial inferior epigastric artery perforator flap surgery were included. Those who underwent free flap breast reconstruction from a nonabdominal donor site were excluded. Also excluded were patients who underwent unilateral reconstruction for prophylactic indications, such as a pathogenic mutation in a patient who had already had a contralateral mastectomy.
Clinical data were obtained from the electronic medical record, and an assessment was made on whether each patient met 2016 National Comprehensive Cancer Network guideline criteria for genetic testing. An independent Dana-Farber Cancer Institute database of genetic test results was queried for completeness. Length of follow-up was calculated by looking at the time between free flap breast reconstruction and the last clinical encounter documented. To ensure accuracy, all extracted data was checked by a second reviewer. Descriptive statistics were then calculated. Financial information was obtained from the Brigham and Women’s Hospital Billing Department and from the Dana-Farber Cancer Institute Center for Cancer Genetics and Prevention.
Between 2007 and 2016, 713 patients underwent free flap breast reconstruction, and of these, 160 met inclusion criteria. Table 1 lists the clinical characteristics of our patient cohort. The timing of reconstruction was immediate in 113 patients (70.6 percent), delayed-immediate in 19 patients (11.9 percent), and delayed in 25 patients (15.6 percent), with average follow-up time of 69 months (range, 23 to 119 months).
Testing Criteria and Status
We examined whether patients met 2016 National Comprehensive Cancer Network guidelines for genetic testing at the time of free flap breast reconstruction and whether testing occurred before free flap breast reconstruction. We found that 62 of 111 patients (55.9 percent) who met 2016 National Comprehensive Cancer Network guidelines at the time of free flap breast reconstruction were tested, whereas 49 of 111 patients (44.1 percent) who met criteria were not tested. Of the 49 patients who did not meet National Comprehensive Cancer Network guidelines for testing before free flap breast reconstruction, 44 of 49 (89.8 percent) were not tested before free flap breast reconstruction and five of 49 (10.2 percent) were tested. Figure 1 depicts this distribution of patients.
Genetic Mutations Identified in Patient Cohort
We identified eight genetic mutations in six patients, and these are summarized in Table 2. The three deleterious mutations detected after free flap breast reconstruction (two BRCA2 and one ATM1) resulted in contralateral mastectomy and reconstruction. Another three patients were found to have five variants of uncertain significance and one deleterious mutation, and in these cases, mastectomy was not pursued and they received close surveillance. The clinical course of the six patients is described in cases 1 through 6.
The patient in case 1 was diagnosed with a second breast primary tumor at age 53 after undergoing breast-conserving therapy at age 46. She had a significant smoking history and a family history of breast, ovarian, and pancreatic cancer. She was referred for genetic testing; however, her insurance company denied coverage and the patient could not afford the costs out-of-pocket. She underwent a unilateral mastectomy and immediate DIEP flap reconstruction, followed by revision, nipple reconstruction, and a contralateral augmentation. Her daughter was found to have a deleterious BRCA2 mutation, and this led to the discovery of the same BRCA2 mutation in the patient. She opted for close surveillance but was found to have contralateral ductal carcinoma in situ 1 year later. She underwent contralateral mastectomy and tissue expander placement but postoperatively developed mastectomy flap necrosis requiring excision, and cellulitis, and ultimately her tissue expander was removed. She has been unable to proceed with additional reconstruction because of financial constraints and limited sick time.
The patient in case 2 was diagnosed with microinvasive ductal carcinoma in situ at age 60. She had no family history of cancer and did not meet National Comprehensive Cancer Network criteria for genetic testing. She underwent unilateral mastectomy and immediate DIEP flap reconstruction, followed by revision and nipple reconstruction. Her daughter was found to have a BRCA2 mutation, which led to the identification of a deleterious BRCA2 mutation in the patient. Three years after her initial DIEP flap, she underwent a right mastectomy and tissue expander placement. A few months later, her expander was exchanged and her DIEP flap revised for symmetry.
The patient in case 3 was diagnosed with ductal carcinoma in situ at age 44. She had a strong family history of breast cancer and BRCA1/2 testing was negative. She underwent unilateral mastectomy and immediate DIEP flap reconstruction, followed by multiple revisions for symmetry. Three years later, more extensive genetic testing identified a pathogenic mutation in her ATM gene. Based on her strong family history, she opted for a contralateral prophylactic mastectomy. She underwent mastectomy and immediate stacked profunda artery perforator flaps. Her postoperative course was complicated by venous congestion requiring two operative reexplorations with salvage of both flaps.
The patient in case 4 was diagnosed with multifocal breast cancer at age 35. She had a strong family history of breast cancer and underwent genetic testing for BRCA1/2 before free flap breast reconstruction. She was found to have a variant of uncertain significance in BRCA2 and contralateral prophylactic mastectomy was not recommended. The patient proceeded to unilateral mastectomy and reconstruction.
The patient in case 5 was diagnosed with breast cancer at age 47. Because of a family history of breast and pancreatic cancer, she was referred for genetic testing, which revealed a deleterious mutation in ATM and a variant of uncertain significance in ATM and CHEK2. The patient opted for close surveillance rather than contralateral prophylactic mastectomy and underwent unilateral mastectomy and reconstruction.
The patient in case 6 was diagnosed with breast cancer at age 31, and her family history was notable for breast cancer. Genetic testing performed before free flap breast reconstruction revealed a variant of uncertain significance in BRCA2 and STK11, and the patient proceeded to unilateral mastectomy and reconstruction.
In summary, of the three patients who were diagnosed with deleterious genetic mutations after free flap breast reconstruction who proceeded to contralateral mastectomy and reconstruction, one met National Comprehensive Cancer Network guidelines and was not tested, one did not meet National Comprehensive Cancer Network guidelines and was not tested, and one was tested for BRCA1/2 only with a later extended panel revealing a mutation. Of note, all three patients had adequate infraumbilical adiposity for bilateral free flap breast reconstruction.
Frequency of Genetic Testing by Year
We examined the rates at which patients who met National Comprehensive Cancer Network criteria were tested by calendar year in which reconstructive surgery was performed. These results are presented in Table 3. On average, 55 percent of patients met National Comprehensive Cancer Network guidelines for testing before free flap breast reconstruction. There was a trend toward an increased percentage of patients who met National Comprehensive Cancer Network guidelines undergoing testing before abdominally based free flap breast reconstruction in earlier years, with 39.5 percent undergoing testing between 2007 and 2011, and 65.6 percent undergoing testing between 2012 and 2016.
Additional Costs Arising from the Delayed Detection of Deleterious Mutations
The billing records for the three patients with pathogenic mutations discovered after free flap breast reconstruction were reviewed to identify additional costs generated by the delayed identification of genetic mutations; these results are presented in Table 3. These dollar figures reflect actual payments to the hospital and not charges.
Costs Related to Expanding Genetic Testing before Abdominally Based Free Flap Breast Reconstruction
To estimate the increased costs from more extensive genetic testing before unilateral abdominally based free flap breast reconstruction, we identified a price point for individual genetic testing. In the current marketplace, there is a minimal cost differential between testing for BRCA1/2 alone and multigene panel testing. Thus, we used the cost of extended panel testing, which is $1000 for insured patients at our institution [using Invitae (San Francisco, Calif.), which charges contracted insurance companies $1000]. Uninsured patients can obtain a direct-to-consumer saliva-based test (Color Genomics Hereditary Cancer Test) for $250, which detects mutations in 12 genes known to predispose to breast cancer.36 For our cost analysis, we used the higher price for genetic testing of $1000 to model the maximal cost that would be encountered. Of the cohort of 160, 67 patients were tested and 93 patients were not tested before free flap breast reconstruction. Therefore, expanding testing to all patients before free flap breast reconstruction would have resulted in an increased cost of 93 patients times $1000/patient = $93,000.
Estimated Net Costs of Expanding Genetic Testing before Unilateral Abdominally Based Free Flap Breast Reconstruction
If all patients were offered genetic testing and those with deleterious mutations underwent bilateral mastectomy with abdominally based free flap breast reconstruction, the additional costs would be $93,000 (for genetic testing) and potentially $355,760 would be saved (see additional costs outlined in Table 4). This would result in a net savings of $262,760 ($355,760 minus $93,000).
The present study identified 1.9 percent of patients (three of 160) who were diagnosed with deleterious genetic mutations after unilateral abdominally based free flap breast reconstruction who proceeded to have contralateral mastectomy and reconstruction during a relatively short follow-up period. Post–free flap breast reconstruction genetic testing was prompted by discovery of deleterious mutations in an offspring in some cases, resulting in additional operations after completed multistage reconstructions and psychosocial and financial burdens for patients and costliness for the health care system. Based on a recent study at our institution where genetic testing was performed for all stage I to III patients, we expect the rate of pathogenic mutations to be close to 10.7 percent.1 Therefore, although the post–free flap breast reconstruction discovery of pathogenic mutation is a low-frequency event, its rate will likely rise with time and has a large impact because of the high cost of additional surgery.
Our results showed that only 55.9 percent of patients of patients who met 2016 National Comprehensive Cancer Network guidelines for genetic testing had documented results of testing. Potential explanations for this seemingly low incidence of testing include that results from outside institutions may have been omitted from the medical record, that patients declined testing, or that insurance companies could have denied coverage. Also possible is that oversight by clinicians occurred, such as failing to calculate initial age at diagnosis for a patient with a history of breast cancer and a new primary tumor, or the age of initial diagnosis for a patient who presents for delayed reconstruction, or failing to recognize two primary tumors as qualifying for testing.14,23
Because the National Comprehensive Cancer Network guidelines are complicated and difficult to remember, offering testing to all candidates for unilateral abdominally based free flap breast reconstruction is simpler and, our data show, also cost-effective. There are multiple potential and expected risks and benefits to expanding genetic testing before abdominally based free flap breast reconstruction, and these are summarized in Table 5. If insurance companies deny coverage for genetic testing, our results could be used to support coverage of these tests. In addition, patients who qualify for genetic testing but who decline it should be counseled that they run a small risk of needing a contralateral prophylactic mastectomy and reconstruction after completing free flap breast reconstruction, with associated financial and other burdens.16,24,37
Prior studies have looked at the cost-effectiveness of expanding genetic testing for breast cancer. One group demonstrated that for every 10,000 women screened for BRCA mutations, approximately four cases of breast cancer and two cases of ovarian cancer could be averted over what family history-based testing would elucidate.30,38–40 Long and Ganz suggested that with a cost of $4000 per test, the cost of BRCA testing would need to drop by 90 percent to make universal testing cost-effective for the general population.41 Kwon et al. project the highest life expectancy when testing all women with breast cancer younger than 50 years.10,11 However, the authors suggest that the cost associated with this approach may be prohibitive, with an incremental cost-effectiveness ratio of $59,503 and $112,908 per year of life and quality-adjusted life-year gained, respectively.10,11 This group supports adopting the next most practical strategy, which is to test women younger than 50 with triple-negative breast cancers, which had a favorable cost-effectiveness—below the acceptable threshold of $50,000 per year of life gained.10,11 However, several factors make our cohort and cost-to-benefit ratio different from these prior studies. First, the cost of genetic testing has declined since these articles were written, as private companies now offer a panel of tests for as little as $250.30,40,41 Second, none of these studies focused on a subset of patients undergoing a complex and expensive type of reconstruction such as abdominally based free flap breast reconstruction, which can balance out the now vastly reduced cost of extended panel genetic testing.10,11,30,38–41
Further commentary is warranted on the finding that two patients with deleterious ATM mutations differed with regard to contralateral surgery. One mutation was detected after free flap breast reconstruction and the patient had contralateral prophylactic mastectomy and reconstruction. The other patient’s mutation was found before free flap breast reconstruction, and contralateral prophylactic mastectomy was not performed. ATM is an example of a recently discovered gene whose breast cancer risk is not clearly established, and so decisions about contralateral prophylactic mastectomy are individualized based on family history and other factors.42 According to the 2016 National Comprehensive Cancer Network guidelines, there is sufficient evidence to support more frequent screening with ATM but insufficient evidence to support contralateral prophylactic mastectomy. However, contralateral prophylactic mastectomy should be considered in the context of the patient’s family history. Recommendations will continue to evolve over time as more long-term data are accrued.
Weaknesses and Limitations
There are several weaknesses of the present study. First, it is possible that we underestimated the percentage of patients who underwent testing before abdominally based free flap breast reconstruction because patients failed to report or were not aware of genetic testing performed at outside institutions. Second, its retrospective nature means we did not capture patients who presented for unilateral reconstruction, but who were found to have pathogenic mutations and subsequently underwent bilateral abdominally based free flap breast reconstruction (Fig. 2). A prospective study would be needed to determine the rate at which conversion from unilateral to bilateral reconstruction occurs based on genetic testing. Third, not every patient had genetic testing, so the true incidence of pathogenic mutations in this patient population is unknown. Only prospective testing of consecutive patients would determine the actual incidence of mutations. Fourth, this study did not address whether it is clinically appropriate and cost-effective to offer extended panel testing preoperatively to patients who have already undergone testing for BRCA1/2.
Traditionally, the need for referral for genetic testing for breast cancer patients has been determined by oncologic features and family history, and not by reconstructive procedure planned. However, this study supports the notion that genetic testing should be offered to all patients for whom a unilateral abdominally based free flap breast reconstruction is planned. Plastic surgeons should take an active role in discussing with patients and their care providers the implications of genetic testing in these cases. As greater numbers of deleterious genetic mutations are discovered, more patients may be affected by positive results. Close communication with genetic counselors is crucial as the complexity in this area continues to grow.
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