Breast Cancer Risk Reduction Decisions of the BRCA -Positive Patient: An Observational Study at a Single Institution

Abstract

Background:

BRCA1 and BRCA2 gene mutations carry with them a 50%–80% risk of developing breast cancer. The best choice for managing breast cancer risk in patients with a BRCA1/2 mutation is a highly personal decision. Options for risk management include surveillance with multiple modalities or prophylactic surgical intervention. The goal of this study was to gain a better understanding of contributing factors affecting the decision for managing breast cancer risk made by patients who are BRCA mutation positive and cancer free.

Methods:

A retrospective chart review of patients, who tested positive for BRCA1/2 gene mutation between 2003 and 2013 without history of breast cancer, was performed. A logistic regression model was used to assess the association between preselected risk factors and the decision of the patient to undergo prophylactic mastectomy versus surveillance.

Results:

Of the 106 patients who were cancer free and BRCA positive, seventy (66%) opted for surveillance, whereas 36 (34%) chose prophylactic mastectomy. Three preselected risk factors were found to significantly affect a patient's likelihood of choosing surgery: having a family member with breast cancer before the age of 50 (OR: 4.67 [95% CI: 1.86–11.68]), p = 0.001), cancer-related death of a relative younger than 50 years old (OR: 2.26 [95% CI: 0.92–5.55], p = 0.07), and prophylactic oophorectomy before planned mastectomy (OR: 3.72 [95% CI: 1.49–9.31], p = 0.005). Patient age less than 30 was found to be significantly associated with the decision to proceed with surveillance (OR: 0.2 [95% CI: 0.05–0.75], p = 0.02).

Conclusion:

Risk-reducing strategy is a very personal decision for the patient with positive BRCA mutation, and many factors go into choosing which options are best for each individual. We found that age of patient, relative with breast cancer or death of a relative before age 50, and prophylactic oophorectomy all play significant roles in which risk reduction strategy is chosen.

Background

B RCA 1 and BRCA 2 are human tumor suppressor genes that when mutated have been linked to hereditary breast cancer and ovarian cancer. Patients who test positive for BRCA1 or BRCA2 mutation have a 50%–80% risk of developing breast cancer by the age of 85.¹ Recommendations for management of BRCA1/2 carriers, according to the 2016 National Comprehensive Cancer Network (NCCN) guidelines, include careful screening with annual mammograms and breast magnetic resonance imaging (MRI) for breast cancer surveillance or consideration of risk-reducing mastectomy. Ovarian cancer surveillance is less defined, and salpingo-oophorectomy is the optimal approach for ovarian cancer risk reduction and is recommended by age 35–40. When performed before menopause, this surgery has the added benefit of reducing breast cancer risk.²

The best choice for managing breast cancer risk in patients with a BRCA1/2 mutation is a multifaceted and a highly personal decision. Multiple studies have shown a reduction in breast cancer risk of up to 90% for patients who are BRCA positive and who undergo prophylactic mastectomy.^3
–5 However, there are currently no prospective data demonstrating a reduction of overall mortality in this patient group.^6,7 Patients testing positive for a BRCA1/2 mutation may opt for nonsurgical risk reduction approaches. Screening exams can be alternated, so there is imaging of the breasts every 6 months. The addition of breast MRI has greatly improved breast cancer detection.⁶

Alternatively, if a patient positive for BRCA mutation finds surveillance unacceptable and desires surgical intervention, several options exist, including simple mastectomy and total skin-sparing mastectomy (TSSM). Although reducing the risk of potential cancer is the primary goal of prophylactic breast surgery, TSSM, which saves the nipple-areola complex (NAC), takes into account the importance of long-term cosmetic outcome. Breast cancer involving the NAC ranges from 5.6% to 31%, and the rate of future cancer occurrence in the retained NAC after risk-reducing mastectomy is less than 1%, according to large pathological studies.⁸ Thus, in certain cases, nipple-sparing mastectomy may provide an aesthetic benefit that could offset the oncologic risk of retaining the NAC.

In this study, we aim at identifying risk-reducing strategies of the patient population that is BRCA positive and cancer free at a single institution and at identifying specific factors associated with these strategies. In addition, we sought to evaluate the subset of patients who underwent prophylactic mastectomy and to determine what factors, if any, were associated with the type of surgery they underwent.

Materials and Methods

Study population

The study population included women seen at the Huntsman Cancer Institute Family Cancer Assessment Clinic at the University of Utah, who underwent BRCA1/2 testing between 2003 and 2013 and were found to have a deleterious mutation. Eligible study participants were identified after obtaining IRB approval. The current analysis focuses on those women who tested positive for a deleterious mutation and had no history of breast cancer.

Data collection

A retrospective chart review was performed by using the electronic medical records of patients from the University of Utah and Huntsman Cancer Hospital. Demographic and clinical information was collected on all patients with no history of breast cancer and who were BRCA positive. The length of follow-up for each patient was defined to be the difference between the date of their genetic testing and the last date of contact with the clinic.

Statistical methods

A logistic regression model was used to assess the association between preselected risk factors and patients undergoing prophylactic mastectomy versus surveillance. Preselected risk factors included patient age, marital status, children, personal history of cancer, family history of cancer, history of family member with breast cancer before the age of 50, death of relative younger than 50 from cancer, obesity (defined as body mass index [BMI] ≥30), and oophorectomy (prior or at the time of planned mastectomy). Family history of cancer was defined as the presence of a first- or second-degree relative with a history of any type of cancer. The Fisher exact test was performed to assess the association between the type of surgery a patient underwent (total skin-sparing versus simple mastectomy) and the preselected risk factors.

Results

Between 2003 and 2013, 106 patients without a current history of breast cancer were found to have pathogenic BRCA1 or BRCA2 mutation. Of those, 89 (84%) patients carried a mutation in BRCA1, 16 (15%) carried a mutation in BRCA2, and 1 carried a mutation in BRCA1 and BRCA2. Ninety (84%) patients were tested for a previously identified familial mutation, and 16 (15%) had their mutations identified through a full analysis of BRCA1 and BRCA2. All genetic testing and mutation classification was performed at Myriad Genetic Laboratories, Salt Lake City, UT. Only patients with mutations classified as pathogenic or likely pathogenic were included in this analysis. No patients were included on the basis of a mutation initially classified as an uncertain variant, but later upgraded to pathogenic.

The 106 patients ranged in age from 18 to 64, with a mean age of 40 years old. Eighty-five (80%) of these patients were married. Eighty-four (79%) patients had children. Although none of these patients had a history of breast cancer, 20 of the 106 (19%) patients did have a history of another type of cancer, 15 of whom had ovarian cancer.

Seventy of the 106 (66%) patients underwent surveillance, and 36 (34%) underwent prophylactic mastectomy (Table 1). Median follow-up for all patients was 31.1 months. Median follow-up for the surgical group was 44 months, ranging from 5.1 to 126.8 months censored at last contact with the clinic. For the nonsurgical group, median length of follow-up was 13.9 months, ranging from 0 to 167.6 months. The discrepancy in median length of follow-up between nonsurgical and surgical groups and the wide time range in both groups was, in part, due to the large catchment area of the Huntsman Cancer Institute. Many patients in the nonsurgical group opted to undergo surveillance via health services closer to home. Likewise, after their initial postoperative follow-up, some patients in the surgical group continued routine care locally.

Table 1.

Univariate Logistic Regression Relating Odds of Choosing Surgery to Preselected Risk Factors

	Surgery	No surgery	OR (95% CI)	p
Age
<30	3 (8.3)	20 (28.6)	0.2 (0.05–0.75)	0.02
30–50	26 (72.2)	35 (50.0)
>50	7 (19.4)	15 (21.4)	0.63 (0.22–1.76)	0.38
Marital status^a
Not married	4 (11.1)	16 (23.2)
Married	32 (88.9)	53 (76.8)	2.42 (0.74–7.86)	0.14
Have children
No	5 (13.9)	17 (24.3)
Yes	31 (86.1)	53 (75.7)	1.99 (0.67–5.92)	0.22
Cancer history
No	30 (83.3)	56 (80.0)
Yes	6 (16.7)	14 (20.0)	0.8 (0.28–2.3)	0.68
Have relative with BC before age 50
No	8 (22.2)	40 (57.1)
Yes	28 (77.8)	30 (42.9)	4.67 (1.86–11.68)	0.001
Family cancer history
No	13 (36.1)	21 (30.0)
Yes	23 (63.9)	49 (70.0)	0.76 (0.32–1.78)	0.52
Relatives' death age <50
No	23 (63.9)	56 (80.0)
Yes	13 (36.1)	14 (20.0)	2.26 (0.92–5.55)	0.07
Oophorectomy
None	14 (38.9)	46 (65.7)
Prophylactic OOPH	17 (47.2)	15 (21.4)	3.72 (1.49–9.31)	0.005
Cancer directed OOPH	5 (13.9)	9 (12.9)	1.83 (0.52–6.35)	0.34

One patient had unknown marital status.

For those patients undergoing surgery, the average time from testing to surgery was 14 months (1–68.5 months). The average age of the surgical group (at surgery) and surveillance group (at testing) was 40 (26–66) and 39 (18–74) years old, respectively. Patients having a family member with breast cancer before the age of 50 were more likely to undergo prophylactic mastectomy versus surveillance (OR: 4.67 [95% CI: 1.86–11.68], p = 0.001). In addition, prophylactic oophorectomy (prior or at the time of planned mastectomy) was associated with undergoing prophylactic mastectomy (OR: 3.72 [95% CI: 1.49–9.31], p = 0.005). Patient age less than 30 was found to be associated with surveillance (OR: 0.2 [95% CI: 0.05–0.75], p = 0.02).

Of those patients undergoing surveillance, no patients were diagnosed with breast cancer on their initial breast imaging after receiving the genetic diagnosis, and one patient was diagnosed on subsequent screening. The one patient diagnosed with breast cancer underwent mastectomy and prophylactic removal of the contralateral breast. Three patients, who had been diagnosed with ovarian cancer before their BRCA testing, died during the follow-up period.

A subgroup analysis of the 36 patients who underwent prophylactic surgery was performed. Twelve patients (35%) underwent simple mastectomy, and 24 (75%) underwent TSSM. Patients who underwent simple mastectomy had a mean age of 43 (30–52 years) years at time of surgery, and those who underwent TSSM had a mean age of 39 (26–66 years) years at the time of surgery. The majority of patients who underwent either simple mastectomy or TSSM were married, 10 out of 12 (83%) and 22 out of 24 (92%), respectively. Sixty-two percent of patients who already had children at the time of surgery underwent TSSM, whereas 80% of those without children underwent TSSM procedures. Of note, all 36 patients who underwent prophylactic mastectomy elected to have breast reconstruction (100%).

During the course of follow-up, no breast cancers were diagnosed among those patients who underwent prophylactic surgery; however, three patients died from ovarian cancer.

Table 2 shows no association between the preselected factors and surgery type, although there was a trend toward simple mastectomy in the obese patient population (p = 0.30). Twenty-two of the 30 nonobese patients underwent TSSM (73%), whereas two of the five obese patients underwent TSSM (40%). One patient had an unknown BMI. All patients younger than 30 years of age underwent TSSM, whereas 65% of patients aged 30–50 and 57% of patients older than 50 underwent TSSM.

Table 2.

Fisher Exact Chi-Square Test Assessing Association Between Surgery Type Chosen and Preselected Factors

		Surgery type
Predictors	Level	Simple mastectomy	Total skin-sparing mastectomy	p
Average age of relative having BC	≥50	3 (25)	5 (20.8)	0.99
	<50	9 (75)	19 (79.2)
Average age of relative death	≥50	8 (66.7)	15 (62.5)	0.99
	<50	4 (33.3)	9 (37.5)
Age of patient	<30		3 (12.5)	0.53
	30–50	9 (75)	17 (70.8)
	≥50	3 (25)	4 (16.7)
Married	No	2 (16.7)	2 (8.3)	0.59
	Yes	10 (83.3)	22 (91.7)
History of any cancer	No	9 (75)	21 (87.5)	0.38
	Yes	3 (25)	3 (12.5)
Having children	No	1 (8.3)	4 (16.7)	0.65
	Yes	11 (91.7)	20 (83.3)
Oophorectomy	None	5 (41.7)	9 (37.5)	0.99
	Prophylactic OOPH	5 (41.7)	12 (50)
	Cancer directed OOPH	2 (16.7)	3 (12.5)
Obesity^a	No	8 (72.7)	22 (91.7)	0.30
	Yes	3 (25)	2 (8.3)

One patient had an unknown body mass index.

Discussion

Women diagnosed with a deleterious mutation in the BRCA1 or BRCA2 gene have a lifetime breast cancer risk of 50%–80% and up to a 40% ovarian cancer risk by the age of 85. This is up to six times greater than the average woman's lifetime risk for breast cancer and 28 times greater for ovarian cancer.^9
–11 In response to this significant increase in risk, the NCCN has created specific guidelines for recommended surveillance and/or prophylactic treatment. Current recommendations for breast cancer surveillance include exam by a physician every 6 months, an annual mammogram, and a breast MRI beginning at age 30. In addition, patients who are BRCA positive should consider risk reduction strategies, which include the use of tamoxifen, bilateral total mastectomy ± reconstruction, and bilateral salpingo-oophorectomy.^2,11

With such a high lifetime breast cancer rate, risk reduction strategies play an important role in the life of a patient with BRCA mutation. Various studies have shown risk reduction for breast and ovarian cancer of up to 90% and 80%, respectively, after prophylactic mastectomy or salpingo-oophorectomy.^3
–5,11 In 2001, Schrag et al.⁷ performed a prospective study evaluating the efficacy of surgery versus surveillance in 3-year risk reduction of patients who are BRCA positive. Of the 76 women who underwent simple mastectomy, zero were diagnosed with breast cancer at the 3 year follow-up, whereas 8 of the 63 women who underwent surveillance developed breast cancer in the 3 year period.

Previous studies have also investigated how the diagnosis of a BRCA gene mutation affects decision making in patients who have been diagnosed with breast cancer. These studies showed that patients who are BRCA positive with breast cancer undergo more aggressive treatment regimens than their non-BRCA-positive counterparts. These regimens often include contralateral risk-reducing mastectomy and prophylactic oophorectomy,^5,6 Recently, Lokich et al.¹² conducted a retrospective review of 302 women who underwent genetic testing after their diagnosis of breast cancer. Of the 32 patients who tested positive for BRCA mutation, 72% changed their initial surgical plan from breast conservation therapy to mastectomy, whereas only 29% of 270 patients who were BRCA negative made the switch. However, very little literature regarding patients with BRCA mutation and no history of breast or ovarian cancer has been published.

Our study focused on the patient with BRCA mutation who had no previous or current diagnosis of breast cancer. We analyzed risk-reducing strategies that patients underwent after finding out they carried a deleterious mutation in either the BRCA1 or BRCA2 gene. Specifically, we aimed at determining what factors were associated with patients undergoing prophylactic mastectomy versus breast cancer surveillance.

Previous studies have identified multiple factors that are associated with the decision to undergo risk-reducing surgery in a patient who is BRCA positive. Some of these factors include age, history of breast biopsy, and family history of breast or ovarian cancer.^9,13 The preselected factors used in our analysis were chosen based on correlations identified in previous studies.

Our results showed that three factors, age of patient, having a relative with a breast cancer diagnosis before the age of 50, and personal history of prior or concurrent prophylactic oophorectomy, were associated with risk-reducing strategies of the patient who is cancer free and BRCA positive. The latter three factors were associated with patients undergoing prophylactic mastectomy, whereas young age was associated with patients undergoing surveillance.

We found that patients who were less than 30 years old were more likely to undergo surveillance instead of surgery when compared with those patients aged 30–50 and greater than 50 years old. It is understandable in this young patient group that there may be a greater desire to keep their breasts, whether for the purpose of breastfeeding children or body appearance, and, therefore, undergoing surveillance could be higher than in older patients. In addition, providers may not recommend risk reduction surgery to this young population, as the addition of MRI screening has improved the detection of early breast cancer and improved the overall risk reduction of surveillance.²

The diagnosis of a family member with breast cancer before the age of 50 was associated with patients undergoing prophylactic mastectomy. In addition, death of a family member from breast cancer before the age of 50 trended toward being associated with patients undergoing prophylactic mastectomy. These findings suggest that personal family history plays an important role in the perception of self-risk within this patient population. Previous studies have also shown that a patient with BRCA mutation is more likely to undergo prophylactic surgical intervention if they have a family history of ovarian cancer or a personal history of breast or ovarian cancer.⁵

Patients who undergo prophylactic oophorectomy also underwent prophylactic mastectomy in our cohort. Within this patient group, the decision to undergo one surgical risk-reducing strategy may make a patient more likely to opt for complete prophylactic surgical risk reduction.

In addition to our primary aim of identifying factors associated with risk-reducing choices of the patient who is BRCA positive and cancer free, we also analyzed the subset of patients who underwent prophylactic mastectomy. We sought to identify what type of prophylactic mastectomy these patients undergo, total skin-sparing versus simple, and what factors are associated with the mastectomy type.

It is often assumed that patients who are positive for BRCA mutation, who choose to undergo prophylactic mastectomy, are opting for the more aggressive risk reduction strategy and in doing so would choose the type of mastectomy that removes the most tissue susceptible to developing breast cancer. Therefore, simple mastectomy would be chosen over TSSM. However, it is possible that the long-term cosmetic outcome is also an important consideration for this patient population.

Our results showed that none of the preselected factors were associated with simple versus TSSM in the patients who underwent risk-reducing surgery. The small number of patients within this subset of our study may account for the lack of significance, as many of the factors trend toward an association with a specific surgery type.

Conclusion

Risk reduction strategies are very personal decisions for the patient who is BRCA positive, and many factors are taken into consideration when patients are choosing which options are best for them. We found that age of patient, having a relative with a breast cancer diagnosis before the age of 50, and personal history of prior or concurrent prophylactic oophorectomy all play significant roles in which risk reduction strategy patients undergo.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Spear

, Carter

, Schwarz

. Prophylactic mastectomy: Indications, options, and reconstructive alternatives. Plast Reconstr Surg, 2005; 115:891–909.

Genetic/Familial High-risk Assessment: Breast and ovarian, NCCN practice guidelines, 2016. Available at: www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf Accessed September 11, 2016 .

Hartmann

, Sellers

, Schaid

, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst, 2001; 93:1633–1637.

Meijers-Heijboer

, van Geel

, van Putten

, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med, 2001; 345:159–164.

Domchek

, Friebel

, Singer

, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 2010; 6:967–975.

Stadler

, Kauff

. Weighing options for cancer risk reduction in carriers of BRCA1 and BRCA2 mutations. J Clin Oncol, 2010; 28:222–231.

Schrag

, Kuntz

, Garber

, et al. Decision analysis-effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med, 1997; 336:1465–1471.

Rusby

, Smith

, Gui

. Nipple-sparing mastectomy. BR J Surg, 2010; 97:305–316.

Uyei

, Peterson

, Erlichman

, et al. Association between clinical characteristics and risk-reduction interventions in women who underwent BRCA1 and BRCA2 testing. Cancer, 2006; 107:2745–2751.

10.

Nelson

, Huffman

, Fu

, Harris

. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: Systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med, 2005; 143:362–379.

11.

Cragun

, Pal

. Identification, evaluation, and treatment of patients with hereditary cancer risk within the United States. ISRN Oncol, 2013; 2013:260847.

12.

Lokich

, et al. Preoperative genetic testing affects surgical decision making in breast cancer patients. Gynecol Oncol, 2014; 134:326–330.

13.

Lodder

, et al. One year follow-up of women opting for presymptomatic testing for BRCA1 and BRCA2: Emotional impact of the test outcome and decisions on risk management (surveillance or prophylactic surgery). Breast Cancer Res Treat, 2002; 73:97–112.