Use of bilateral prophylactic nipple-sparing mastectomy in patients with high risk of breast cancer

Abstract

Background

Nipple-sparing mastectomy (NSM) is being performed increasingly for risk reduction in high-risk groups. There are limited data regarding complications and oncological outcomes in women undergoing bilateral prophylactic NSM. This study reviewed institutional experience with prophylactic NSM, and examined the indications, rates of postoperative complications, incidence of occult malignant disease and subsequent breast cancer diagnosis.

Methods

Women who had bilateral prophylactic NSM between 2000 and 2016 were identified from a prospectively maintained database. Rates of postoperative complications, incidental breast cancer, recurrence and overall survival were evaluated.

Results

A total of 192 women underwent 384 prophylactic NSMs. Indications included BRCA1 or BRCA2 mutations in 117 patients (60·9 per cent), family history of breast cancer in 35 (18·2 per cent), lobular carcinoma in situ in 29 (15·1 per cent) and other reasons in 11 (5·7 per cent). Immediate breast reconstruction was performed in 191 patients. Of 384 NSMs, 116 breasts (30·2 per cent) had some evidence of skin necrosis at follow-up, which resolved spontaneously in most; only 24 breasts (6·3 per cent) required debridement. Overall, there was at least one complication in 129 breasts (33·6 per cent); 3·6 and 1·6 per cent had incidental findings of ductal carcinoma in situ and invasive breast cancer respectively. The nipple–areola complex was preserved entirely in 378 mastectomies. After a median follow-up of 36·8 months, there had been no deaths and no new breast cancer diagnoses.

Conclusion

These findings support the use of prophylactic NSM in high-risk patients. The nipples could be preserved in the majority of patients, postoperative complication rates were low, and, with limited follow-up, there were no new breast cancers.

Graphical Abstract

This study reviewed an institutional experience with prophylactic nipple-sparing mastectomy, and examined the indications, rates of postoperative complications, incidence of occult malignant disease and subsequent breast cancer diagnosis. This institutional experience supports the use of prophylactic nipple-sparing mastectomy in high-risk patients.

Graphical Abstract.

Safe option

Introduction

Nipple-sparing mastectomy (NSM) provides patients the opportunity to preserve the nipple–areola complex and provides a more natural cosmetic result than traditional skin-sparing mastectomy. This procedure is being performed increasingly¹ in the prophylactic setting among patients at increased risk of developing breast cancer, such as those with a genetic predisposition, strong family history or atypia.

Women with a BRCA mutation have a risk of developing breast cancer of 60–80 per cent during their lifetime^2–4. Prophylactic NSM⁵ has been shown to be an effective method for risk reduction in this population, with a 93 per cent relative risk reduction^6,7. Ideal candidates for NSM include women with small breasts, absence of ptosis, low BMI and those who are not active smokers⁸. Nonetheless, single-institution studies^1,9 have reported similarly on the expansion of the eligibility criteria for NSM over time to include women with larger breasts, without compromising oncological outcomes. The more desirable cosmetic outcomes achieved with preservation of the nipple–areola complex have shown quality-of-life benefits. Patients undergoing NSM have better psychosocial and sexual well-being, and improved cosmesis, body image and nipple sensation^10–15. Concerns, however, remain regarding the oncological safety of the procedure because of the potential for residual breast tissue beneath the nipple–areola complex or elsewhere on the chest wall, and the lack of long-term outcome data for patients at highest risk of developing breast cancer^16–19. Short-term studies^20–25 have reported a low incidence of occult cancer after prophylactic mastectomy; however, long-term follow-up is lacking.

In 2011, a recent NSM experience at Memorial Sloan Kettering Cancer Center was reported²⁰ including 196 prophylactic procedures. The goal of this study was to review and provide an updated follow-up of the indications, complications and incidence of occult malignancies for bilateral prophylactic NSM performed at this institution.

Methods

The study was approved by the Institutional Review Board of Memorial Sloan Kettering Cancer Center, New York. Informed consent was obtained from all participants included in the study. All procedures were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Memorial Sloan Kettering Cancer Center's prospectively maintained breast database was queried to identify patients who underwent bilateral prophylactic NSM between January 2000 and December 2016. Patients with known invasive breast cancer or ductal carcinoma in situ (DCIS) undergoing NSM were excluded. An electronic medical records review was performed to update the follow-up status for each patient. Variables retrieved for the analysis included: age; family history of breast/ovarian cancer (at least 1 first- or second-degree family member with breast cancer); genetic testing, if performed, and mutations detected; smoking status at the time of surgery; history of radiation; use of preoperative MRI; history of cancer (except breast); and type of reconstruction.

Information on complications, such as nipple excision, need for reoperation, skin desquamation (defined as partial-thickness skin loss not requiring surgical debridement), skin necrosis (full-thickness skin loss requiring surgical debridement), development of haematoma and need for implant/expander removal, was obtained by review of the records. All procedures were performed at Memorial Sloan Kettering Cancer Center by a breast surgeon and a plastic surgeon. Each mastectomy was considered an individual event.

Statistical analysis

Patient and disease characteristics are summarized as median (range) for continuous data, and frequency (percentage) for categorical variables. Overall survival was estimated from the date of surgery to date of death. Time to a new breast cancer diagnosis was estimated from date of surgery to date of diagnosis. All statistical analyses were conducted using R software version 3.4.1 (R Core Development Team, Vienna, Austria).

Results

Between January 2000 and December 2016, 192 women underwent bilateral prophylactic NSMs. Fig. 1 shows the time trend for the use of the procedure. The median age for the entire cohort was 41·5 (range 23–65) years (Table 1). Among the 192 patients, 125 (65·1 per cent) had at least one first-degree relative with breast cancer and 19 (9·9 per cent) had at least one first-degree relative with ovarian cancer. Genetic testing was performed in 148 patients (77·1 per cent). The majority of patients (145, 75·5 per cent) had never smoked, 43 (22·4 per cent) were former smokers, and only four (2·1 per cent) were current smokers. Twenty-one women had received radiation therapy previously in one or both breasts, either for a breast cancer or mantle radiation. Preoperative MRI was undertaken in 142 patients (74·0 per cent).

Fig. 1.

Institutional trends in prophylactic nipple-sparing mastectomy

Table 1.

Patient characteristics

	No. of patients*  (n = 192)
Age (years) †	41·5 (23–65)
Family history
Breast cancer (≥ 1st-degree relative)	125 (65·1)
Ovarian cancer (≥ 1st-degree relative)	19 (9·9)
Genetic testing	148 (77·1)
No mutation detected	24 (16·2)
BRCA1 mutation	72 (48·6)
BRCA2 mutation	45 (30·4)
BRCA1 – VUS	1 (0·7)
BRCA2 – VUS	4 (2·7)
CHEK2 mutation	1 (0·7)
ATM mutation	1 (0·7)
History of cancer (not breast)	13 (6·8)
History of breast cancer	8 (4·2)
Smoking status
Never smoker	145 (75·5)
Former smoker	43 (22·4)
Current smoker	4 (2·1)
Preoperative MRI	142 (74·0)
Type of reconstruction
No reconstruction	1 (0·5)
Permanent implant	10 (5·2)
Tissue expander	176 (91·7)
Autologous flap	5 (2·6)

^*With percentages in parentheses unless indicated otherwise;

^†values are median (range). VUS, variants of uncertain significance.

Prophylactic NSMs were performed for BRCA mutations in 117 of the 192 women (60·9 per cent), and for ATM and CHEK2 mutations in two (1·0 per cent); the indication was lobular carcinoma in situ (LCIS) in 29 women (15·1 per cent), and family history or personal history of breast cancer in 35 (18·2 per cent) and four (2·1 per cent) respectively (Table 2).

Table 2.

Indications for prophylactic nipple-sparing mastectomy

	No. of patients (n = 192)
BRCA mutation	117 (60·9)
ATM mutation	1 (0·5)
CHEK2 mutation	1 (0·5)
Family history	35 (18·2)
Lobular carcinoma in situ	29 (15·1)
Risk reduction	3 (1·6)
History of breast cancer	4 (2·1)
History of radiation therapy	2 (1·0)

Values in parentheses are percentages.

Almost all patients underwent immediate breast reconstruction, including tissue expander reconstructions in 176 (91·7 per cent), direct-to-implant procedures in ten (5·2 per cent) and autologous flap procedures in five (2·6 per cent). Only one woman (0·5 per cent) preferred not to undergo reconstruction.

The nipple–areola complex was ultimately preserved in 378 of 384 breasts (98·4 per cent); six nipples were excised (1·6 per cent), three (0·8 per cent) owing to incidental DCIS at the nipple margin, and the rest because of necrosis. Some degree of skin desquamation was present in 116 breasts (30·2 per cent), but this was usually mild and resolved fully without intervention (Table 3). Twenty-four breasts (6·2 per cent) had skin necrosis requiring debridement. Sixteen breasts (4·2 per cent) had a complication that required reoperation, and implant removal was necessary in eight (2·1 per cent). Sixteen patients (4·2 per cent) were treated for infection.

Table 3.

Complications among prophylactic procedures

	No. of breasts (n = 384)
Any complication	129 (33·6)
Nipple excision	6 (1·6)
Reoperation for complication	16 (4·2)
Skin desquamation	116 (30·2)
Skin necrosis	24 (6·3)
Haematoma	5 (1·3)
Implant/expander removal	8 (2·1)
Infection	16 (4·2)

Values in parentheses are percentages.

Of the 384 breasts, 20 (5·2 per cent) harboured unsuspected cancers; three (0·8 per cent) were invasive ductal carcinomas, 14 (3·6 per cent) were DCIS only and three (0·8 per cent) were invasive lobular carcinomas only.

After a median follow-up of 36·8 (range 1·3–194) months, there had been no new breast cancer diagnoses or deaths.

Discussion

Prophylactic bilateral NSM is considered as an option to decrease the risk of developing breast cancer in BRCA1/2 mutation carriers and high-risk women. The overall survival benefit is, however, not clearly defined in the literature^26,27. A recent multicentre study²⁸ evaluated the associations between bilateral breast reduction mastectomy, and overall and breast cancer-specific mortality rates for BRCA1 and BRCA2 mutation carriers separately. The authors reported lower overall and breast cancer-specific mortality rates among BRCA1 mutation carriers opting for risk-reduction mastectomy than among those kept under surveillance; however, for BRCA2 mutation carriers, surgery was not significantly associated with improvements in overall survival compared with surveillance. Ultimately, prophylactic mastectomy provides the greatest reduction in risk of breast cancer development. Improved cosmetic outcomes have led to its increased use as a risk-reducing procedure in this group of women.

In the present cohort, most women undergoing bilateral prophylactic NSM were BRCA1/2 carriers (60·9 per cent), followed by women with a family history of breast cancer (18·2 per cent) and those with a diagnosis of LCIS (15·1 per cent). These groups represent a population with a lifetime risk of developing breast cancer that ranges from 60 to 70 per cent in BRCA carriers^2–4, and from 15 to 30 per cent in women with LCIS^29–31. As a result, there have been concerns regarding whether or not this technique is appropriate in such a population.

Although there have been no RCTs comparing NSM with skin-sparing or simple mastectomy, the safety of the technique has been validated in both prophylactic and therapeutic settings in multiple prospective series. The major concerns with NSM, however, include its oncological safety and the appropriate surgical technique. Previous studies^5,32–35 have demonstrated that NSM leaves a small amount of ductal tissue behind the nipple. Additionally, this technique requires the mastectomy to be performed through a smaller, more cosmetic incision, possibly leading to inadequate removal of breast tissue. This has raised oncological concerns regarding the potential for increasing local recurrence risk^32,36.

In a series³⁷ of 150 patients (298 breasts) undergoing NSM for risk reduction, occult disease was found in only four patients (2·7 per cent) and, after a mean follow-up of 32·6 (range 1–76) months, there was only one cancer event and no disease at the nipple–areola complex. Several other retrospective studies, with follow-up ranging from 6 weeks to 92 months, reported excellent results after treatment with NSM for risk reduction³⁸.

In the present study, after a median follow-up of 36·8 months, there were no local recurrences among patients with incidental invasive breast cancer or DCIS, and no new diagnoses of breast cancer in those who had prophylactic surgery. Although this study evaluated a cohort of patients with a high or moderately increased breast cancer risk without previous evidence for a diagnosis of breast cancer, the findings support previous reports^34,39–41 that NSM is an oncologically safe prophylactic option for women at increased risk of developing breast cancer, at least with short follow-up.

The results of previous retrospective studies^33–35,42 evaluating whether this technique has a higher risk of perioperative complications, such as skin flap necrosis, reoperation, nipple loss, infection and haematoma, have been inconsistent. A more contemporary study⁴³ has reported an increased risk of skin flap necrosis with the use of NSM. Major complications were infrequent in the present study, with 116 women (30·2 per cent) having some degree of skin necrosis at follow-up. Nevertheless, this resolved spontaneously in most patients, with only 24 breasts (6·2 per cent) requiring debridement. Other complications, including wound infection, expander/implant removal and haematoma were noted in 1·3–4·2 per cent of patients. NSM divides the blood supply to the nipple–areola complex, which can result in ischaemia. Here, nipple–areola complexes were preserved entirely in 378 mastectomies; only three required nipple excisions secondary to some degree of nipple–areola complex necrosis. The rate of nipple–areola complex necrosis in this study supports the premise that NSM can be performed with a low rate of necrosis similar to that reported in the literature^{39–40,44–47}.

Strengths of this study include its evaluation of a large cohort of patients who underwent prophylactic NSM over an extended period. The results suggest that NSM in the prophylactic setting did not affect oncological outcomes. Limitations of this study include its retrospective nature. The absence of any breast cancer diagnoses during the follow-up of 36·8 months suggests that NSM may be oncologically safe in this patient group; however, longer follow-up is needed to establish the long-term safety of the procedure.