The Angelina Jolie effect: Contralateral risk-reducing mastectomy trends in patients at increased risk of breast cancer.

Contralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987-2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie's announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11-54) days after the index cancer surgery. Rates of CRRM doubled following AJ's news, from 23.9% pre-AJ to 50.0% post AJ (p < 0.001). Rates of CRRM were found to decrease with increasing age at breast cancer (p < 0.001) and tumour TNM stage (p = 0.040), and to increase with the estimated lifetime risk of breast cancer (p < 0.001) and tumour grade (p = 0.015) on univariable analysis. After adjusting for these factors, the step-change increase in CRRM rates post-AJ remained significant (odds ratio: 9.61, p < 0.001). The AJ effect appears to have been associated with higher rates of CRRM amongst breast cancer patients with increased cancer risk. CRRM rates were highest amongst younger women and those with the highest lifetime risk profile. Clinicians need to be aware of how media news can impact on the delivery of cancer related services. Communicating objective assessment of risk is important when counselling women on the merits of risk-reducing surgery.

Current knowledge of risk reducing mastectomy: Indications, techniques, results, benefits, harms.

The last twenty years have seen a complete change in society's attitude to the strategy of risk reduction of breast cancer in high-risk individuals by means of proactive mastectomy. Once termed 'prophylactic mastectomy', risk reducing mastectomy (RRM) was considered two decades ago not only extreme, but in some quarters almost unethical. RRM is now commonly undertaken in specialist breast units for women at high individual breast cancer risk, by virtue of an inherited breast cancer related gene mutation or from calculated high statistical risk from family history data, and the efficacy of RRM in reducing subsequent incident diagnoses of breast cancer has been published from a number of centres. RRM is offered routinely in conjunction with total breast reconstruction, using the whole range of reconstructive surgical techniques. The public announcement by the actor Angelina Jolie in 2013 that she had inherited and harboured a BRCA1 gene mutation, and was undergoing RRM and breast reconstruction to lower her intrinsic breast cancer risk, had a significant effect on public attitudes and perception. Whilst there are other means of lowering breast cancer risk by means of selective oestrogen receptor modulators, such as tamoxifen and raloxifene, their lowering effect on risk of breast cancer remains substantially less than that afforded by surgical removal of 'at risk' breast tissue. The progressive development and increasing sophistication of techniques of breast reconstructive surgery has paralleled the trend for more RRM surgery, and the substantial majority of women who opt for RRM choose immediate breast reconstruction.

Novel Approach for Risk-Reducing Mastectomy: First-Stage Implant Placement and Subsequent Second-Stage Mastectomy.

BACKGROUND: Risk-reducing mastectomy with tissue expander and then implant-based breast reconstruction conventionally involved immediate submuscular placement of tissue expanders during mastectomy and then, after expansion, replacement of expanders for permanent implants in a second-stage operation. Use of acellular dermal matrix can achieve a single-stage operation; however, acellular dermal matrices are costly and may have potential complications. The authors aim to assess the feasibility of placement of implants as a first-stage procedure before risk-reducing mastectomy as a novel technique of reconstruction that avoids the need for serial outpatient expansion and acellular dermal matrix. METHODS: Patients for whom risk-reducing mastectomy was planned were offered first-stage dual-plane placement of fixed volume silicone gel permanent implants by means of inframammary fold incisions. Risk-reducing mastectomy was undertaken several months later as the second operation, leaving the implants in place protected by the muscle and capsule pocket. Nipples were preserved or reconstructed according to the patient's choice. RESULTS: Eight patients with 15 operated breasts were recruited. Anatomically shaped implants were used in all patients, and complete coverage of each implant was achieved. Mean implant volume was 433 ml (range, 290 to 545 ml). There were no complications, and good aesthetic outcomes were achieved. CONCLUSIONS: This proof-of-principle study finds that placement of implants before risk-reducing mastectomy is a novel technique for women at high breast cancer risk that could reduce the use of tissue expanders and acellular dermal matrices and their associated problems. Two-stage risk-reducing mastectomy with first-stage implant placement and subsequent risk-reducing mastectomy leaving the implants in place is feasible, with no complications, and can produce a good cosmetic outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Hyaluronan, TSG-6, and inter-α-inhibitor in periprosthetic breast capsules: reduced levels of free hyaluronan and TSG-6 expression in contracted capsules.

BACKGROUND: The exact mechanism of capsular contracture (CC) is still unknown. The covalent modification of hyaluronan (HA) with the heavy chains (HC) of inter-α-inhibitor (IαI) has been identified as an important pathway in inflammation and tissue remodeling, where HC·HA formation is catalyzed by TSG-6 (the protein product of tumor necrosis factor stimulated gene-6). OBJECTIVE: The authors quantitatively assess the correlation between severity of CC (measured by Baker grade) and expression of HA, TSG-6, and IαI (ie, the polypeptides HC1, HC2, and bikunin) in periprosthetic breast capsules. METHODS: Immunofluorescent staining for HA, TSG-6, HC1, HC2, and bikunin was carried out on periprosthetic breast capsules (n = 7) of each Baker grade from four anatomical locations. Quantitative analysis was performed to identify differences in staining intensity. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine differences in TSG-6 gene expression levels. RESULTS: Severity of contracture was associated with reduced staining for both free HA (Pearson correlation coefficient, r = -0.645, P < .001) and TSG-6 (r = -0.642, P = .002). RT-qPCR showed a significant negative correlation between severity of contracture and TSG-6 gene expression levels (r = -0.750, P = .001). CONCLUSIONS: The negative correlation between TSG-6 expression levels and severity of CC suggests a possible protective role for TSG-6 in the context of CC formation, and this may have a clinically relevant role in prevention of breast CC.

Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.

PURPOSE: The uptake of risk-reducing surgery in women at increased risk of breast and ovarian cancer is highly variable between countries and centers within countries. We have investigated the rate, timing, and age of uptake of surgery in the northwest of England to report the results after up to 7 years in a Regional Genetics center. METHODS: Uptake was documented in 211 known unaffected BRCA1/2 mutation carriers from 509 families and in 3,515 women at >25% lifetime risk of breast cancer without known mutations. RESULTS: Of the 211 mutation carriers, 40% opted for bilateral risk-reducing mastectomy (BRRM) and 45% underwent bilateral risk-reducing salpingo-oophorectomy (BRRSPO). Uptake of BRRM was significantly related to lifetime risk and age but continued over several years. In women not known to carry a BRCA mutation, 6.4% of women at 40% to 45% lifetime risk, 2.5% of women at 33% to 39% lifetime risk, and 1.8% of women at 25% to 32% lifetime risk underwent BRRM (P < 0.005). BRRSPO uptake was greater in BRCA1 (52%) than BRCA2 (28%) carriers but in both groups tended to occur within the first 2 years after gene test (except in the youngest age group) and in women between the ages of 35 and 45. CONCLUSION: To truly assess the uptake of risk-reducing surgery, longer-term follow-up is necessary particularly in younger women who are likely to delay BRRSPO. Careful risk counseling does seem to influence women's decisions for surgery, although the effect is not immediate.