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Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers

Published:January 21, 2013DOI:https://doi.org/10.1016/j.ajog.2013.01.026

      Objective

      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 investigates factors that might influence decision making regarding prophylactic surgeries among women with BRCA mutations.

      Study Design

      Unaffected BRCA mutation carriers who were counseled at our 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.

      Results

      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.

      Conclusion

      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.

      Key words

      The risks of breast and ovarian cancer in women with mutations in the BRCA1 or BRCA2 gene are elevated substantially, with an estimated lifetime risk of breast cancer of 56-84%, and a lifetime risk of ovarian cancer of up to 54% for BRCA1 and 27% for BRCA2.
      • Rebbeck T.
      • Kauff N.
      • Domchek S.
      Meta-analysis of risk reduction estimates associated with risk-reducing salpingo oophorectomy in BRCA1 or BRCA2 mutation carriers.
      • Kauff N.
      • Domchek S.
      • Fruebel T.
      • et al.
      Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
      Currently, the management options for women with BRCA mutations are somewhat limited and include: (1) increased surveillance to maximize early detection of cancers, with or without the use of antihormonal agents for cancer prevention, or (2) prophylactic surgeries to reduce cancer risk.
      The most effective cancer prevention strategy for individuals at high risk is prophylactic surgery. Risk-reducing mastectomy (RRM) reduces breast cancer risk among BRCA mutation carriers by at least 95%.
      • Domchek S.
      • Friebel T.
      • Singer C.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      Risk-reducing bilateral salpingo-oophorectomy (RRBSO) reduces breast cancer risk by 50% when completed before menopause and reduces ovarian/fallopian tube/peritoneal cancer risk by at least 80%.
      • Rebbeck T.
      • Kauff N.
      • Domchek S.
      Meta-analysis of risk reduction estimates associated with risk-reducing salpingo oophorectomy in BRCA1 or BRCA2 mutation carriers.
      The combination of both RRM and RRBSO at age 40 years has been shown to improve survival more than either intervention alone.
      • Domchek S.
      • Friebel T.
      • Singer C.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      • Kurian A.
      • Bronislava M.
      • Plevritis S.
      Survival analysis of cancer risk reduction strategies for BRCA 1/2 mutation carriers.
      Despite the substantial survival benefits, only a portion of unaffected women with BRCA mutations elect to undergo prophylactic surgeries. In an international study by Metcalfe et al,
      • Metcalfe K.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • et al.
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      the United States had the highest uptake of all countries with 36.3% of 703 BRCA mutation carriers undergoing RRM and 71.1% undergoing RRBSO. Poland had the lowest rates with 2.7% for RRM and 34.9% for RRBSO. The variations in uptake rate of prophylactic surgeries worldwide may be influenced by a number of factors including differences in health care access, provider recommendations, and social mores.
      • Madakubsjam J.
      • van Beurden M.
      • Bleiker E.M.
      • et al.
      Predictors of prophylactic bilateral salpingo-oophorectomy compared with gynecologic screening use in BRCA1/2 mutation carriers.
      Individually, perception of risk, body image, and sexuality clearly influence decisions, although studies have shown that the majority of women who have undergone prophylactic mastectomy have high levels of satisfaction with the procedure and no significant changes in levels of self-esteem.
      • Frost M.
      • Slezak J.
      • Tran N.
      • et al.
      Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance.
      Los Angeles, CA, is a demographic with very high access and cultural permissiveness toward plastic surgery, making it an interesting study population for investigation of uptake of preventive mastectomy and breast reconstruction.
      The purpose of our study was to: (1) quantify the uptake of prophylactic surgery among BRCA mutation carriers at our center; and (2) investigate factors that might influence decision making regarding prophylactic surgery including age, parity, and family history of cancer. With our large cohort of BRCA mutation carriers and long-standing interest in barriers to risk reduction, we sought to evaluate history of cancer among extended family members and total cancer burden as potential influential factors in the decision-making process.

      Materials and Methods

      Study subjects were women without a personal history of cancer who had been identified as carriers of deleterious mutations in the BRCA1 and/or BRCA2 genes and were prospectively followed up in the Gilda Radner breast and ovarian cancer screening program. The Gilda Radner registry follows up women who are carriers of a BRCA mutation, both with and without a personal history of cancer. Women who had a personal history of cancer were excluded from this analysis. Year of genetic testing ranged from 1998 through 2010, and study subjects were divided into 2 cohorts: tested before and after 2005. This midpoint in the testing decade was chosen for comparison because in 2005 national guidelines were published regarding BRCA testing and there were significant changes in insurance coverage for testing, greatly increasing awareness and availability of genetic testing.
      Study subjects were followed up after testing for a minimum of 1 year and up to 11 years. Medical records, operative reports, and family pedigrees were reviewed after approval from the Institutional Review Board at Cedars-Sinai Medical Center. Data collected included each woman's age, ethnicity, parity, mutation type, history of breast biopsy, previous cosmetic surgeries, and the uptake of prophylactic surgeries. Pedigree analysis was conducted to assess cancer penetrance and degree of relationship of affected individuals to the proband. First-degree relatives (mother, father, sibling, offspring) and/or second-degree relatives (aunts or uncles, and/or grandparents) with cancer were included. Cancer sites included in our analysis were those associated with hereditary breast and ovarian cancer syndrome: breast, ovarian, fallopian tube, peritoneal, prostate, pancreatic, and melanoma. Family members with a nonspecific diagnosis of cancer were excluded from further analysis.
      All data are presented as means and SD or counts and percentages where appropriate. Differences between groupings were compared using t tests or χ2 tests. Unadjusted odds ratios (ORs) and their 95% confidence intervals were computed using logistic regression modeling. Using forward-stepwise selection methods, an adjusted logistic regression model of a set of significant factors in predicting likelihood of women to have received RRM was constructed. All tests were 2-sided with the level of statistical significance set at P < .05. All statistical analysis was performed using SAS v9.3 (SAS Institute, Cary, NC).

      Results

      There were 136 unaffected women with BRCA mutations and adequate follow-up time who were included in the study population. A total of 71% were self-identified as being of Ashkenazi Jewish background and the remainder were non-Jewish Caucasian (19%), Hispanic (2%), African American (1%), or other or mixed race (8%). None were first-degree relatives of each other. In all, 65% reported having had some college education or higher (Table 1).
      TABLE 1Demographics of study participants undergoing mastectomy vs screening
      DemographicTotal (N = 136)Mastectomy (n = 57)No mastectomy (n = 79)P valueOR (95% CI)
      n%n%n%
      Age at time of genetic testing, y (mean ± SD)44.3 ± 11.339.9 ± 9.940.2 ± 12.7.8891.0 (1.0–1.0)
      Age at time of surgery, y (mean ± SD)43.7 ± 8.1
      Age ≥50 y443218322633.8700.9 (0.5–2.0)
      Caucasian1158543757291.8411.2 (0.2–6.8)
      Other races2115142579ref
      Ashkenazi Jewish
      Eastern European Caucasian descent.
      967141725570.6491.2 (0.5–2.7)
      Non-Jewish402916282430ref
      Some college or higher (n = 97)636530884470.0423.2 (1.0–10.5)
      Genetic testing ≥2005614530533139.1211.7 (0.9–3.4)
      BRCA1826037654557.6871.4 (0.7–2.8)
      BRCA2513819333241ref
      BRCA1 and BRCA2321223
      Parity ≥1856345794051.0013.7 (1.7–7.9)
      RRBSO715236633544.0302.2 (1.1–4.3)
      Mother with breast cancer574226463139.4571.3 (0.7–2.6)
       Mother deceased from breast cancer2115142579.0123.3 (1.3–8.9)
      Sister with breast cancer19147121215.6290.8 (0.3–2.1)
      First-degree family death from breast cancer22161425810.0282.9 (1.1–7.5)
      Both first- and second-degree family death from breast cancer129101823.0088.2 (1.7–39.0)
      Mother with pelvic cancer554018323747.0740.5 (0.3–1.1)
       Mother deceased from pelvic cancer352614252117.7900.9 (0.4–2.0)
      Sister with pelvic cancer433511.3094.3 (0.4–42.7)
      Only maternal second-degree affected (any BRCA-related cancer)432423.7401.4 (0.2–10.3)
      Only paternal second-degree affected (any BRCA-related cancer)542434.9300.9 (0.2–5.7)
      Personal history of breast biopsy262210241621.7291.2 (0.5–2.9)
      Previous cosmetic surgery21187171419.7870.9 (0.3–2.4)
      CI, confidence interval; OR, odds ratio; ref, reference; RRBSO, risk-reducing bilateral salpingo-oophorectomy.
      Singh. Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers. Am J Obstet Gynecol 2013.
      a Eastern European Caucasian descent.

      Risk-reducing mastectomy

      The uptake of RRM in our population was 42% (57/136). Of these 57 women, 37 (65%) had a BRCA1 mutation, 19 (33%) had a BRCA2 mutation, and 1 (2%) had both BRCA1 and BRCA2 mutations, the same proportion seen in women who did not undergo RRM (P = .687). There were no significant differences in the mean age at time of testing among those who had RRM and those who did not (39.9 ± 9.9 vs 40.2 ± 12.7 years; P = .889), however, women without RRM were less parous (parity ≥1 79% vs 51%; P < .001; OR, 3.7). The mean age at time of RRM was 43.7 ± 8.1 years. Uptake of RRM did not increase at age >50 years (32% vs 33%; P = .870) (Table 1). The majority of subjects who opted for RRM (72%) had the procedure within 2 years of genetic testing.
      Significantly more women in the RRM group had lost their mother to breast cancer than those who did not have RRM (25% vs 9%; P = .012; OR, 3.3). In addition, more women in the RRM group reported any first-degree relative (mother or sister) being deceased from breast cancer than those who did not have RRM (25% vs 10%; P = .028; OR, 2.9). Those with both first- and second-degree relatives deceased from breast cancer were also more likely to have RRM than those who did not (18% vs 3%; P = .008; OR, 8.2) (TABLE 1, TABLE 2). There were no significant differences in uptake of RRM based upon personal history of breast biopsy or previous cosmetic surgery (Table 1). In multivariable modeling the most significant factors to predict the likelihood of RRM uptake were having both first- and second-degree relatives deceased from breast cancer (OR, 11.0; P = .005), already having had at least 1 childbirth (OR, 4.2; P = .001), and more recent genetic testing (OR, 2.8; P = .014) (Table 2).
      TABLE 2Adjusted logistic regression modeling: factors contributing to likelihood of risk-reducing mastectomy
      VariableOR (95% CI)P value
      Both first- and second-degree relative death from breast cancer11.0 (2.1–57.9).005
      Parity ≥14.2 (1.8–10.0).001
      Genetic testing >20052.8 (1.2–6.4).014
      CI, confidence interval; OR, odds ratio.
      Singh. Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers. Am J Obstet Gynecol 2013.

      Risk-reducing bilateral salpingo-oophorectomy

      The uptake of RRBSO in our population was 52% (71/136). Of these women, 46 (65%) had BRCA1 mutations, 24 (34%) had BRCA2 mutations, and 1 (1%) had both, with a similar distribution in the non-RRBSO group (P = .492). Women who had RRBSO were older at the time of genetic testing than those who did not (44.7 ± 9.4 vs 34.9 ± 11.7 years; P < .001) and more parous (parity ≥1 82% vs 42%; P < .001) (Table 3). The mean age at time of RRBSO was 45.2 ± 8.4 years. The proportion of women aged ≥50 years who had RRBSO was 51% as compared to only 12% uptake among those aged <50 years (P < .001; OR, 7.3). The majority who opted for RRBSO had the procedure within 2 years of genetic testing.
      TABLE 3Demographics of study participants undergoing oophorectomy vs screening
      DemographicTotal (N = 136)RRBSO (n = 71)No RRBSO (n = 65)P valueOR (95% CI)
      n%n%n%
      Age at time of genetic testing, y (mean ± SD)44.3 ± 11.344.7 ± 9.434.9 ± 11.7< .0011.2 (1.1–1.2)
      Age at time of surgery, y (mean ± SD)45.2 ± 8.4
      Age ≥50 y44323651812< .0017.3 (3.1–17.6)
      Caucasian1158563895280.1642.0 (0.8–5.1)
      Other races21158111320ref
      Ashkenazi Jewish
      Eastern European Caucasian descent.
      967151724569.3681.4 (0.7–3.2)
      Non-Jewish402920282031ref
      Some college or higher (n = 97)636539763576.9651.0 (0.4–2.5)
      Genetic testing ≥2005614524343757.0070.4 (0.2–0.8)
      BRCA1826046653655.3531.4 (0.7–2.8)
      BRCA2513824342742ref
      BRCA1 and BRCA2321123
      Parity ≥1856358822742< .0015.8 (2.6–12.9)
      Mastectomy574236512132.0302.2 (1.1–4.3)
      Mother with breast cancer574227383046.3380.7 (0.4–1.4)
       Mother deceased from breast cancer2115162369.0612.6 (0.9–7.3)
      Sister with breast cancer19141217711.3061.7 (0.6–4.6)
      First-degree family death from breast cancer2216162369.0412.9 (1.0–7.8)
      Both first- and second-degree family death from breast cancer129111512.02011.7 (1.5–93.6)
      Mother with pelvic cancer554037521828.0042.8 (1.4–5.8)
       Mother deceased from pelvic cancer3526294169< .0016.8 (2.6–17.8)
      Sister with pelvic cancer433412.3742.8 (0.3–27.9)
      Only maternal second-degree affected (any BRCA-related cancer)431135.2960.3 (0.1–2.9)
      Only paternal second-degree affected (any BRCA-related cancer)541146.1780.2 (0.1–2.0)
      CI, confidence interval; OR, odds ratio; ref, reference; RRBSO, risk-reducing bilateral salpingo-oophorectomy.
      Singh. Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers. Am J Obstet Gynecol 2013.
      a Eastern European Caucasian descent.
      The uptake of RRBSO was higher among women who had mastectomy than those who did not (63% vs 44%; P = .030; OR, 2.2), and as with RRM, uptake of RRBSO also strongly correlated with particular features of the family history of cancer. Women who lost their mother to pelvic cancer were more likely to have RRBSO than those without this history (52% vs 28%; P = .004; OR, 2.8). In addition, those who reported first- or second-degree relatives being deceased from breast cancer were also more likely to have RRBSO than those who did not (15% vs 2%; P = .020; OR, 11.7) (Table 3). Multivariable analysis demonstrated that the combined factors together that predicted uptake of RRBSO were having both first- and second-degree relatives die from breast cancer (OR, 23.6; P = .015), a mother lost to pelvic cancer (OR, 10.5; P < .001), already having had at least 1 childbirth (OR, 9.4; P < .001), age ≥50 years (OR, 7.7; P < .001), and testing after 2005 (OR, 0.7; P = .0426) (Table 4).
      TABLE 4Adjusted logistic regression modeling: factors contributing to likelihood of risk-reducing bilateral salpingo-oophorectomy
      VariableOR (95% CI)P value
      Both first- and second-degree relative death from breast cancer23.6 (1.9–36.7).015
      Mother died of pelvic cancer10.5 (3.0–36.7)< .001
      Parity ≥19.4 (3.1–28.1)< .001
      Age ≥50 y7.7 (2.5–23.8)< .001
      Genetic testing >20050.7 (0.3–1.8).0426
      CI, confidence interval; OR, odds ratio.
      Singh. Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers. Am J Obstet Gynecol 2013.

      Comment

      Our study suggests that family history has a significant impact on the uptake of risk-reducing surgeries among BRCA mutation carriers. Specifically, women who lost their mother to breast cancer were most likely to have RRM. Similarly, those who lost their mother to pelvic cancer were more likely to have RRBSO. Overall, increased cancer death burden among other relatives was also predictive of RRM and RRBSO. These findings suggest that perceptions of cancer risk are heavily influenced by the family history and are motivators in preventive surgery more than the actual risk estimations themselves. Family history is key for practitioners in not only identifying those at risk, but also in understanding of their patient's experiences and attitudes regarding disease.
      The ratio of BRCA1 to BRCA2 reflected the higher frequency of BRCA1 mutations in our predominantly Ashkenazi Jewish population. Previous studies have shown higher uptake of RRBSO among women with BRCA1 mutations compared to those with BRCA2 mutations, reflecting perhaps understanding of higher incidence of ovarian cancer among BRCA1 mutation carriers and earlier age of onset.
      • Manchanda R.
      • Burnell M.
      • Abdelraheim A.
      • et al.
      Factors influencing uptake and timing of risk reducing salpingo-oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis.
      We found no such differences in our population. Studies have also shown the average age at the time of RRM and RRBSO to be 35-45 years,
      • Evans D.
      • Lalloo F.
      • Ashcroft L.
      • et al.
      Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.
      similar to our findings. Most women in our population who underwent prophylactic surgeries had surgery within the first 2 years after genetic testing, which was similar to that previously reported by Evans et al.
      • Evans D.
      • Lalloo F.
      • Ashcroft L.
      • et al.
      Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent.
      Having children was predicted to increase uptake of prophylactic surgeries, and this was the case for both RRM and RRBSO. However, the overall uptake of RRBSO was much less among our population than that previously reported for the United States at 52% vs 71%, respectively. This may reflect a tendency for later age at completion of childbearing among our population as compared to other populations in the United States and worldwide. In addition, the average age of those women who were continuing with ovarian surveillance in our population was 34.9 years, still below the highest risk years for ovarian cancer, while the US population in the Metcalf study with higher RRBSO uptake rates had a mean age of 46.0 years.
      • Metcalfe K.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • et al.
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      The uptake of RRBSO in our population did correlate with uptake of RRM, suggesting that women who opt for prophylactic surgery at one site are more apt to have surgery at a second site. It is likely that the uptake rate of RRBSO also increases after menopause, but does not provide the maximum survival benefit as has been shown for surgery at age <40 years.
      • Domchek S.
      • Friebel T.
      • Singer C.
      • et al.
      Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
      • Kurian A.
      • Bronislava M.
      • Plevritis S.
      Survival analysis of cancer risk reduction strategies for BRCA 1/2 mutation carriers.
      RRBSO was in fact found to be much higher among women who were at least perimenopausal at ages ≥50 years than among women <50 years of age (51% vs 12%, respectively).
      We hypothesized that women reporting history of breast biopsy might be more motivated to have RRM, however we found no increase in uptake with this history. We also found no differences in uptake of RRM based on prior cosmetic surgery. In 2005, the US Preventive Task Force published recommendations on BRCA testing and level-A evidence for surgical prevention. In addition, during that same time period, Medicare began covering BRCA testing much more liberally to include all Ashkenazi Jewish women with a history of breast or ovarian cancer, regardless of age. This resulted in many women who did not come from very high-risk pedigrees undergoing genetic testing and being discovered to carry mutations. We predicted that this greater awareness and acceptance of prophylactic mastectomy and salpingo-oophorectomy among physicians and the lay community would increase the choice toward risk-reducing surgeries in the more recently tested cohort, and our results support this trend.
      Our study reports on the uptake of prophylactic surgeries among BRCA mutation carriers at a single center in Los Angeles, CA. The mean age of our population was 44 years and the population was similar in terms of cultural and socioeconomic backgrounds. Most of the women had insurance coverage for costs of genetic counseling and testing, as well as for prophylactic and therapeutic surgeries. They were all counseled in an environment where breast and plastic surgeons are abundant and easily accessible. Despite this, only a minority elected to have RRM, though our uptake rates still surpass those reported by other centers across the United States and are much higher than in other countries.
      • Metcalfe K.
      • Birenbaum-Carmeli D.
      • Lubinski J.
      • et al.
      International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
      Strengths of our study included the uniformity of the patient population because it diminished impact that competing cultural factors or socioeconomic influences may have on decision making regarding prophylactic surgeries. In addition, genetic counseling with a clinical geneticist at a single center also eliminates large differences in counseling content as might be seen among various providers. However, these factors may potentially make our findings less applicable among a more diverse patient population or in geographical areas where access to specialized health care may be limited. Studies comparing surgical uptake and screening behaviors in BRCA carriers in other regional and ethno/cultural groups is clearly needed.
      In a recent study, Wenzel et al
      • Wenzel L.
      • Osann K.
      • Lester J.
      • et al.
      Biopsychological stress factors in BRCA mutation carriers.
      found that BRCA mutation carriers with a known maternal transmission whose mother is deceased report higher perceived stress, more intrusive thoughts related to cancer, and more anxiety. Beyond the obvious psychosocial burdens, the impact of familial cancer may influence the uptake of prophylactic surgeries. For example, a very young woman who has suffered the loss of her mother may be insistent on prophylactic oophorectomy well before she has entered the high-risk years of her life. Recognizing that a woman may be requesting oophorectomy earlier than would be medically recommended because of her family history influence is important in counseling her to make the most appropriate decision. The converse is also true: a woman with virtually no family history may be under-concerned about her risks for breast or ovarian cancer. Sensitivity with regard to the impact her personal family history may have on her perception of risk will allow focused discussion on empiric risks relative to that patient's age and medical history. Additional studies are needed to assess whether directly addressing family experiences, or lack thereof, during the genetic counseling sessions influences patient behavior regarding surveillance vs prophylactic surgery.
      All women in our study had a family history of cancer, although the severity of the family history varied broadly. There was an especially significant impact from losing a mother to cancer. History of mother being deceased from cancer and/or an increased cancer burden within the family (numbers of affected first- and second-degree relatives) may be of underrecognized import in patient attitudes regarding prophylactic procedures and has significant implications for genetic counseling. With the explosion of BRCA testing by primary care obstetricians and gynecologists, awareness of subtle factors beyond the statistical risk for cancers is relevant when counseling at-risk women. Formal genetic counseling with a clinical genetics specialist providing dedicated attention to family history is important for directing decision making, with the goal of not only educating the patient regarding her risks, but also understanding her attitudes regarding management options, and ultimately providing a personalized plan for greatest cancer risk reduction based upon her individual life circumstances.

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