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Postmenopausal Hormone Replacement Therapy: Effect on Diagnosis and Outcome in Early-Stage Invasive Breast Cancer Treated With Conservative Surgery and Radiation

From the Division of Population Science, Department of Biostatistics, and Departments of Radiation Oncology, Radiology, Pathology, and Surgery, Fox Chase Cancer Center, Philadelphia, PA.

Address reprint requests to Barbara Fowble, MD, Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; e-mail b_fowble{at}fccc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To compare the pretreatment characteristics and outcome of postmenopausal women with stage I-II breast cancer treated with conservative surgery and radiation who had a history of hormone replacement therapy (HRT) with those who had never received HRT.

MATERIALS AND METHODS: From 1979 to 1993, 485 postmenopausal women underwent excisional biopsy, axillary dissection, and radiation for stage I-II breast cancer. The median follow-up was 5.9 years. One hundred forty-one patients reported a history of HRT. The median length of use was 5 years. Three hundred forty-four patients reported no history of HRT.

RESULTS: Statistically significant differences between the two groups were observed for median age (HRT 60 years v no HRT 64 years; P = .0009), median weight (HRT 142 lbs v no HRT 152 lbs; P = .004), clinical tumor size 2 cm (HRT 77% v no HRT 66%; P = .02), and the use of re-excision (HRT 62% v no HRT 49%; P = .01). The method of detection by mammogram only (HRT 52% v no HRT 42%; P = .06) was of borderline statistical significance. The HRT patients had a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence (8% v 2%; P = .02), a statistically significant decreased cumulative incidence of distant metastases (HRT 6% v no HRT 17%; P = .01), and a borderline statistically significant improvement in cause-specific survival at 10 years (HRT 92% v no HRT 86%; P = .07). Postmenopausal women with a history of HRT did not have an increased risk of contralateral breast cancer or second non–breast cancer malignancy.

CONCLUSION: This study failed to identify an adverse effect of HRT on breast cancer mortality in patients with stage I-II disease treated with conservative surgery and radiation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE BENEFICIAL EFFECTS of estrogen replacement therapy (ERT) or a combination of estrogen and progesterone (hormone replacement therapy [HRT]) in postmenopausal women in terms of amelioration of menopausal symptoms,^1,2 decreased coronary events,^3-11 favorable modification of lipid profiles and fibrinogen levels,^12-15 prevention of osteoporosis and hip fractures,^4,6,13,15-18 and ultimately a decrease in overall mortality^19-21 have been established by multiple individual case-control and cohort studies as well as meta-analyses. However, these benefits have been offset by a modestly increased risk of breast cancer,^22,23 primarily in women who were current users of HRT and whose duration of use was 5 years.^23-26 Although they may have an increased risk of breast cancer, women with a history of HRT who develop breast cancer have been found to have improved breast cancer survival.^19,20,27-32 This favorable effect on breast cancer mortality has been attributed, in part, to more intensive screening despite the fact that postmenopausal HRT has been reported to result in both an increase in breast density^33-36 and a lower mammographic specificity and sensitivity.³⁵ Unfortunately, there is little information on the method of detection of breast cancer in these women, disparate results on their long-term survival, and no data on outcome of treatment with conservative surgery and radiation. We chose to address these issues by comparing the pretreatment characteristics and outcome of postmenopausal women with a history of HRT to women who had never taken HRT and who had undergone breast conservation therapy with radiation for early-stage invasive breast cancer.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between 1979 and 1993, 1,660 women with clinical stage I and II³⁷ unilateral (at the time of diagnosis) invasive breast cancer underwent excisional biopsy, level I-II axillary node dissection, and definitive radiation at Fox Chase Cancer Center (881 patients) or the University of Pennsylvania (779 patients). The patients from the University of Pennsylvania were treated and/or followed by one of the authors (B.F.). Four hundred eighty-five of these women were postmenopausal and had reported information regarding their use of HRT in a questionnaire completed at the time of their diagnosis of breast cancer. These women comprised the study population. Their median age was 63 years (range, 37 to 88 years), and the median follow-up for all patients was 5.9 years (range, 0.1 to 15.6 years). The number of patients at risk at 5 and 10 years was 291 and 67, respectively. Four hundred seven women in the study population were treated at Fox Chase Cancer Center and 78 were treated at the University of Pennsylvania.

Ninety-four percent of the patients were white and 5% were black. Forty-five percent of the women had their primary cancer detected solely by mammography, and 69% had tumors 2 cm. Thirty-one percent had a positive family history of breast cancer, including 86 women with a first-degree relative and seven with three or more affected relatives.

An excisional biopsy was performed in all patients and 53% had a re-excision. The final margin of resection was negative (> 2 mm) in 72% (350 patients), close ( 2 mm) in 10% (49 patients), positive (invasive cancer or ductal carcinoma in situ) in 6% (27 patients), and unknown in 12% (59 patients). All patients underwent level I-II axillary dissection, the results of which were negative in 76% (368 patients). Ninety-four patients (19%) had one to three positive axillary nodes, and 23 (5%) had four positive nodes.

Radiotherapy consisted of treatment delivered with tangential fields to the entire breast to a total dose of 46 to 50 Gy in 1.8- to 2-Gy fractions over a period of 4.5 to 5 weeks. In addition, 88 patients received treatment to the supraclavicular nodes with a single anterior field angled 12° with or without a posterior axillary field. A dose of 46 to 50 Gy was delivered at a depth of 3 cm over 4.5 to 5 weeks. A 6-MV linear accelerator was used for the majority of patients. Women with large breasts or a separation 21 to 22 cm were treated with 10-, 15-, or 18-MV photons with a beam spoiler. The primary site received an additional 14 to 20 Gy with electrons, external beam, or an iridium-192 implant.

Two hundred fifty-one patients received no adjuvant systemic therapy, 50 received chemotherapy alone, 149 tamoxifen alone, and 35 a combination of both. Seventy-six percent of chemotherapy patients received cyclophosphamide, methotrexate, and fluorouracil, and the remainder received cyclophosphamide, doxorubicin, and fluorouracil. During this treatment period, tamoxifen was administered for a minimum of 5 years.

Of the study population, 141 women reported a history of HRT: 40% within 6 months of diagnosis of their breast cancer, and 28% more than 6 months from diagnosis. The timing of HRT and the diagnosis of breast cancer was unknown in 33%. Estrogen (most commonly, conjugated equine estrogen) alone was used by 74%, and 26% used a combination of estrogen and progestin. The median duration of use was 5 years (range, < 1 to 24 years). None of these patients continued HRT after their diagnosis of breast cancer. Three hundred forty-four women reported no history of HRT. The comparability of these two groups was assessed in terms of the clinical factors of age, race, weight, family history, age of menopause, method of detection and mammographic findings, and primary tumor size; the pathologic factors of histology, final margin status, histologic grade, pathologic nodal status, estrogen and progesterone receptor status; and the treatment-related factors of the use of re-excision, total dose to the primary site and region(s) treated with radiation, and the use of adjuvant systemic therapy. Statistical comparisons of categoric covariates were evaluated by Pearson's ² statistic or Fisher's exact test.^38,39 Distributions for continuous variables were compared using nonparametric Wilcoxon test.⁴⁰ All reported significance levels are based on two-sided tests.

Outcome results are presented in terms of ipsilateral breast tumor recurrence, regional node failure, distant metastases, cause-specific and overall survival, and contralateral breast cancer. An ipsilateral breast recurrence was defined as first site of failure in the treated breast with or without a simultaneous regional node failure but without distant metastases. An isolated regional node failure was defined as first site of failure in the ipsilateral axillary, internal mammary, or supraclavicular nodes without a simultaneous breast or distant failure. Estimates of ipsilateral breast tumor recurrence, regional node recurrence, distant failure, and contralateral breast cancer were made using the methodology of cumulative incidence, and comparisons were made with Gray's test.^41,42 Events for cause-specific survival included only deaths from breast cancer. Survival estimates were calculated using Kaplan-Meier methodology,⁴³ with time beginning at the initiation of radiation. Statistical comparisons between curves were evaluated using the log-rank test.⁴⁴ Statistically significant differences were conferred by P values .05. Results are presented at 5 and 10 years. For some subgroups, results are not reported at 10 years because of the small number of patients at risk.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Table 1 shows a comparison of clinical characteristics for the two groups. Significant differences were observed for clinical tumor size, median age, and median weight. Patients who reported a history of HRT had a statistically significant greater percentage of primary tumors 2 cm (77% v 66%; P = .02), a younger median age (60 v 64 years; P = .0009), and a lower median weight (142 lbs v 152 lbs; P = .004). There were no significant differences in race, family history, or median age of menopause. Of particular interest is the fact that women receiving HRT more often had their cancers detected by mammography alone (52% v 42%; P = .06). For patients with positive mammograms, the most common finding in both groups was the presence of a mass with or without associated calcifications (80% HRT v 84% no HRT; P = .54).

Table 2 presents a comparison of pathologic features for the two groups. There were no significant differences for any of the factors evaluated. The most common histology for both groups was an invasive ductal carcinoma with an associated ductal carcinoma in situ. However, the presence of an extensive intraductal component was uncommon and was found in only 5% of assessable patients without a history of HRT and 8% of the patients with a history of HRT. The HRT patients did not have a higher incidence of histologic grade 3 tumors or estrogen or progesterone receptor–negative tumors. Excluding the unknowns, 45% of the no-HRT patients had grade 3 tumors compared with 46% of the HRT patients. Estrogen and progesterone receptor–positive tumors were found in 82% and 65% of the no-HRT patients and 78% and 68% of the HRT patients, respectively. The majority of patients in both groups had negative axillary nodes (76% no HRT v 77% HRT; P = .94).

Table 3 presents a comparison of the treatment-related factors. Although the HRT patients more often underwent a re-excision (62% v 49%; P = .01), the final margin of resection was negative in 70% of the no-HRT patients and 76% of the HRT patients (P = .24). Seventeen percent of no-HRT patients received chemotherapy with or without tamoxifen, compared with 20% of the HRT patients. Tamoxifen alone was used by 31% of both groups. None of these differences was statistically significant. The majority of patients in both groups received radiation to the breast only (82% no HRT and 81% HRT; P = .71), and there were no significant differences in the median total dose to the primary site.

Table 4 presents patterns of failure. Statistically significant differences (P = .01) were observed for the two groups. Only seven patients (2%) had an ipsilateral breast tumor recurrence (with or without simultaneous distant failure) in the no-HRT group, compared with eight patients (5.6%) in the HRT group. The median interval to an ipsilateral breast tumor recurrence was 4 years for the HRT patients and 4.6 years for the no-HRT patients. Sixty-two percent of the recurrences in the HRT patients were in the vicinity of the primary tumor, compared with 80% in the no-HRT patients. A single patient in HRT group developed a recurrence that diffusely involved the breast. No patients in the HRT group experienced regional node failure, compared with five in the no-HRT group. Distant metastases as a first site of failure occurred in 13% of the no-HRT patients and 5% of the HRT patients. Distant metastases occurred in three of five no-HRT patients who experienced an initial isolated local failure, compared with two of eight HRT patients with an initial isolated local failure. Therefore, the total incidence of distant failure was 14% in no-HRT patients and 6% in the HRT patients. Patterns of first failure were not significantly different when comparing the timing of the HRT with the diagnosis of breast cancer; therefore, for subsequent analyses, these groups were combined.

Table 5 presents 5- and 10-year actuarial survival outcome. There were no significant differences between the two groups for overall or cause-specific survival for all patients, axillary node–negative patients, or axillary node–positive patients. Cause-specific survival at 10 years was slightly better for HRT patients (92% HRT v 85% no HRT; P = .07) and may be related to a higher proportion of T1 tumors in this group despite no differences in axillary node positivity between the two groups. Six percent of patients in both groups died from causes other than breast cancer.

Table 5 also presents the cumulative incidence of an ipsilateral breast tumor recurrence, regional node recurrence, distant metastasis, and contralateral breast cancer. Regional node recurrences were infrequent in both groups. Patients with a history of HRT had a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence at 10 years (8% v 2%; P = .02) and a statistically significant decreased rate of distant metastases (6% v 17%; P = .01), which was observed in both node-negative and node-positive patients but was only statistically significant in the node-negative group (P = .03). The cumulative incidence of contralateral breast cancer at 10 years was 9% in the no-HRT group and 6% in the HRT group (P = .38). Second non–breast cancer malignancies occurred in 13 (9%) of the HRT patients and 34 (10%) of the no-HRT patients. The distribution of these cancers was as follows: HRT patients: skin (n = 5), lung (n = 1), gastrointestinal (n = 0), gynecologic (n = 5), urologic (n = 1), and lymphoma (n = 1); non-HRT patients: skin (n = 15), lung (n = 1), gastrointestinal (n = 5), gynecologic (n = 2), urologic (n = 4), lymphoma (n = 1), carcinoid (n = 1), and leukemia (n = 1). The most common second non–breast cancer malignancy in both groups was a nonmelanoma skin cancer. There were no gastrointestinal malignancies in the HRT patients, and 38% of the second non–breast cancers in this group were gynecologic, compared with 6% in the no-HRT group.

Table 6 presents clinical, pathologic, and treatment-related factors assessed for their impact on the 5- and 10-year cumulative incidence of an ipsilateral breast tumor recurrence. The cumulative incidence of an ipsilateral breast tumor recurrence was significantly increased for all patients in the HRT group, for those whose disease was detected by mammography alone, for those who underwent re-excision, and for those with negative margins, negative axillary nodes, positive family history, and age 51 to 64 years. There were no breast recurrences in women younger than 50 years of age in either group. In the HRT group, axillary node–positive women and those with an extensive intraductal component had an increased breast recurrence rate when compared with similar patients in the no-HRT group, although the differences were not statistically significant. There were two breast recurrences in the eight HRT patients with an extensive intraductal component, and both had negative margins. The 10-year cumulative incidence of an ipsilateral breast tumor recurrence did not seem to be diminished by chemotherapy or tamoxifen in either group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present study found significant differences in the clinical characteristics of postmenopausal women with a history of HRT when compared with those without such a history. The HRT women were younger and had a lower median weight. In a population-based cohort study of 477 postmenopausal women with breast cancer from Finland, Holli et al⁴⁵ reported that HRT users were younger than nonusers (59 v 65 years), and Strickland et al²⁷ found that current users of HRT were significantly younger than nonusers who had a median age that was identical to past users. However, Magnusson et al⁴⁶ reported a mean age of 64 years for 121 HRT users with breast cancer compared with 62 years for 1,468 nonusers in Sweden. Hormone users without breast cancer have also been reported to be leaner than nonusers,^47,48 and the combination of younger age and lower body weight have contributed to the premise of a "healthy-user" effect, ie, healthier women are more often prescribed HRT.

The present study also found a marginally significant trend for early-stage invasive breast cancer in HRT users to be more frequently detected by mammography alone (52% v 42%; P = .06). Two studies^45,49 also demonstrated a higher proportion of cancers detected by mammography alone in women with a history of unopposed estrogen or a combination of estrogen and progesterone use. In a case control study of Swedish women matched for age, Persson et al³³ reported increased mammographic breast density in users of HRT and especially in women older than 50 years who were on a continuous combination regimen. The investigators concluded that the increased density could reduce the ability of mammography to detect small cancers in these women. Laya et al³⁵ reported a decreased sensitivity and specificity for mammographic screening in current users of ERT who were enrolled in a health maintenance organization breast cancer screening program in western Washington state. Wilson et al³⁶ reported no difference in the positive predictive value of mammographically detected breast cancer in 101 ERT users compared with 131 nonusers, despite the fact that 66% of the users and 43% of the nonusers (P = .0001) had dense or moderately dense breasts. In the present study, there were no significant differences in the mammographic findings for HRT users versus nonusers, with the primary indication of malignancy being a mass in both groups. Bonnier et al⁵⁰ found mammographic masses with or without calcifications in 80% of HRT users compared with 79% of nonusers. Calcifications alone were the sole finding in 20% of HRT users and 21% of nonusers.

Table 7 lists tumor-related characteristics for postmenopausal women, comparing HRT users with nonusers from several series. Four of six studies reported a higher percentage of primary invasive tumors 2 cm in HRT users,^45,46,51 and in the present study this difference was statistically significant. The smaller primary tumor size in HRT users correlated with increased mammographic detection in the present study, as well as that reported by Holli et al.⁴⁵ Unlike other investigators,^27,46,51 we observed no significant differences in the incidence of nodal positivity when comparing users with nonusers. Harding et al⁵² also reported no differences in nodal positivity between these two groups in a series of screen-detected breast cancers. Bonnier et al⁵⁰ reported a 39% nodal positivity rate in current HRT users and a 40% rate in nonusers. However, only 9% of the users had four or more positive nodes compared with 18% of the nonusers. Two additional studies reported that HRT users had a 7% rate of four or more positive nodes.^51,53 In the present study, 4% of HRT users had four or more positive nodes compared with 5% of nonusers. Several investigators reported a higher percentage of low-grade tumors in HRT users, a finding not confirmed in the present study, although one third of the patients had unknown histologic grade.^45,50,52,53 Squitieri et al⁵¹ and Holli et al⁴⁵ also reported lower S-phase fractions in HRT users, although differences in ploidy or DNA index have not been found. Similar to other investigators, we observed no significant differences in the estrogen or progesterone receptor status of users compared with nonusers.^{27,45,46,50-52} However, Lower et al⁵⁴ reported a higher mean estrogen and progesterone content in HRT users.

The present study is the first known series to report outcome in postmenopausal women with a history of HRT treated with conservative surgery and radiation. The majority of patients used unopposed conjugated estrogens, and the median duration of use was 5 years. We observed a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence at 10 years in HRT users (8% v 2%; P = .02). The increased cumulative incidence was statistically significant for women aged 51 to 64 years, those with a positive family history, those whose primary tumor was detected by mammography alone, those who underwent re-excision, and those with negative margins or negative axillary nodes. The addition of adjuvant tamoxifen or chemotherapy did not diminish the cumulative incidence of ipsilateral breast tumor recurrence in either the HRT users or nonusers. It should be emphasized that the 10-year 8% cumulative incidence of an ipsilateral breast tumor recurrence in HRT users, although statistically significantly different from that in nonusers, represents a rate that should not dissuade these women from choosing breast conservation therapy. In addition, the higher rate of ipsilateral breast tumor recurrence did not translate into a higher incidence of distant metastases or a decreased cause-specific survival. The 10-year cumulative incidence of distant metastases was statistically significantly lower in all HRT users and those with negative axillary nodes. The 5-year cumulative incidence of distant metastases was also lower in HRT users with positive axillary nodes, although the differences were not statistically significant. The lower rate of distant metastases in HRT users was observed in the absence of differences in the use of adjuvant systemic therapy or the number of positive nodes.

Several investigators have reported a decreased breast cancer mortality in postmenopausal women with a history of HRT.^19,20,27-32 Bergkvist et al³⁰ reported a statistically significant improvement in the 5- and 8-year relative survival of HRT patients in a cohort study from Sweden. The improvement was primarily noted in current users of HRT and in women 50 years and older. Yeun et al⁵⁵ reported an update of this population-based study with 12-year follow-up and continued to find no increased breast cancer mortality in these women. Magnusson et al⁴⁶ expanded the study population to include women registered from 1977 to 1991 and reported a nonsignificant decrease in breast cancer mortality in HRT users (16% v 21%; P > .05). Gambrell²⁸ reported a statistically significant decrease in breast cancer mortality in all HRT users and those with negative axillary nodes. The study population consisted of 256 postmenopausal women diagnosed with breast cancer at Wilford Hall United States Air Force Medical Center between 1972 and 1981. Eighty-four of these women had a history of HRT use (61 current users, 21 past users). Strickland et al²⁷ updated this series and reported a statistically significant improvement in median survival for current HRT users when compared with those who never used HRT that disappeared when stratified by stage. Willis et al²⁹ reported a 16% decrease in the risk of fatal breast cancer that was statistically significant in ERT users. The study was based on information obtained prospectively from postmenopausal participants in the Cancer Prevention Study II from 1982 to 1991. The decreased risk was greater in past users rather than current users and those who initiated ERT before the age of 40 years. The risk of fatal breast cancer was unrelated to duration of ERT use. Four additional series reported a nonsignificant decrease in breast cancer mortality in HRT users.^19,20,46,50 However, two reports from the Nurses' Health Study indicated an increased mortality from breast cancer in current users of primarily conjugated estrogens whose duration of use was more than 5²² or 10 years.²⁰ In the present study, HRT users had a non–statistically significant improvement in 5- and 10-year actuarial cause-specific survival that was observed in all patients and axillary node–negative patients.

Several explanations have been suggested for the possible beneficial effect of HRT on breast cancer mortality, including an increased awareness and use of screening programs in HRT users and the possible promotion of tumors with a more favorable biology. Arguments for increased screening are supported by the studies by Holli et al,⁴⁵ Bonnier et al,⁵⁰ and Colditz et al⁴⁹ and by the present study, in which a greater proportion of breast cancer in HRT users was detected by mammography alone when compared with nonusers. HRT users have been reported to have smaller primary tumors^45,51 and tumors of lower histologic grade with a lower S-phase fraction.^45,50-52 However, in the majority of reports,^45,49,50,52 including the present one, these favorable features have not resulted in a significantly lower incidence of positive axillary nodes. It seems that when controlling for stage, HRT users may have an outcome similar to that of nonusers,^27,52 and the smaller primary tumor size may account for the decreased mortality observed in some series for axillary node–negative women. There is uniform agreement that differences in estrogen and progesterone receptor status do not account for the improvement in breast cancer mortality in HRT users because HRT users do not seem to have a higher percentage of receptor-positive tumors.^{27,45,46,50-52}

An improvement in all-cause mortality for HRT users has been reported in several series.^19-21 In the current study, there was a trend for improvement in 10-year actuarial overall survival for all HRT users and for axillary node–negative and –positive HRT users. However, a similar percentage (6%) of deaths in both groups were from causes other than breast cancer. A possible healthy-user effect was observed in women with a history of HRT in that they were younger and had a lower body weight at the time of diagnosis. There was no increased incidence of contralateral breast cancer in HRT users, and 37% of nonusers received tamoxifen with or without chemotherapy compared with 42% of HRT users. Second non–breast cancer malignancies were reported in 9% of the HRT users compared with 10% of the nonusers. Of note is the absence of gastrointestinal malignancies in the HRT users. Several recent reports indicated a decreased risk of colon cancer in HRT users.^56-58

In summary, we have not identified an adverse effect of HRT on breast cancer mortality in this group of postmenopausal women treated with conservative surgery and radiation. HRT users had primary tumors that were significantly smaller than those of nonusers, although there were no significant differences in their pathologic axillary nodal status, histologic grade, or estrogen or progesterone receptor status. A greater percentage of HRT users had their disease detected by mammography alone, with the cancer primarily manifesting as a mass with or without calcifications. These findings suggest that changes in parenchymal breast density associated with postmenopausal HRT did not preclude the early detection of breast cancer. The use of HRT was associated with a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence, although the magnitude of this risk was only 8% at 10 years. HRT was not associated with an increased risk of contralateral breast cancer or second non–breast cancer malignancy. A possible protective benefit for colon cancer was observed. It is hoped that these findings may allay some of the concerns regarding breast cancer that develops in postmenopausal women who take HRT.

	NOTES

 
Presented at the 40th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Phoenix, AZ, October 28, 1998.

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Submitted November 23, 1998; accepted February 8, 1999.

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