ANTIHISTAMINE FOR USE IN TREATMENT OF BREAST CANCER

Abstract

Disclosed herein is desloratadine or ebastin for use in treatment of a patient diagnosed with breast cancer. Also disclosed is desloratadine or ebastin for use in treatment of a patient diagnosed with a cancer type susceptible to immunotherapy.

Claims

1. A method of treating breast cancer in a patient, the method comprising administering to the patient an effective amount of desloratadine or ebastin.

2. The method of claim 1, wherein the breast cancer is selected from the group consisting of positive and negative ER, PR, her2 breast cancer molecular subtypes, and invasive breast carcinomas.

3. The method of claim 1, wherein the breast cancer is selected from the group consisting of positive and negative ER invasive breast carcinomas.

4. The method of claim 1, wherein the treatment is continuous for at least 50 days.

5. The method of claim 1, wherein said treatment seeks to improve the prognosis for the patient diagnosed with breast cancer.

6. The method of claim 1, wherein said treatment seeks to increase the survival time for the patient diagnosed with breast cancer.

7. The method of claim 1, wherein the daily dose of the desloratadine or ebastin corresponds to the defined daily dose (DDD).

8. The method of claim 1, wherein the dose of the desloratadine is between 2.5 to 45 mg per day.

9. The method of claim 1, wherein the dose of the desloratadine is between 45 to 250 mg per day.

10. The method of claim 1, wherein the dose of the ebastin is between 2.5 to 100 mg per day.

11. The method of claim 1, wherein the dose of the ebastin is between 100 to 500 mg per day.

12. The method of claim 1, wherein the patient is not diagnosed with a seasonal allergic condition.

13. The method of claim 1, wherein the patient is perioperational.

14. The method of claim 1, wherein the patient further is treated with radiotherapy, chemotherapy and/or hormonal treatment.

15. A method of treating cancer of a type susceptible to immunotherapy in a patient, the method comprising administering to the patient an effective amount of desloratadine or ebastin.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0067] These and other aspects, features and advantages of which the invention is capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which

[0068] FIG. 1 is a graph showing breast cancer survival according to ever-use of antihistamines for allergic purposes.

[0069] FIG. 2 is a graph showing breast cancer survival according to ever-use of antihistamines of Cetirizine, Klemastine and Loratadine.

[0070] FIG. 3 is a graph showing breast cancer survival according to ever-use of antihistamines of Desloratadine, Ebastin and Fexofenadine.

[0071] FIG. 4 is a graph showing breast cancer survival according to ever-use of antihistamines of Cetirizine, Klemastine and Loratadine in a late entry model.

[0072] FIG. 5 is a graph showing breast cancer survival according to ever-use of antihistamines of Desloratadine, Ebastin and Fexofenadine in a late entry model.

[0073] FIG. 6 is a graph showing breast cancer survival according to duration of use of desloratadine in a late entry model; and

[0074] FIG. 7 is a graph showing breast cancer survival according to when the women used desloratadine in a late entry model.

[0075] A cohort consisting of all Swedish women, without a previous cancer, diagnosed with BC from 2000 through 2008 was used. The study was approved by an ethical board in Sweden. Date of birth, date of BC diagnosis and TNM-stage was gathered from the Swedish Cancer Registry. The women's pharmaceutical records with start from the 1st of July 2005 were gathered from the Swedish Pharmaceutical Register. Date of death was gathered from the Swedish Population Register up until the 31st of December 2013. Cause of death was also gathered from the Swedish Population Register, but was only available up to 31st of December 2012. Women over 50 years of age at BC diagnosis were considered postmenopausal, whereas women under 50 were considered premenopausal. A group consisted of all women with a prescription of antihistamines for allergic purposes were created, and then also split into group according to which antihistamine that had been used the most. The control group consisted of all women without a prescription of an antihistamine for allergic purposes. In the ever-use model, all women who have had a prescription of antihistamines in the Swedish Pharmaceutical Register from the 1st of July 2005 are included.

[0076] The stages of breast cancer is described using the American Joint Committee on Cancer (AJCC) TNM system. The TNM staging system classifies cancers based on their T, N, and M stages:

[0077] The letter T followed by a number from 0 to 4 describes the tumor's size and spread to the skin or to the chest wall under the breast. Higher T numbers mean a larger tumor and/or wider spread to tissues near the breast.

[0078] The letter N followed by a number from 0 to 3 indicates whether the cancer has spread to lymph nodes near the breast and, if so, how many lymph nodes are affected.

[0079] The letter M followed by a 0 or 1 indicates whether the cancer has spread to distant organs—for example, the lungs or bones.

[0080] The T-stage data was recoded into a variable set from 1 to 5, where 1-4 corresponded to the reported T-stage and for 5 missing T-stage. The N-stage data was recoded into a variable set from 0 to 4, where 0-3 corresponded to the reported N-stage and 4 for missing N-stage. M-stage was recoded into a variable of either 0 and 2, where 0 corresponded to the reported 0 M-stage and 2 missing M-stage. All this data came from the Swedish Cancer Registry.

[0081] Since ever-use of antihistamines for allergic purposes was investigated, the majority of the users bought their prescribed antihistamines after BC diagnosis. It was decided to look at survival and hazard in two ways—by dividing the groups according to ever-use and secondly by using a late entry model to reduce the survival bias in the first model. In the late entry model all women with unknown N-status and all cases before 1st of July 2005 was excluded to get a more precise result.

[0082] Using an extended breast cancer material of all cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) linking the data with the Drug Prescription Registry a replication study was carried out. The data from this extended study are represented in tables 10 and 11.

[0083] Statistics

[0084] Statistical analyses were performed using IBM SPSS 22.0 and R studio v 0.98.983.

[0085] Univariate BC specific survival was estimated using Kaplan-Meier for a group combined of all antihistamine users and for each specific antihistamine group. The distribution was tested using the Log-rank test.

[0086] Hazard Ratios (HR) were calculated using cox proportional hazard. HR was calculated for each group of antihistamine users and adjustments were made for age at BC diagnosis (linear), T-stage (T1, T2, T3, T4, Missing), N-stage (N0, N1, N2, N3, Missing), M-stage (M0, M1, Missing). The multivariate analysis was also stratified for ER-status. HR were estimated with 95% confidence intervals (CI). Two-tailed p-values were used for all analyses. A p-value of less than 0.05 was regarded as statistically significant.

[0087] The late entry cox proportional hazard analyses done in R studio, HR was calculated for each group of antihistamine users and adjustments were made for age at BC diagnosis (linear), T-stage (T1, T2, T3, T4, Missing) and N-stage (N0, N1+). This analysis was also stratified for ER-status. HR were estimated with 97.5% confidence intervals (CI). Two-tailed p-values were used for all analyses. A p-value of less than 0.05 was regarded as statistically significant.

[0088] Results

[0089] This study included 47350 women with invasive BC. Patient characteristics can be seen in table 1. 18724 were included after 1st of July 2005, when the Swedish Pharmaceutical Register began. Their patient characteristics can be seen in table 2. A replication study including of all BC cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) is shown in table 10.

TABLE-US-00001 TABLE 1 Patient characteristics for women with divided into groups according to their main antihistamine used. The table includes all patients from 2000-2008. Main antihistamine No AH Cetirizine Klemastine Loratadine Desloratadine Ebastin Fexofenadine 37573 3001 2278 2132 1895 326 145 Age at BC Mean 64.25 58.33 61.15 59.12 58.36 58.28 58.38 diagnosis Follow-up Mean 6.79 7.31 7.39 7.48 7.90 7.88 7.63 in years Dead in BC Yes 20.2% 18.0% 13.8% 11.7% 7.1% 6.7% 9.0% Menopause Yes 82.6% 71.3% 79.1% 75.7% 74.6% 72.1% 73.8% at BC diagnosis T stage 1 32.0% 34.3% 36.1% 36.6% 41.4% 38.7% 31.7% 2 20.2% 23.1% 21.8% 23.3% 18.6% 21.2% 24.1% 3 3.1% 4.1% 4.0% 4.4% 2.7% 2.5% 3.4% 4 2.3% 1.6% 1.4% 1.4% .8% .9% 2.1% Missing 42.4% 36.9% 36.7% 34.3% 36.4% 36.8% 38.6% N stage 0 37.3% 40.3% 42.4% 45.5% 46.8% 49.4% 40.0% 1 16.2% 19.5% 18.7% 18.9% 15.5% 13.2% 18.6% 2 .6% 1.1% 1.0% 1.0% .3% .6% .7% 3 .3% .5% .3% .2% .2% 0.0% 1.4% Missing 45.6% 38.6% 37.6% 34.3% 37.4% 36.8% 39.3% M stage 0 43.4% 46.0% 49.1% 54.8% 52.2% 51.2% 48.3% 1 1.9% 1.6% 1.3% .8% .8% 0.0% 1.4% Missing 54.7% 52.4% 49.6% 44.4% 47.0% 48.8% 50.3%

TABLE-US-00002 TABLE 2 Patient characteristics for women with divided into groups according to their main antihistamine used. The table includes all patients from 1st of Jul. 2005-31st of Dec. 2008. Main antihistamine No AH Cetirizine Klemastine Loratadine Desloratadine Ebastin Fexofenadine 14192 1392 1034 1038 859 140 69 Age at BC Mean 64.62 58.99 61.57 59.36 59.34 57.92 58.83 diagnosis Follow-up Mean 5.00 5.17 5.13 5.46 5.48 5.54 5.20 in years Dead in BC Yes 15.4% 16.5% 14.3% 10.4% 8.1% 5.7% 11.6% Menopause Yes 82.5% 71.8% 77.5% 75.3% 74.5% 70.7% 73.9% at BC diagnosis T stage 1 47.1% 43.4% 47.0% 46.0% 56.8% 52.9% 44.9% 2 29.7% 32.9% 31.4% 31.5% 25.0% 31.4% 30.4% 3 4.4% 5.5% 6.1% 6.2% 3.7% 2.1% 5.8% 4 3.3% 2.5% 2.0% 1.4% .9% 1.4% 2.9% Missing 15.5% 15.7% 13.4% 14.9% 13.5% 12.1% 15.9% N stage 0 55.1% 54.1% 56.8% 56.6% 61.8% 65.0% 50.7% 1 20.8% 24.8% 23.5% 25.2% 20.1% 19.3% 24.6% 2 1.2% 1.8% 2.1% 1.3% .6% 1.4% 1.4% 3 .5% 1.1% .3% .3% .2% 0.0% 2.9% Missing 22.4% 18.2% 17.3% 16.6% 17.2% 14.3% 20.3% M stage 0 61.4% 60.3% 65.3% 69.2% 67.6% 71.4% 59.4% 1 2.7% 1.8% 2.0% .6% 1.3% 0.0% 1.4% Missing 35.9% 37.9% 32.7% 30.3% 31.1% 28.6% 39.1%

[0090] Ever-Use Model

[0091] FIG. 1 shows the breast cancer survival according to ever-use of antihistamines for allergic purposes. N=9777 in the No AH group and N=37573 in the AH group.

[0092] Univariate Analyses

[0093] Women using a H1 receptor antihistamine of any kind had a statistically significant longer BC specific survival, compared to controls. (FIG. 1) Women using klemastine, loratadine, desloratadine, ebastin and fexofenadine had a statistically significant longer BC specific survival, compared to controls. Women using cetirizine initially had a higher survival percentage compared to controls, but with time it became lower compared to controls. (FIGS. 2 and 3). FIG. 2 shows the breast cancer survival according to ever-use of antihistamines of Cetirizine, Klemastine and Loratadine. N=37573 in the No AH group, N=3001 in the Cetirizine group, N=2278 in the Klemastine group and N=2132 in the Loratadine group. FIG. 3 shows the breast cancer survival according to ever-use of antihistamines of Desloratadine, Ebastin and Fexofenadine. N=37573 in the No AH group, N=1895 in the Desloratadine group, N=326 in the Ebastin group and N=145 in the Fexofenadine group.

[0094] Multivariate Analyses

[0095] The HR for the combined group of antihistamine users adjusted for age at BC diagnosis and TNM was 0.70 (0.66-0.75) (Table 3).

TABLE-US-00003 TABLE 3 Cox proportional harzard Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .037 .001 2005.719 1 0.000 1.037 1.036 1.039 T1 1331.374 4 .000 Ref T2 .945 .037 656.457 1 .000 2.573 2.393 2.766 T3 1.478 .052 814.214 1 .000 4.384 3.961 4.852 T4 1.579 .056 803.066 1 .000 4.848 4.347 5.407 T missing .412 .044 87.816 1 .000 1.509 1.385 1.645 N0 687.278 4 .000 Ref N1 .837 .034 597.630 1 .000 2.310 2.160 2.471 N2 .962 .088 118.202 1 .000 2.616 2.200 3.112 N3 1.011 .118 73.029 1 .000 2.748 2.179 3.465 N missing .853 .043 385.863 1 .000 2.347 2.155 2.555 M0 1030.324 2 .000 Ref M1 1.514 .050 933.373 1 .000 4.546 4.125 5.009 M missing −.021 .033 .377 1 .539 .980 .918 1.046 Antihistamine use −.353 .031 133.427 1 .000 .702 .661 .746

[0096] Hazard ratios for women with ever-use of antihistamines compared to controls adjusted for age at breast cancer diagnosis and TNM-stage.

[0097] Table 4 shows HR for each group of antihistamine users adjusted for age at BC diagnosis and TNM. Women using desloratadine had a HR of 0.41 (0.35-0.49). Loratadine users had a HR of 0.64 (0.56-0.72). Cetirizine users had a HR of 0.97 (0.89-1.06) and Klemastine users had a HR of 0.69 (0.62-0.77). Ebastin users had a HR of 0.40 (0.27-0.61) and Fexofenadine users had a HR of 0.49 (0.29-0.85).

TABLE-US-00004 TABLE 4 Cox proportional harzard Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .037 .001 2009.883 1 0.000 1.037 1.036 1.039 T1 1322.645 4 .000 Ref T2 .940 .037 649.372 1 .000 2.561 2.382 2.753 T3 1.473 .052 808.650 1 .000 4.364 3.943 4.831 T4 1.579 .056 805.349 1 .000 4.850 4.349 5.409 T missing .416 .044 89.433 1 .000 1.515 1.390 1.651 N0 678.184 4 .000 Ref N1 .832 .034 589.279 1 .000 2.298 2.148 2.457 N2 .958 .088 117.541 1 .000 2.607 2.192 3.099 N3 .995 .118 70.861 1 .000 2.706 2.146 3.411 N missing .849 .043 381.777 1 .000 2.337 2.146 2.545 M0 1030.468 2 .000 Ref M1 1.508 .049 929.330 1 .000 4.517 4.100 4.977 M missing −.028 .033 .694 1 .405 .973 .911 1.038 No antihistamine 206.497 6 .000 Ref Cetirizine −.030 .045 .447 1 .504 .970 .889 1.060 Klemastine −.371 .058 41.580 1 .000 .690 .616 .772 Loratadine −.453 .065 49.183 1 .000 .636 .560 .722 Desloratadine −.889 .087 104.341 1 .000 .411 .347 .488 Ebastine −.907 .214 18.047 1 .000 .404 .266 .613 Fexofenadine −.709 .278 6.520 1 .011 .492 .286 .848

[0098] Hazard ratios for women with ever-use of 6 different antihistamines compared to controls adjusted for age at breast cancer diagnosis and TNM-stage.

[0099] Late Entry Model

[0100] Univariate Analyses

[0101] Women using, loratadine, desloratadine and ebastin had a statistically significant longer BC specific survival, compared to controls. Women using cetirizine, klemastine and fexofenadine had a non-statistically significant longer BC specific survival compared to controls (FIGS. 4 and 5). FIG. 4. Breast cancer survival according to ever-use of antihistamines of Cetirizine, Klemastine and Loratadine in a late entry model. All cases before 1st of July 2005 and all women with unknown N-status have been censored. N=14192 in the No AH group, N=2298 in the Cetirizine group, N=1777 in the Klemastine group and N=1745 in the Loratadine group. FIG. 5. Breast cancer survival according to ever-use of antihistamines of Desloratadine, Ebastin and Fexofenadine in a late entry model. All cases before 1st of July 2005 and all women with unknown N-status have been censored. N=14192 in the No AH group, N=1338 in the Desloratadine group, N=205 in the Ebastin group and N=97 in the Fexofenadine group.

[0102] Multivariate Analyses

[0103] Table 5 shows HR for each group of antihistamine users adjusted for age at BC diagnosis and TN. Women using desloratadine had a HR of 0.69 (0.52-0.91). Loratadine users had a HR of 0.74 (0.60-0.93). Cetirizine users had a HR of 1.13 (0.96-1.33) and Klemastine users had a HR of 0.98 (0.80-1.19). Ebastin users had a HR of 0.50 (0.22-1.12) and Fexofenadine users had a HR of 0.73 (0.30-1.76). This analysis was also stratified for ER-status, but the results did not differ noticeably (data not shown).

TABLE-US-00005 TABLE 5 Cox proportional harzard - late entry model Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .034 .002 358.809 1 .000 1.034 1.031 1.038 T1 536.967 4 .000 T2 1.074 .062 295.987 1 .000 2.927 2.590 3.308 T3 1.732 .084 426.138 1 .000 5.651 4.794 6.660 T4 1.759 .098 320.958 1 .000 5.807 4.790 7.039 T missing .825 .173 22.794 1 .000 2.283 1.627 3.204 N0 215.445 3 .000 N1 .736 .053 194.105 1 .000 2.087 1.882 2.315 N2 .910 .111 66.769 1 .000 2.483 1.997 3.089 N3 1.054 .154 46.672 1 .000 2.870 2.121 3.883 M0 361.237 2 .000 M1 1.605 .086 347.594 1 .000 4.976 4.204 5.890 M missing −.006 .059 .012 1 .912 .994 .885 1.115 No antihistamine 17.485 6 .008 Cetirizine .178 .084 4.506 1 .034 1.194 1.014 1.407 Klemastine .000 .100 .000 1 .996 1.000 .821 1.217 Loratadine −.203 .112 3.310 1 .069 .816 .655 1.016 Desloratadine −.354 .143 6.138 1 .013 .702 .530 .929 Ebastine −.615 .410 2.255 1 .133 .541 .242 1.207 Fexofenadine −.220 .448 .241 1 .624 .802 .333 1.932

[0104] Hazard ratios for women with ever-use of 6 groups of antihistamines compared to controls adjusted for age at breast cancer diagnosis and TN-stage. All cases before 1st of July 2005 and all women with unknown N-status have been censored.

TABLE-US-00006 TABLE 6 Cox proportional harzard - late entry model. Hazard ratios for women according to duration of use of desloratadine, adjusted for age at breast cancer diagnosis and TN-stage. Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .036 .001 1337.898 1 .000 1.036 1.034 1.038 T1 2057.966 5 0.000 1.000 T2 .949 .040 569.204 1 .000 2.582 2.389 2.791 T3 1.550 .056 756.783 1 .000 4.710 4.218 5.260 T4 1.924 .059 1066.933 1 .000 6.846 6.100 7.684 Tis −.962 .081 141.377 1 .000 .382 .326 .448 T missing .121 .049 6.042 1 .014 1.128 1.025 1.242 NO 683.655 4 .000 1.000 N1 .833 .037 514.688 1 .000 2.299 2.140 2.471 N2 1.146 .095 145.253 1 .000 3.145 2.610 3.789 N3 1.355 .130 109.057 1 .000 3.876 3.006 4.998 N missing .834 .044 363.880 1 .000 2.301 2.113 2.507 Never desloratadine 7.089 2 .029 1.000 Over 400 days desloratadine −.473 .183 6.671 1 .010 .623 .435 .892 Less than 400 days desloratadine −.059 .087 .457 1 .499 .943 .795 1.118

TABLE-US-00007 TABLE 7 Cox proportional harzard - late entry model. Hazard ratios for women according to when women used desloratadine, adjusted for age at breast cancer diagnosis and TN-stage. Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .036 .001 1338.520 1 .000 1.036 1.034 1.038 T1 2057.946 5 0.000 1.000 T2 .949 .040 569.371 1 .000 2.582 2.389 2.792 T3 1.551 .056 757.728 1 .000 4.715 4.222 5.265 T4 1.924 .059 1067.598 1 .000 6.851 6.104 7.689 Tis −.962 .081 141.279 1 .000 .382 .326 .448 T missing .122 .049 6.202 1 .013 1.130 1.026 1.244 N0 683.819 4 .000 1.000 N1 .833 .037 514.852 1 .000 2.300 2.140 2.471 N2 1.143 .095 144.258 1 .000 3.135 2.601 3.777 N3 1.356 .130 109.190 1 .000 3.880 3.009 5.003 N missing .835 .044 364.620 1 .000 2.304 2.115 2.510 Never desloratadine 6.983 3 .072 1.000 Desloratadine before .200 .186 1.148 1 .284 1.221 .847 1.760 diagnosis Desloratadine after −.204 .092 4.979 1 .026 .815 .681 .975 diagnosis Desloratadine before and −.235 .259 .828 1 .363 .790 .476 1.312 after diagnosis

TABLE-US-00008 TABLE 8 ER Negative Breast Cancer - late entry model. Hazard ratios for women according to breast cancer ER molecular subtype, adjusted for age at breast cancer diagnosis and TN-stage. Women using desloratadine had a HR of 0.60 (0.45-0.81). Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .027 .002 277.120 1 .000 1.028 1.025 1.031 Tconv 766.748 4 .000 Tconv(1) 1.271 .072 311.734 1 .000 3.564 3.095 4.103 TconV(2) 1.737 .096 326.802 1 .000 5.678 4.704 6.855 Tconv(3) 2.217 .101 482.971 1 .000 9.178 7.531 11.184 Tconv(4) .009 .090 .009 1 .924 1.009 .845 1.204 Nconv 326.017 4 .000 Nconv(1) 1.131 .066 296.048 1 .000 3.100 2.725 3.526 NconV(2) 1.359 .147 85.344 1 .000 3.892 2.917 5.192 Nconv(3) 1.472 .207 50.761 1 .000 4.356 2.906 6.530 Nconv(4) .714 .083 74.026 1 .000 2.041 1.735 2.402 Cetirizin .400 .078 25.949 1 .000 1.491 1.279 1.739 Klemaslin .246 .094 6.835 1 .009 1.279 1.064 1.539 Loraladin −.057 .103 .304 1 .581 .945 .773 1.156 Desloratadin −.506 .147 11.777 1 .001 .603 .451 .805 Ebastin −.219 .291 .566 1 .452 .804 .454 1.421 Fexofenadin −1.153 .579 3.967 1 .046 .316 .102 .982

TABLE-US-00009 TABLE 9 ER Positive Breast Cancer - late entry model. Hazard ratios for women according to breast cancer ER molecular subtype, adjusted for age at breast cancer diagnosis and TN- stage. Women using desloratadine had a HR of 0.62 (0.51-0.75). Variables in the Equation 95.0% CI for Exp(B) B SE Wald df Sig. Exp(B) Lower Upper Age at BC diagnosis .039 .001 1074.232 1 .000 1.040 1.038 1.042 Tconv 916.224 4 .000 Tconv(1) .812 .047 302.089 1 .000 2.252 2.055 2.468 TconV(2) 1.405 .068 427.535 1 .000 4.076 3.567 4.656 Tconv(3) 1.741 .071 594.017 1 .000 5.705 4.960 6.563 Tconv(4) .218 .059 13.590 1 .000 1.244 1.108 1.397 Nconv 477.143 4 .000 Nconv(1) .769 .044 302.308 1 .000 2.157 1.978 2.352 NconV(2) 1.139 .117 95.226 1 .000 3.123 2.484 3.925 Nconv(3) 1.415 .156 81.835 1 .000 4.117 3.030 5.594 Nconv(4) .982 .054 332.528 1 .000 2.669 2.402 2.966 Cetirizin .773 .054 205.458 1 .000 2.166 1.949 2.407 Klemaslin .420 .062 45.177 1 .000 1.521 1.346 1.719 Loratadin .084 .076 1.222 1 ..269 1.087 .937 1.262 Desloratadin −.484 .098 24.490 1 .000 .616 .509 .747 Ebastin −.594 .237 6.268 1 .012 .552 .347 .879 Fexofenadin −.191 .290 .431 1 .511 .826 .468 1.460

[0105] Using an extended breast cancer material of all cases from the Swedish Cancer Registry 2000-2013 (n=103 500 cases) linking the data with the Drug Prescription Registry, a replication study was carried out, as shown in table 10. Due to the large number of cases, a higher resolution is achieved, confirming the better overall and BC specific survival for users of desloratadine or ebastin compared with non-users.

TABLE-US-00010 TABLE 10 Breast cancer survival and overall survival adjusted for age and divided into two time periods 2005-2008 and 2009- 2013. Use of different antihistamines after diagnosis in relation to tumour stage. Late entry models. Breast cancer survival Overall survival 95% confidence 95% confidence HR interval HR interval Survival 2005-2008 Stage 1 1.0 1.0 Stage 2 4.98 3.57-6.95 3.37 2.70-4.22 Stage 3 12.76  9.00-18.07 6.82 5.34-8.72 Stage 4 45.93 32.20-63.52 22.55 18.07-28.14 Cetirizine 1.08 0.81-1.44 1.41 1.15-1.74 Clemastine 1.43 1.09-1.87 2.07 1.72-2.49 Loratadine 0.77 0.54-1.14 1.05 0.80-1.37 Desloratadine 0.47 0.28-0.79 0.47 0.31-0.72 Ebastin 0.25 0.04-1.80 0.48 0.16-1.51 Fexofenadine 1.20 0.39-3.75 1.40 0.58-3.37 Survival 2009-2014 Stage 1 1.0 1.0 Stage 2 3.60 3.16-4.11 2.36 2.17-2.59 Stage 3 8.63 7.46-9.99 4.82 4.34-5.3  Stage 4 35.37 30.68-40.77 15.97 14.34-17.78 Cetirizine 1.21 1.06-1.39 1.09 0.97-1.22 Clemastine 0.94 0.80-1.10 1.08 0.96-1.21 Loratadine 0.93 0.78-1.11 0.86 0.75-0.99 Desloratadine 0.74 0.60-0.91 0.71 0.61-0.84 Ebastin 0.75 0.46-1.23 0.91 0.65-1.27 Fexofenadine 0.85 0.40-1.78 0.65 0.34-1.25

[0106] Looking at the years before 2009 the survival is greatly improved for desloratadine users compared with non users HR=0.63. The overall effect for better breast cancer survival with desloratadine is summarized in table 11. It is also of great interest to note that cetirizine and clemastine negatively affects survival.

TABLE-US-00011 TABLE 11 Summary of breast cancer survival at use of desloratadine for one year (late entry model). Desloratadine use N HR 95% CI ≧400 days 597 0.62 0.44-0.89  <400 days 2030 0.94 0.80-1.10 Never 51779 1.00