IJC International Journal of Cancer

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1 IJC International Journal of Cancer Breast cancer incidence trends in Norway explained by hormone therapy or mammographic screening? Solveig Hofvind 1,2, Solveig Sakshaug 3, Giske Ursin 1,4,5 and Sidsel Graff-Iversen 3,6 1 Cancer Registry of Norway, N-0310 Oslo, Norway 2 Oslo University College, Faculty of Health Science, N-0130 Oslo, Norway 3 Division of, Norwegian Institute of Public Health, N-0473 Oslo, Norway 4 Department of Nutrition, University of Oslo, N-0317 Oslo, Norway 5 Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 6 Institute for Community Medicine, University of Tromsø, N-9037 Tromsø, Norway A decline in breast cancer incidence has been observed in several countries after Reduced use of menopausal hormonal therapy (HT), as a consequence of the publication of results from the Women s Health Initiative, has been argued to be the main reason. In Norway, the governmentally funded Norwegian Breast Cancer Screening Program (NBCSP) was implemented during the same time period as the increased use of HT. This study investigated trends in breast cancer incidence by use of HT and introduction of the screening program. We obtained rates of breast cancer from the Cancer Registry of Norway and sales data of HT preparations from the Norwegian Institute of Public Health. Mammography rates were estimated from published reports. Breast cancer incidence rates increased steadily from 1956 to the end of the 20th century, particularly in women aged during residing in the counties where the NBCSP was first introduced. The rates declined after HT use increased in , peaking around year In particular, sales of combined estrogen and progestogen preparations declined after Among women aged 55 59, rates of hormone receptor positive breast cancers peaked in No such trend was seen in other age groups. In conclusion, the interpretation of breast cancer incidence trends in Norway from 1987 to 2009 is complicated because the NBCSP was introduced during a period with increasing HT use. Both factors likely contributed to the observed trends, and the role of each may vary across age groups. After decades with increased breast cancer incidence, 1 a decline has been observed in several countries after Reduced use of menopausal hormonal therapy (HT), as a consequence of the publication of results from the Women s Health Initiative (WHI) 13 has been argued to be the main reason for the declined incidence. Observational epidemiological studies as well as randomized clinical trials have consistently demonstrated that HT with combined estrogen and progestogen therapy (EPT) increases the risk of breast cancer Despite this evidence, HT use continued to increase until results from the WHI trial revealed a substantial increased risk of breast cancer, stroke and thrombotic events by use of EPT, and did not confirm any cardiovascular benefit. 13 The publication of these results resulted in a drop in sale of HT preparations in the Key words: breast cancer, incidence, hormone therapy, mammographic screening, Norway DOI: /ijc History: Received 5 Apr 2011; Accepted 16 Jun 2011; Online 5 Jul 2011 Correspondence to: Solveig Hofvind, Cancer Registry of Norway, Postbox 5313 Majorstua, N-0304 Oslo, Norway, solveig.hofvind@kreftregisteret.no United States (US), 2 5 as well as in Europe, 7 12 including Norway. 28,29 Several studies have reported a decline in breast cancer incidence as a result of the reduced HT use Scandinavian EPT users have been found to have higher risk of breast cancer than their American counterparts. 17,30,31 The higher risk could be due to use of EPT preparations containing different estrogens and progestogens than in the US. 32,33 It has also been argued that Scandinavian women for a long time used relatively high dose continuous EPT, which may also have contributed to this difference. 32 Thus, one would expect the drop in EPT use to have a stronger effect on breast cancer rates in Scandinavia than in other countries. It has also been suggested that the reduced use of mammography may be partially responsible for the decline in breast cancer incidence observed worldwide after ,5 However, the reduced use has not been large enough to explain the entire decrease in breast cancer incidence. 4,5,34,35 In Norway, there has been no decline in mammography use since Contrary, the governmentally funded Norwegian Breast Cancer Screening Program (NBCSP) was slowly introduced over a 9-year period from The program targets women aged Given the particular characteristics in Norway with first increased use of high dose EPTs in the 1990s, and subsequently both a decline in use and marked changes in dose, combined with increased mammographic screening over time, as well as the availability of high quality population-

2 Hofvind et al based registries, we decided to conduct an ecological study to describe breast cancer rates over time and determine how they correlate with use of EPT and mammography. Material and Methods Breast cancer incidence Data on breast cancer incidence were obtained from the population-based Cancer Registry of Norway. The Registry was established in 1951, and cancer has been a reportable disease by law since The incidence database used for this study covers more than 98% of all cases. 37 We included data on all invasive breast cancers diagnosed in Norwegian women during the period Nationwide age standardized incidence rates were computed using a direct method with the Norwegian female population as of January 1981 as the standard. All rates are provided per 100,000 women-years (/100,000) in the age groups 25 39, 40 49, 50 59, 60 69, and 80þ years for We also present crude incidence rates in five year age groups (45 49, 50 54, 55 59, 60 64, and years) for the whole country, as well as for the first four counties in the NBCSP (Akershus, Hordaland, Oslo and Rogaland; pilot counties), and the rest of the counties (15 counties; non-pilot counties). The pilot counties represented about 40% of the female population aged in Norway when the program started in NBCSP was expanded to the non-pilot counties later (September 1999 to February 2004) and the NBCSP became nationwide during We conducted log-linear joinpoint regressions using the weighted least squares method ( joinpoint/). Hormone receptor status was available for screen-detected breast cancers diagnosed in the NBCSP. We estimated incidence rates of estrogen- and progesterone receptor positive (ERþPRþ) and negative (ER PR ) tumors per 100,000 women estimated to have been screened in NBCSP Data were obtained from the NBCSP database at the Cancer Registry, where results on hormone receptor status was extracted from pathology reports. Hormone receptor status was determined by immunohistochemistry assays during this time period and the cut point defining positive hormone receptor status was 10%. 38 Hormone therapy We obtained data on sale of HT preparations from two nationwide databases at the Norwegian Institute of Public Health: (i) The Norwegian Drug Wholesales statistics ( and (ii) the Norwegian Prescription Database ( The Drug Wholesales database was established in the 1970s, while the Prescription database includes data from Data from the Drug Wholesales database were used to study the long-term trend in sale of HT preparations. This database includes the total annual sale of both prescription medications and non-prescription medications. All medications in Norway are classified according to the Anatomical Therapeutic Chemical (ATC) classification system and the defined daily dose (DDD) is linked to each medicine ( The annual sale of HT preparations was provided as number of defined daily doses (DDDs). DDDs per 1000 women per day was calculated to represent a surrogate estimate of the rate of daily users assuming that the dose consumed is equal to the DDD. From the wholesale statistics, we retrieved data on total sale of ET and EPT (ATC groups G03C and G03F, respectively) in the period The Norwegian Prescription Database includes information from all dispensed prescriptions in Norway on an individual level (encrypted data). The prescription data was used to study the prevalence (percentage) of women using HT, aged 45 49, 50 54, 55 59, 60 64, and years. The data were provided for Norway overall, the pilot counties and the non-pilot counties. We retrieved data on the number of women (users) who had at least one prescription dispensed of ET or EPT preparations during a year for the period One year prevalence was defined as number of HT users per 1000 women in the selected population. ET preparations used for treatment of postmenopausal vaginal atrophy only (i.e., all preparations with estriol and formulations for vaginal application) were excluded since these formulations are available both with and without prescriptions, and inclusion of prescription products only, would be misleading. Mammography Information about the use of mammography was obtained from published sources Mammography performed outside the NBCSP is not registered in Norway but health care providers must record a minimum of information on all women undergoing mammographic examinations in order to obtain reimbursements from the government. The Norwegian Radiation Protection Authority has used this source to extract information on the number of mammograms performed for 1993 and 2002 to estimate the X-rays doses in the population. 39,40 We used these reports and personal communication with the authors (Widmark A for Ref. 39 and Lysdahl KB for Ref. 40) and estimated the number of women who underwent mammographic examinations. In 1993 this was done by dividing the number of examinations by two because the number of breasts examined was reported. 39 For 2002, we used a factor of 0.66 for estimating the number of examinations (except for those performed in the NBCSP). The factor was estimated based on the reported codes. In addition, we subtracted the estimated number of recalled women in the NBCSP in order to count these women only once. The number of women having undergone mammographic examination in 2005 and 2008 was provided from a report 41 without any estimation. Only women aged are included in the report and we consider the number of women in the age group below and above as neglected. The number and percentages of screening examinations in the NBCSP was estimated based on the number of women in the

3 2932 Breast cancer incidence trends in Norway Figure 1. Age specific incidence of invasive breast cancer in Norway, (age standardized for the 1981 population). The yellow box indicates the peak period of sale of HT preparations. target group of the program and participation rates between 75 and 80%. 36 All numbers and percentages were given as approximations. No ethical committee or Data Inspectorate approval was necessary for this study, as all data were on an aggregate level (rates), and most are available online. Results Incidence of invasive breast cancer The incidence of breast cancer increased in Norway during the period in all age groups, except for women aged where the rate remained constant (Fig. 1). In women aged the incidence was 1.8 times higher in 2008 as in In the age group years, the rate was 1.5 times higher in 1992 as in 1956, and more than doubled in the period to 2001 when the rate peaked. In 2008, the rate was down about 10% from the peak. Women aged followed the same trend as the age group 50 59, but started out at a higher level. Women aged 70 and older had the highest incidence of breast cancer until the mid 90s when the incidence rates among women aged and crossed their curves. The incidence trends from the 1990s and onwards differed substantially for the age groups 55 59, and 65 69, compared with the other age groups (Fig. 2a). In the NBCSP pilot counties, the incidence increased extensively in 1996 for women in the target group of the program, with a peak corresponding to the first screening round in women aged (Fig. 2b). Women in the age group had the most extensive increase in incidence in the period corresponding to the first screening round, from 220 in 1995 to 470/100,000 in In that age group, two peaks were observed, in 1997 and In women aged a substantial drop was observed around 2000, after which the rate remained stable. In the non-pilot counties, the trends did not show any marked change until 2000 (Fig. 2c). For women aged a substantial increase started in 2000 and reached a peak in 2002 (women aged and 60 64) and 2003 (women aged 65 69). For women aged there was a steady increase until 2000 and rather stable rates thereafter. For women aged a relatively stable incidence was observed during the observation period. Hormone receptor status In women aged 50 54, the annual incidence rate of ERþPRþ screen-detected tumors increased slowly during the period with no obvious peak, while the incidence of ERþPRþ tumors peaked in 2002 (280/100,000) for women aged For women aged 60 64,therateincreasedintheperiodfrom1996to2009.For the age group there was almost a U-shaped curve in incidence rate of ERþPRþ cancer, with the bottom reached in TheannualincidencerateofER PR tumors was 65/100,000 or less for all age groups during the observed period. Use of hormone therapy The sale of ET preparations increased from 1987 to 2001 and thereafter decreased until the end of the observation period

4 Hofvind et al (Fig. 3a). The sale of tibolone peaked in 2002 and decreased gradually afterwards. The majority of the ET sold in 2009 was preparations used for treatment of vaginal atrophy only (estriol and estrogens for vaginal application). Sale of EPT preparations increased gradually from 1987 to 1999 (Fig. 3b). The sale leveled off in the period and from 2002 the sale decreased rapidly to the end of the observation period, Fixed combinations with estradiol 2 mg and norethisterone acetate 1 mg (Kliogest VR ) and sequential regimen with estradiol and norethisterone acetate (Trisekvens VR ) were the dominant preparations sold in Norway until The low dose fixed combination of estradiol 1 mg and norethisterone 0.5 mg (Activelle VR ) was marketed in This preparation has gradually replaced the high dose fixed preparations with higher content of hormones. Data from the prescription database confirm the trends in sales and show that use of HT decreased in all age groups during the period both in Norway overall, the pilot counties and the non-pilot counties (Fig. 4). The highest prevalence of HT use was observed in the age group 55 59, followed by the age groups 50 54, 60 64, 65 69, and years. Similar reduction was seen for all three groups (Norway, pilot and non-pilot counties). The prevalence of HT use was higher in women residing in the pilot counties than among those residing in the non-pilot counties. Mammographic examinations The estimated number of women who underwent mammographic examinations in Norway increased from 5,000 to 295,000 in the period (Fig. 5). In 1993, the majority of examinations were performed in private clinics, while most of the examinations were performed as part of the NBCSP in The pilot counties covered about 40% of the women in the target group in Norway during the first screening round (1996 and 1997) (Fig. 6). Full coverage of the NBCSP was reached during 2004 and The participation rate was 75 80% during the study period, but since the screening interval is 2 years, 37 40% of the women in the target group are screened every year. Figure 2. Age specific (45 49, 50 54, 55 59, 60 64, and 70 74) incidence of invasive breast cancer in (crude rates) for (a) Norway; (b) Pilot counties in the NBCSP*; (c) Nonpilot counties in the NBCSP*. The yellow box indicates the peak period of sale of HT preparations. *Norwegian Breast Cancer Screening Program. Discussion The incidence of breast cancer rose in Norway in the period from 1956 to the beginning of the 20th century, particularly in among women aged residing in the NBCSP pilot counties. After , the incidence declined in women aged 55 59, and However, in the period , a trend towards two incidence peaks was observed in these age groups. The first peak, in 1997 was most pronounced in the pilot counties, while the second peak, observed around 2003 was greatest in the nonpilot counties. The first peak corresponded to the period when the first screening round (prevalent screens) was performed in the pilot counties, while the second peak was observed at the end of, or just after the peak in sale of HT preparations. Interestingly, the rate of ERþPRþ tumors and EPT use was highest in women in the age group The sale of HT preparations reached a peak plateau in , which was within the period the NBCSP was introduced ( ). The increased breast cancer incidence observed from 1996 to 2003 in women aged might thus be explained by a combination of these two concurrent events. Further, the decline in incidence coincided with a reduced sale of HT preparations and a shift from mainly first to repeated (subsequent) mammographic

5 2934 Breast cancer incidence trends in Norway Figure 3. Sales of plain estrogens [(a), upper graph] and fixed or sequential combinations of estrogens and progestogens [(b), lower graph] in Norway, given in number of DDDs per 1,000 women per day, (data from the Norwegian Drug Wholesales statistics). examinations in the NBCSP. These concurrent events complicate the interpretation of the changes in breast cancer incidence in Norway during the last decades. Introduction of organized mammographic screening, such as the NBCSP, is expected to increase the incidence rate of breast cancer up to three times the background (pre-screening) incidence rate, leading to a prevalent peak. 42 Among the subsequently screened women an incidence rate 1.5 times the background incidence is expected due to a lead time effect, as a result of detecting pre-clinical cancers. A drop in incidence is expected in women who leave the screening program due to age. 42,43 Our findings were consistent with these expected changes.

6 Hofvind et al Figure 4. One year prevalence of hormonal therapy (plain estrogens, ATC gr. G03C* and estrogens and progesterone in combination, G03F) per 1000 women in five year age groups in the pilot counties and in Norway (data from the Norwegian Prescription Database). *Sale of products only used for treatment of vaginal atrophy is excluded (i.e., vaginal applications and estriol). Figure 5. Estimated number of mammograms performed in Norway, In women aged 50 54, we observed the expected increase, but the increase was followed by a slight increase in incidence instead of a decrease. The missing drop, particularly nationwide and in the non-pilot counties might be due to the gradual introduction of the NBCSP across the country, implicit prevalent screening examinations. However, the missed drop is also likely to be due to increased or stable HT use at a high level. A drop was observed for the pilot counties, but it was smaller than expected and less pronounced than in women aged This might be due to continuous prevalent screening examinations in women aged The breast cancer incidence followed almost the same trend in the age groups 55 59, and However, the incidence peaks were more pronounced in the oldest compared to the youngest age groups in the pilot-counties. This was expected since the difference in cancer detection rate among screened women has been shown to increase substantially by age. 36,42 A decreased incidence in women aged was observed in 2000 on in the pilot counties. The pilot counties included women aged 70 and 71 in the screening program in 1998 and 1999, which might be the reason why the drop was smaller and occurred later as expected. The stable low level of HT use in this age group was in line with the observed incidence rate. This study showed a fourfold increase in sale of ET preparations and sixfold increases in of EPT preparations in the period A substantial reduction in sale was observed from 2002 for both ET and EPT. The decline was similar to the worldwide reduction in HT use after publication of the WHI results in The reduction in HT use was strongest for EPT (75%) in the period from 2001 to This decline in HT use was therefore at the same time as the volume of mammographic examinations reached a peak plateau and the NBCSP changed from prevalent to subsequent screening examinations. Both changes in HT use as well the introduction of NBCSP probably modified the observed incidence rates of breast cancer. Studies from the US have estimated that the reduced HT use in the actual time period might explain about half of the decrease in incidence, 44,45 and it has been argued that part of the decrease was due to declined use of mammographic examinations. In Norway, on the other hand, a trend toward an increased use

7 2936 Breast cancer incidence trends in Norway of mammographic examinations was observed. Thus it is possible that the trends were similar to what was observed in Denmark, where increased use of mammography may have partially masked the decline in breast cancer incidence rates caused by decreased HT use. 12 Another factor that may have modified incidence rates innorwayisthechangefromanaloguetodigitalequipments. Several studies have shown that digital mammography has a higher detection rate, as compared with analogue systems. 46 EPT use has been reported to predominantly increase the risk of breast tumors that express ER and PR. 14,22,47 If the change in EPT use was the main explanation for the change in breast cancer incidence, one would have expected the increased incidence to be predominantly for hormone receptor positive tumors, and that this increase would be expected at the same time or after the peak in EPT use, depending on where in the carcinogenic process EPT acts. A decline would thus be expected in 2004 and after. We observed such a trend in women aged 55 59, the group with the highest rate of EPT users. No such trend was seen in the other age groups, and in fact, we observed almost the inverse, i.e., a U-shaped trend among women aged However, this was also the age group with the highest prevalent peak of breast cancer after introduction of NBCSP in the pilot counties. It is therefore possible that the declined rate of ERþPRþ tumors observed the first few years after 1996 was due to a large proportion of ERþPRþ tumors among the prevalently screendetected cancers. It is also important to keep in mind that we only had hormonal receptor status from screen-detected cancers. We have previously reported that EPT use increases the risk of both interval and screen-detected cancers in Norway, 31 and it is possible that the results would have differed if information about interval cancers, as well as on cancers detected outside of the NBCSP was included. Figure 6. Estimated percent of women resident in Norway who were invited and screened in the Norwegian Breast Cancer Screening Program (NBCSP), [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] References Strengths and limitations This study was based on data from nationwide databases with high quality. The registration was based on the unique 11-digit personal identification number given at birth to all inhabitants of Norway. An obvious limitation of the study was the use of aggregate data. We did not link individual records. We did not have detailed data on mammograms obtained outside of the governmental mammographic screening program. Data from wholesales and prescription databases were used as surrogates for HT consumption, and we had no information about duration of HT use in our study, which is an important determinant of breast cancer risk. 6,30 32 The lack of information on duration is of particular limitation in the age groups 60þ, as many of these women probably were long-term users. In addition, we had no data on other possible confounding factors such as socioeconomic status, reproductive factors, age of menopause and body mass index. Summary This ecologic study showed that the incidence of breast cancer in Norway increased steadily from 1956 until Thereafter there was a marked increase in women aged 50 69, particularly among those residing in the NBCSP pilot counties. After a peak period in , the incidence dropped for this age group. The NBCSP was gradually introduced in Norway during the period The program targets women aged The trends for breast cancer incidence were consistent with changes that could be expected from the introduction of the screening program. Sale of HT preparations increased from 1987 and reached a peak plateau in From 2002 the sale decreased, particularly for EPT. The HT use has remained higher in the pilot counties, which represent urban areas, than the non-pilot counties of the NBCSP. The concurrent peak in sale of EPT preparations and introduction of the NBCSP makes interpretation of the trends in incidence of breast cancer challenging. Both are likely responsible for the changing incidence trends of breast cancer during this period, and it is possible that the relative importance of each factor vary across age groups, with EPT being possibly most important in the age group Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents, vol. VIII. IARC Scientific Publication No 155. Lyon: IARC Press, Krieger N, Löwy I, Aronowitz R, Bigby J, Dickersin K, Garner E, Gaudillière JP, Hinestrosa C, Hubbard R, Johnson PA, Missmer SA, Norsigian J, et al. Hormone replacement therapy, cancer, controversies, and women s health: historical, epidemiological, biological, clinical, and advocacy perspectives. J Epidemiol Community Health 2005;59:

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