Prescribing Hrt In The Risk Of Breast Cancer Biology Essay

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The selected studies were critically appraised using the specific critical appraisal tools by the Solutions of Public Health (SPH) as described in the methodology section. To interlink the essence of the results of all the studies and bring forth some meaningful and constructive information so as to answer the research question, benefits and risks issues were categorized. This simplified the process of understanding the issues and comparing the perspectives of each paper (Aveyard, 2010).

This research study investigates the benefits for prescribing HRT in the presence of the risk of breast cancer. The literature review methodology helped synthesise the findings and view the literature in the viewpoint of the other to understand the issues associated with the use of HRT (Aveyard, 2007). After the information was extracted from the selected studies codes were assigned to grade them and develop themes which are addressed as issues in this dissertation (Bryman, 2008). This helps to understand one study findings in the perspective of the other and generalise the findings (Bryman, 2008).

Data was extracted from every study to collect specific information into two categories:

1) Issue 1 - Benefits

2) Issue 2 -Risks

These two issues will be evaluated to explore different factors which could be associated with the benefits of HRT and the risk of breast cancer with focus to answer the research question.

1) ISSUE - BENEFITS ASSOCIATED WITH THE USE OF HRT

This section will summarise the issue of benefits associated with the use of HRT extracted from the studies which were critically appraised. In order to make the study more generalised the benefits from each study are presented in context with the studies which reported similar findings. Every study has limitations depending on their design, participants selected, geographical distribution and various aspects. These studies are also not devoid of limitations which are mentioned below. The gradation of the studies of their reliability explains the validity of their findings which is an integral part of critically appraising studies (SPH, 2010).

The findings are based mostly on the relative risk which is a measure of relationship between the exposure that is HRT and the outcome that is the disease. A relative risk of 1 show's no relation between the exposure and outcome, greater than 1 show's exposure increases the risk of the disease and lesser than 1 shows a decreased risk of the disease (Aschengrau, 2008).

The various benefits reported by the studies are analysed to explore and extract the associating factors which influence them which are explained below.

1) Use of HRT decreases the risk of death overall (Sener et al, 2009) in women with a family history of breast cancer (Sellers et al, 1997) and is associated with recurrence, metastasis-free survival and better overall and disease-free survival than HRT nonusers in the univariate analysis (Bonneir et al, 1998; Sener et al, 2009)

Based on the findings of the hazard ratio of 0.438 (0.263-0.729) the Sener et al (2009) study reported that the use of HRT decreases the risk of death overall. And this was associated with better overall and disease-free survival than HRT nonuse.

This study had the limitations of no standardized treatment plan for all breast cancer patients and potential confounding factors were not collected. No information on the duration of HRT use and type of pill was considered in the design or analysis. These limitations graded this study as a reasonably reliable study and presented high benefits.

Sellers et al (1997) study findings were in line with the findings of the Sener et al (2009) study of use of HRT decreasing the risk of death overall and they added in women with a family history of breast cancer despite the increased risk of breast cancer. This was based on the outcome of 0.55 (0.28-1.07) for total mortality in women with a family history of breast cancer and in women without a family history of breast cancer it was 0.84 (0.67-1.06) for current use of HRT for more than 5 years. This study presented medium benefits and the limitation as per the investigators was no validation of family history of cancer and inadequate information on composition of HRT, exposure status of HRT and reasons of using HRT. Despite these limitations this study was highly reliable as all the aspects of the study were well defined.

The Bonneir et al (1998) study also concluded in line with the Sener er al (2009) study that there was no significant difference seen with regard to recurrence of breast cancer, metastasis-free survival and overall survival in HRT users. This finding was concluded on the base of the proportion of glandular opacities which was observed in 53.4% HRT users as compared to 58.2% in HRT non-users.

Though this study was conducted a span of 10 years it was less reliable and scored the least points in this dissertation primarily due to the fact that the outcome was measured in the hospital laboratory and there was no mention of the study design. However this study presented potential benefits and more benefits from this study are discussed later in context with other studies.

The common synopsis of these findings presented a new opinion that HRT is associated

with better disease free survival and that family history of breast cancer and use of HRT for

more than 5 years perhaps has a role to play in these benefits associated with the use of HRT.

2) HRT does not increase the risk of breast cancer when administered after exclusion of other risk factors and decreases incidence of Benign Breast Disease's (BBD). No association exists between breast cancer and use of oral contraceptives (OC) and it reduces the BBD incidence (Tzingounis et al, 1996).

As in the previous findings it was seen that family history of breast cancer could influence the benefits of HRT, the Tzingounis et al (1996) study evaluated breast disorders with the use of OC and HRT. This study concluded potential benefits with the findings that HRT does not increase the risk of breast cancer when administered to a selected patient with exclusion of other risk factors however they did not mention what are the risk factors. They further added that there is no associated breast cancer risk with use of HRT and the use of HRT decreases the incidence of benign breast disease (BBD). Only a minor proportion of women using HRT would have cysts which are a type of BBD compared to women not using HRT. This conclusion was based on the risk difference for BBD incidence in women who didn't take HRT and women who took HRT which was 11.04 and was statistically significant.

No association between breast cancer and use of OC exist was also reported by this study. And that use of OC reduces the incidence of benign breast disease based on the risk difference for BBD incidence in women who didn't take OC and women who took OC which was 26.92 and was statistically significant; however they warned against over acceptance of these findings. The limitation of no mention of confounding factors in neither design nor analysis made this a reasonably reliable study.

This study presented that use of oral contraceptive could be beneficial and the opinion of excluding risk factors for not increasing the risk of breast cancer should be considered.

3) There is an inverse relationship between HRT and mortality due to coronary heart disease, stroke and cancers other than breast but increased risk of death due to breast cancer in women with family history of breast cancer and ever users of HRT (Sellers et al, 1997).

Sellers et al (1997) along with their findings of use of HRT decreasing the risk of death overall, reported the beneficial finding of an inverse relationship between HRT ever users and mortality due to coronary heart disease, stroke and cancers other than breast cancer in women with family history of breast cancer. This was based on the outcome of the relative risk of 0.56 (0.30-1.04), 0.81 (0.24-2.70) and 0.65 (0.41-1.01) respectively. Though an increased risk of death due to breast cancer with the relative risk of 1.91 (0.64-5.69) in women with a family history of breast cancer and ever users of HRT is seen.

This study presented the opinion that family history of breast cancer could affect the beneficial effect of HRT.

4) Use of HRT results in fewer locally advanced cancers and smaller and better-differentiated cancers with lesser nodes involvement compared to non-use of HRT (Bonneir et al, 1998) and more favorable cancers than in non HRT users (Sener et al, 2009).

The Bonneir et al (1998) study reported an important finding that patients who developed breast cancer while using HRT had lesser locally advanced cancers and smaller and better-differentiated cancers with lesser Lymph-node involvement as compared to non-users of HRT. The Sener et al (2009) study similarly reported that HRT users were more likely to develop cancers which were smaller, of lower grade and were node negative. They added the new aspect to these biologically lesser aggressive cancers which they addressed as favorable cancers and which would occur in HRT users than those developing in non HRT users. The frequency of ductal carcinoma and positive Estrogen Receptor status was nearly similar for HRT users and non HRT users. However no other study used the term of favourable cancers associated with use of HRT other than the Sener et al (2009) study.

5) HRT is a favourable prognostic factor for breast cancer since it helps early diagnosis (Bonneir et al, 1998) of otherwise clinically undiagnosed cancers which helps improve survival of breast cancer patients (Cobleigh et al, 1999).

Though the Bonneir et al (1998) study presented similar findings to that of Sener et al (2009), it did not classify breast cancers due to use of HRT as favourable cancers. It actually concluded that HRT is a favourable prognostic factor for breast cancer as it facilitated regular examination leading to early detection of smaller lesions.

The Cobleigh et al (1999) study also presented similar finding that early diagnosis of cancers assisted by use of HRT is responsible for healthier survival of breast cancer patients and that use of HRT helps early diagnosis of other wise clinically undiagnosed cancers.

The assessors considered this study as not a population based study and insufficient information on the variables was known. Overcoming this limitation would have made the study highly reliable. This study was a reasonably reliable study like the Tzingounis et al (1996) study and presented medium benefits like the Sellers et al (1997) study.

These studies brought forth the aspect of early diagnosis with regular examination which involves patient follow up which could affect the beneficial effect of HRT.

6) HRT has an inverse relationship with colorectal cancer and endometrial cancer (Corrao et al, 2008; Rossouw et al, 2002) with fewer hip fractures (Rossouw et al, 2002). And use of HRT counteracts the increased incidence of breast cancer with the lower incidence of other tumors. (Olsson et al, 2001).

The famous Women's Health Initiative (WHI) study was a well documented and randomised controlled trial conducted in the United States and it was the only randomised controlled trial study in this dissertation (Rossouw et al, 2002). The results of this study could be generalized as the inclusion criteria were quite broad and the process was fully random.

This study reported low benefit and concluded that 6 fewer colorectal cancers and 5 fewer hip fractures would occur in 10000 women taking estrogen plus progestin compared with placebo over duration of one year.

The intervention studied was the combined oestrogen plus progestin hormone regime and the outcome measured were cardiovascular disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture and death due to other cancers. Generally randomised controlled trail have the biggest advantage of reducing confounding and selection bias (Smith and Ryan, 2008). Hence this is a highly reliable study like the Sellers et al (1997) and Olsson et al (2001) study however it does have limitations such as that the results can not be applied to lower dosage of the drug, duration. Though this study was originally scheduled to have a follow up time of 8.5 years but the trial was prematurely called-off after a mean of 5.2 years as risks exceeded the benefits (Rossouw et al, 2002).

The Corrao et al (2008) study had a different objective than the WHI study (Rossouw et al, 2002) had similar findings in line with the (Rossouw et al, 2002) study but reported high benefits. They reported an inverse relationship between use of HRT for more than 2 years and incidence of colorectal cancer with hazard ration of 0.78 (0.68-0.92) and incidence of endometrial cancer with hazard ration of 0.62 (0.36-1.09).

Like the Tzingounis et al (1996) and Ewertz et al (2005) studies the Corrao et al, (2008) study also had the limitation of inadequate information of potential confounding factors and no control of its distorting effects which did not keep it away from being a highly reliable study like the Banks et al (2003), Ewertz et al, (2005), Lund et al (2007), Olsson et al (2001), Rossouw et al (2002) and Sellers et al (1997) studies.

Olsson et al (2001) study concluded in line with Corrao et al (2008) and Rossouw et al (2002) studies. They presented high benefits and concluded that there is an increased incidence of breast cancer but there is no overall increase in cancer incidence after use of HRT though they did not specify the type of cancer. They further added that the use of HRT neutralizes the increased incidence of breast cancer with the lower incidence of other tumors.

According to the assessors the limitation of this study was inadequate estimation of hazard ratio for women who have reported no use of HRT which did not keep it away from being a highly reliable study.

With the aspect of duration of one year and more than 2 years these studies presented the aspect that duration could affect the beneficial effect of HRT.

7) Use of trans-dermal HRT compared to the oral use of HRT is associated with lesser risk of breast cancer (Banks et al, 2003; Corrao et al, 2008) which is presumed by the (Rossouw et al, 2002) and no difference was reported by (Ewertz et al, 2005).

Corrao et al, (2008) study uncovered a different aspect to the use of HRT. They reported that less risk of breast cancer was associated with trans-dermal use of HRT with hazard ratio of 1.27 (1.07-1.51) compared to the oral use of HRT with the hazard ratio of 2.14 (1.43-3.21), however the assessors report that further studies would be needed specially to evaluate the effect of low-dose HRT regimens.

The landmark million women study (MWS) (Banks et al, 2003) also concluded in line with the Corrao et al (2008) study and reported the type of HRT in past users did not affect the residual increase of breast cancer. However they reported that compared to transdermal oestrogen preparation; oral and implanted oestrogen preparation showed an increase in breast cancers though not significant with a relative risk of 1.24 (1.11-1.39), 1.32 (1.21-1.45) and 1.65 (1.26-2.16) respectively. Though this study is highly reliable like the Olsson et al (2001) Rossouw et al (2002) and Sellers et al (1997) studies it does have the limitation that the number of deaths attributed to HRT could not be concluded.

The investigators also concluded that more follow-up of this study was needed for the findings on the transdermal oestrogen preparation. Perhaps future research is needed to explore the effect of different modes of HRT formulations on the risk of breast cancer. This study reported high benefits associated with the use of HRT also concluded in line with the major previous studies that reported that compared to the past use, current and recent use of HRT increases the risk of breast cancer (Collaborative group, 1997).

The findings of the effects of the type of HRT could have on the risk of breast cancer reported by the Banks et al (2003) Corrao et al (2008) was presumed by the WHI (Rossouw et al, 2002) study as they reported that other methods of administration like the transdermal ratio would perhaps present a different risk benefit ratio.

Ewertz et al (2005) reported no material risk difference with the composition of Oral HRT regimes which was based on the relative risk of 1.35 (0.97-1.73) for oestrogen only and 1.36 (0.89-2.28) for progestin only preparation. Though it was 0.57 (0.26-1.29) for combined therapy, it was not considered due to small number of 6 patients reporting it. There is mention of most of the important confounding factors however according to the investigators more information on the potential confounding factors of age at menopause and body mass index (BMI) could be added which was a limitation. Hence they added that perhaps there could be an association between use of HRT and BMI. This study was a highly reliable study and presented medium benefit.

These all studies brought forth the opinion that the type of HRT and a possible association with BMI should be reviewed which could influence the affect of the benefits associated with the use of HRT.

8) HRT users had a normal incidence of breast cancer as compared to non-HRT users (Espie et al, 2006). There was no risk of breast cancer associated with past use of HRT (Lund et al, 2007; Stahlberg et al, 2004) or after 5 years of stopping it (Ewertz et al, 2005) (Banks et al, 2003) (Olsson et al, 2001).

The MISSION (Espie et al, 2006) study presented medium benefit and reported that the European standardized incidence rate of breast cancer in the non-HRT user group was significantly higher than in the French reference population with the comparative incidence figure ratio (CIFR) of 2.24 (1.50-3.36) and CIFR of 1.04 (0.35-3.15) for HRT users. This was based on the high prevalence of breast cancer with 6.21% for the non HRT users and 1.01% for the HRT users. Depending on all these factors they reported an incidence rate of breast cancer which they categorized as "abnormally high" for HRT users and 'normal' for non HRT users after calculation of standardized incidence rates.

This difference was attributed to the French gynecologists' handling method of not prescribing HRT to high-risk women, to varied HRT regimens and their associated effects which are mostly prescribed in France. This result opened up many aspects of treatment, understanding high-risk low-risk women and different HRT regimes. Perhaps limitation of no information on the duration of use of HRT made this a reasonably reliable study like the Cobleigh et al (1999), Stahlberg et al, (2004) and Tzingounis et al (1996) studies.

The Danish Nurses Cohort (Stahlberg et al, 2004) study again brought forth the aspect of duration of use of HRT. They reported that no increased risk was seen for past users of HRT. This conclusion was in line with the findings of the MWS (Banks et al, 2003) which had a nearly similar conclusion and reported that compared to past users current HRT users had higher risk of breast cancer. They presented medium benefits and added that longer duration of HRT did not increase the risk of breast cancer which was nearly same for use from 5 years to 15 years. The limitation of inadequate report by women on use of HRT at baseline and no information of mammographic screening made this a reasonably reliable study like the Tzingounis et al (1996) and Cobleigh et al (1999) studies.

The Lund et al (2007) study findings were in line with the findings of the Stahlberg et al (2004) study who reported that there was no risk of breast cancer associated with past use of HRT based on the finding that there was no increased risk of breast cancer in former use of HRT with relative risk of 0.85 (0.59-1.22).

Thought Lund et al (2007) study was a highly reliable study like the Banks et al (2003), Ewertz et al, (2005), Olsson et al (2001), Rossouw et al (2002) and Sellers et al (1997) studies it had the limitation of inadequate update on use of HRT in the follow up period. This study reported low benefit.

The Olsson et al (2001) study added another aspect to the findings of no risk associated with past use of HRT by the Stahlberg et al (2004) and the Lund et al (2007) study with their finding that recent HRT users were at increased risk of breast cancer whereas there is no increased risk after 5 years of stopping the regime which was based on the declining SIR from 1.18 (0.85-1.58) after 48 months of use to 1.06 (0.95-1.18) for 0 months or never users.

Similarly Banks et al (2003) reported that the risk of breast cancer decreases with time reaching baseline risk levels within 5 years which was based on the relative risk of 1.01 (0.92-1.12) for a duration of 1-4 years of past use of HRT. Ewertz et al, (2005) had a similar conclusion with was based on the relative risk of 1.13 (0.85-1.49) for duration of 2-5 years since last use of HRT and 0.87 (0.61-1.23) for duration of more than 5 years since last use of HRT.

These study findings the important aspect of duration of use of HRT and the doctor's method of prescribing could influence the benefits of HRT.

9) No increased risk for past HRT users (Banks et al, 2003; Stahlberg et al, 2004) for women between the ages of 40-49 (Ewertz et al, 2005).

The aspect of duration of use of HRT was further carried by the MWS (Banks et al, 2003) by the finding that there was little or virtually no increase in the relative risk of breast cancer in past users of HRT which was based on the relative risk of 1.01 (0.94-1.09) for past users and 1.66 (1.58-1.75) for current users. The Danish Nurses Cohort (Stahlberg et al, 2004) also reported similar finding that no increased risk was seen for past users of HRT which was based on the relative risk of 1.14 (0.76-1.69).

The Ewertz et al, (2005) added the new dimension of age which could also affect the beneficial effect of HRT with their finding that there was no risk of breast cancer associated with use of HRT women between 40-49 years of age. This was based on the relative risk of 0.56 (0.07-2.01) for women between age 40-44 and 0.88 (0.62-1.22) for women between age 45-49 years of age.

The findings of these studies suggested that age along with duration could affect the beneficial effects associated with the use of HRT.

2) ISSUE 2- RISK OF BREAST CANCER ASSOCIATED WITH THE USE OF HRT

This section will summarise the issue of risk of breast cancer associated with the use of HRT extracted from the studies which were critically appraised. In an attempt to answer the research question the risk of breast cancer reported by the studies would be analysed so as to explore their relation with the associating factors that affect them. The strength of these studies will be presented in this section which will help ascertain the facts behind these findings.

It was seen that various factors like duration of use of HRT, family history of breast cancer, OC, past personal history of HRT, opinion of excluding risk factors, age, follow up and types of HRT affected the associated benefits of HRT. This section will look into the factors that affect the risk of breast cancer with the use of HRT.

1) Increased risk of breast cancer after use of HRT for duration of 2 years or more (Corrao et al, 2008) higher risk with at least 4 years of HRT use (Olsson et al, 2001) in women with family history of breast cancer (Sellers et al, 1997).

The aspect of duration of use of HRT affecting the effect of benefit was also seen for the risk of breast cancer. The Corrao et al, (2008) study reported on the link of the duration of use of HRT like the Sellers et al (1997), Banks et al (2003) and the Lund et al (2007) studies with their finding that women using HRT for more than 2 years have higher risk of breast cancer with hazard ratio of 1.34 (1.13-1.58). The Corrao et al, (2008) study presented medium risk and the strength of the study was that it used the regional outpatient prescription drug database to collect detailed information of all HRT drugs prescribed in Italy with different hormone regimens (estrogens or estradiol alone or conjugated with progestin and route of administration (pills, ovules, gels, creams and patches) which were assessed separately.

The Olsson et al (2001) study reported low risk and their findings were nearly similar to that of the Corrao et al (2008) study with the difference that they doubled the duration of use of HRT. They reported that a higher risk of breast cancer is associated with use of HRT for duration of at least 4 years which increases with further use. The strength of this study was the response rate of 74% and that there was no loss to follow up.

In line with the Olsson et al (2001) and Corrao et al (2008) studies the Seller et al (1997) reported that the risk of breast cancer may be increased with HRT use for current HRT users with duration of 5 years or less with multivariate adjusted relative risk of 1.37 (0.59-3.18) with family history of breast cancer. They added that women who used HRT and had a family history of breast cancer had an increased rate of death from breast cancer which was 1.3 fold higher (0.6-3.0) though not statistically significant compared to women who did not use HRT and did not have a family history. This study present medium risk and the strength of this study was the use of questionnaires to reach all women with a valid Iowa drivers license in 1985 by means of which detailed information was collected on Education level, marital status, smoking history, usual alcohol intake during the past year, physical activity, reproductive history, history of various medications including diabetes and heart disease, duration of use of HRT, information on participants mother, sister and daughter having breast cancer was collected.

These studies uncovered the role which duration of use of HRT could play in the associated risk of breast cancer and that that family history of breast cancer could affect it further.

2) The risk of breast cancer increases with increasing duration of use of HRT (Lund et al, 2007) and decreases with time (Banks et al, 2003; Ewertz et al, 2005; Olsson et al, 2001). Higher risk of breast cancer in seen in current users of HRT compared to past users of HRT (Banks et al, 2003; Stahlberg et al, 2004) and fatal breast cancer (Banks et al, 2003).

The duration of use of HRT which was already seen affecting the risk of breast cancer is further presented as increasing risk with increasing duration of use.

The Lund et al (2007) study reported an increasing risk with increasing duration of use based on the relative risk of 1.56 (1.25-1.95) in current users of HRT when taken for less than 5 years which increased to 2.00 (1.58-2.53) for duration of more than 5 years. The Lund et al (2007) study reported medium risk and the strength was that the outcome to be measured was breast cancer and the follow up ended with the outcome of diagnosis of breast cancer which was obtained from the Cancer Registry of Norway and information of time of death or emigration was received from the central population register in Statistics Norway.

The MWS (Banks et al, 2003) study also further added to this important finding that the risk of breast cancer increases with increasing duration of use of HRT. This was based on the relative risk of 1.74 (1.60-1.89) for duration of 1-4 years and 2.17 (2.03-2.33) for duration of 5-9 years. This study reported medium risk and the striking feature of the MWS (Banks et al, 2003) study was the huge number of 1,084,110 participants in it which made it a true representative of the postmenopausal population. The results of this study had a large effect on the way HRT was prescribed. In Netherlands a decline was seen in HRT prescriptions which were due to women discontinuing the use or not initiating it (Faber et al, 2005).

The Ewertz et al, (2005) study in line to the previous duration findings of Banks et al, (2003) and reported an increased risk of breast cancer with current use of HRT in women which increased with increased use which was based on the relative risk of 1.61 (1.38-1.88) for current users of HRT. This risk decreased with time and is nullified after 5 years. This study reported low risk and the strength of this study was that the results were well presented for different age groups which made the results more applicable to the general population.

The Olsson et al, (2001) study reported similarly that a higher risk of breast cancer is associated with use of HRT for at least 4 years or more. And this risk decreases with time, this was based on the findings of the Standard Incidence Ratio which was 1.92 (1.32-2.70) for duration of use between 48 to 120 months and this SIR decreased to 1.18 (0.85-1.58) for duration between 1 to 48 months.

The Banks et al (2003) study classified the risk of breast cancer as risk of fatal breast cancer with their report that there was a higher risk of breast cancer and fatal breast in current users than in past users. This was based on the HRT use at baseline with relative risk of fatal breast cancer which was 1.22 (1.05 - 1.41) in current users and decreased to 1.05 (0.85 - 1.29) in past users.

The Stahlberg et al, (2004) study reported low risk with the conclusion that current HRT users were at increased risk of breast cancer with the relative risk of 2.70 (1.96-3.73). The strength of this study was the study population which was of nurses who had a good level of education and occupation. Questionnaires were used which helped bring in all related detailed information the potential confounding factors like menarche, parity, age at first child birth, alcohol intake, physical activity, body mass index (BMI), benign breast disease, intake of OC's, hysterectomies, menopausal status and type of menopause which would have been otherwise unreported with average education.

These studies again brought forth the factor of duration of use of HRT which would increase or decrease the risk of breast cancer.

3) Women who used combined estrogen and progestin HRT regime are at an increased risk of breast cancer (Banks et al, 2003; Stahlberg et al, 2004) and long term oral HRT use is associated with a higher risk of breast cancer than trans-dermal use of HRT (Banks et al, 2003; Corrao et al, 2008). More CHD events, strokes, Pulmonary Embolism and invasive breast cancers would occur with use of combined HRT over a year's duration of use (Rossouw et al, 2002).

The opinion that the type of HRT administered could also affect the risk of breast cancer was presented by the Banks et al (2003) study with their finding that the risk of breast cancer with use of HRT was greater for combined therapy than for other types of HRT. This conclusion was based on the baseline relative risk of 2 (1.91-2.09) for breast cancer in users of combined HRT and of 1.30 (1.22 - 1.38) in users of oestrogen.

Stahlberg et al, (2004) reported that women who used combined estrogen and progestin HRT regime were at increased risk of breast cancer with the relative risk of 2.70 (1.96-3.73) compared to women using only estrogen preparation with the relative risk of 1.96 (1.16-3.35).

The Banks et al (2003) study reported that compared to transdermal oestrogen preparation; oral and implanted oestrogen preparation showed an increase in breast cancers though not significant as mentioned above. The Corrao et al, (2008) also reported similar findings that long term use of oral HRT was associated with higher risk of breast cancer as compared to women using trans-dermal HRT.

The WHI study (Rossouw et al, 2002) reported high risk with the conclusion that 7 more Coronary Heart Disease events, 8 more strokes, 8 more Pulmonary Embolism and 8 more invasive breast cancers would occur in 10000 person-years of women taking estrogen plus progestin compared with placebo over one year duration. The strength of the WHI study was that the participants were blinded to the medicine and both the combined estrogen and progestin tablet and placebo were similar. In the wake of premature stopping of the trial and the results which showed that the risk exceeds the benefits they concluded that longer follow-up may be needed to assess the impact of the incident diseases on total mortality. Though the WHI study was a very famous well conducted study no other study from this dissertation presented similar findings.

These studies together uncovered the factor that the type of HRT used and duration of use of HRT could increase or decrease the risk of breast cancer.

4) Increased risk of breast cancer with current use of HRT (Banks et al, 2003) in women of 50 years of age and above which increased with increased use (Ewertz et al, 2005).

The MWS (Banks et al, 2003) study reported a higher risk of breast cancer in current users than in past users as mentioned previously. The Ewertz et al, (2005) study further added to these findings with their report that there is an increased risk of breast cancer with current use of HRT in women of 50 years of age and above with the relative risk of 1.61 (1.38-1.88) and this risk increased with increased use.

These studies again repeated the aspect of age which could influence the risk of breast cancer.

5) The risk of breast cancer increased in women who were current HRT users and had used OC in the past (Lund et al, 2007).

The Lund et al (2007) study agreed to the previous findings of increased risk in current HRT users; however they added the history of use of OC. They reported that there was a higher risk of breast cancer associated with women who were current HRT users and had used OC in the past with a relative risk of 2.45 (1.92-3.12) compared to the relative risk of 1.67 (1.32-2.12) for women who were current HRT users but never used OC.

This study added the aspect that history of use of OC also affects the risk of breast cancer.

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