Overview: Breast Cancer and the Pill

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Q-3H: Why is it important to study women who are under age 45?

Women who are under age 45 are more likely to have used OCPs prior to having a child than women over 45. For example a 55-year old women who had breast cancer in 1990 would have been very unlikely to have taken the OCP for a significant period of time prior to giving birth since OCPs were just coming to the US in the early 1960s when the cited woman would have been in her late 20s.

Q-3I: What do the four largest studies, which take the bulk of their data after 1980, state regarding women who used OCPs prior to first term pregnancy (FTP)?

The table shows the results of the four largest studies which examined women under age 45 and which took most of their data after 1980.

Table 3A: Risk of Breast Cancer in Women with OCP Use Prior to First Birth
Author Years Studied Size of Study Findings
Wingo CASH
12/80-82 2089 less than age 45 40% increase; ages 20-44
Rosenberg [18] 1977-1992 1427 less than age 45 88% increase*
White [19] 1983-1990 747 less than age
(Parous women)
50% increase:
for use within
5 years of
Brinton [15] 5/90-12/92 1648 less than
45 years old
42% increased risk*

*Computed from data from study,
increase reflects the odds ratio

The four largest retrospective studies** of parous women under the age of 45 all show at least a 40%increased risk for women who took OCPs prior to their FFTP or witnin 5 years of menarche. Two studies (Rosenberg and Brinton) did not list a formal risk but it was calculated from the data in their paper

**An example of a retrospective study is one in which women with breast cancer would be interviewed and asked questions about their risk factors such as family history, OCP use, induced abortion, etc.

Q-3J: Has anyone done a meta-analysis of retrospective studies that examined the question of risk in women under age 45 who had taken OCPs prior to full term pregnancy?

Yes. Two different researchers have addressed this question. Thomas et al, in 1991, found that women who took OCPs for extended periods of time prior to FTP had a 44% increased risk [RR=1.44 (1.23-1.69)] [20]. A more refined meta-analysis in 1990 by Romieu et al restricted her analysis to those studies done after 1980. The study showed that women under age 45 who had taken OCPs for four or more years prior to FFTP had a 72% increased incidence [RR=1.72 (1.36-2.19)] of breast cancer [21]

Q-3K: Can you comment on why a recent large study published by researchers at Harvard claimed to show no increased risk of developing breast cancer in women who had taken OCPs for five years or more prior to their first term pregnancy?

In 1997, a group of researchers at Harvard Medical School led by Dr. Hankinson published a study in Cancer Causes and Control [22]. It based its conclusions on data taken from the Nurses' Health Study and claimed to show that women who took oral contraceptive pills for five years or more prior to their first term pregnancy had no increased risk of developing breast cancer compared to women who never took OCPs [RR=0.57: (0.24-1.31)]. The study's conclusions appear to have been based on a flawed analysis.

Q-3L: Can you describe the problems with the study?

Yes. The researchers compared women with breast cancer who took OCPs for five years or more prior to first term pregnancy (FTP) [let's refer to these women as Group A] to women with breast cancer who never took OCPs [Group B].

It is known that women took OCPs for longer periods of time and earlier in their reproductive lives in the 1980s and 1990s than in the 1960s and 1970s as was clearly noted in the Oxford study [17, p9S; Tables 14, 15]. So any group of women who had taken OCPs for five years or more prior to their FTP (ie, Group A) would have been more likely to have done so while in their late teens and 20s in the 1980s or 1990s, while women in Group B (who never took OCPs) would be more likely to contain a distribution of women who would have been in their late teens and 20s in either the 1960s, 1970s, 1980s or 1990s. But this strongly supports the contention that women in Group A would have a lower average age and a shorter follow-up time than the women in Group B, which would of course invalidate the study's conclusions.

It is frightening to note that the Harvard team presented NO DATA on either the average age of women in the noted groups or their respective lengths of follow-up time. The research team instead chose to follow the noted groups in "person-years" as their measure of follow-up time. This is the length of a follow-up period derived from the number of women followed, multiplied by the average number of years they were followed. For example, if group A had 100 women who were followed for 10 years, the total amount of follow-up time would be 100 x 10 = 1,000 "person-years". But if group A had 250 women who were followed for 4 years it would also have 1,000 "person-years" of follow-up. This is totally inadequate since the measure of "person-years" gives no data on the length of follow-up time in actual years and without this information the study must remain suspect since it was noted that women in group A most likely had both a younger average age and were followed for a shorter period of time than the women in group B.

Q-3M: Is there any way that the public will ever have access to the necessary data that was not presented in the Harvard study?

I am not sure. This author tried in vain to obtain the answers to three basic questions over a six month period of time from three different researchers involved in the Harvard study via e-mail, phone calls and certified mail. It is ironic that one cannot access data from these researchers especially since their study obtained its data from the Nurses' Health Study, a study which was funded by our tax dollars through a grant via the NCI (National Cancer Institute). The essential questions that need to be answered are presented at the end of this chapter. If the Harvard team had answered these questions the average age and follow-up time period for both Group A and Group B's women could have been easily calculated. Until the noted researchers at Harvard make their data available for all to see, the study's conclusions must remain suspect.

Q-3N: Have any other recent studies had methodological problems?

Yes, a large prospective study conducted in England by Beral et al [23] claimed that a "cohort" (ie, the group being examined in a prospective study) of 23,000 women who took the OCP had no greater risk of developing breast cancer than 23,000 women who did not take the pill. The main problem with the study is that women entered it from 1968 to 1969. But many of these women were taking the pill after they had a full term pregnancy because as we noted earlier, women took OCPs for shorter periods of time and later in their reproductive lives in the 1960s and 1970s than in the 1980s and 1990s [17]. The study's claim that OCP use had no long-term risk of increasing breast cancer cannot be applied to the subset of women who took (or currently take) OCPs for longer periods of time prior to their first term pregnancy (FFTP).

Q-3O: Can you give an overall statement regarding early OCP use and breast cancer?

Yes. If a woman takes the oral contraceptive pill before her first child is born, she suffers a 40% increased risk of developing breast cancer compared to women who do not take the pill. If she takes OCPs for four years or more prior to her FFTP, she may have an even higher risk, as noted by Dr. Romieu earlier.

Q-3P: Are any other groups of women at high risk?

Yes. Women who take OCPs for long periods of time (ie, four years or more) [14,24,25], are at increased risk for developing breast cancer. Other women at risk are those who use them after age 25 [26,27,28] and nulliparous women who use them for a long time (ie, four or more years) [14,29]. All three categories of women seem to be at increased risk, with individual studies ranging from 40% to over 200% increased risk. Women who took OCPs for longer time periods and started using them at an early age appear to be at an even greater risk. For example, the Brinton study [15] is significant in that she allowed a longer latent period to pass and found a 210% increased risk of developing breast cancer in young women (ie, under age 35) who took OCPs for more than 10 years, if they began taking them before age 18 [RR=3.1 (1.4-6.7)].

Q-3Q: The studies you cited involved women who were less than 45 years old from data taken after 1980. What will happen to the risk of developing breast cancer for these women as they grow older?

No one knows. It would be wise to learn from history. In the late 1940s an artificial female hormone named DES (Diethylstilbestrol) was given to women to prevent miscarriages. For more than 25 years researchers maintained that DES did not increase the risk of breast cancer in women who took it. Finally, in the 1980s, it was discovered that DES increased breast cancer by about 35%, especially in older women [30]. A similar phenomenon may be occurring with OCPs. The truth is, no one knows how dangerous OCPs will be in women as they grow older.

Q-3R: It has been noted that OCPs reduce the rate of uterine and ovarian cancer. Is this true?

Yes, it is true. However it must be noted that OCPs also increase the risk of cervical and liver cancer [31,32,33]. For example the largest study to date, performed by the World Health Organization, examined over 2,300 women and found that use of the pill before age 25 increased the risk of invasive cervical cancer by 45% [34]. In addition, more women get breast cancer in the US, than all of the other alluded to cancers combined, making this the most dangerous risk in western countries. Oral contraceptives may be particularly risky in Asian and African countries where cervical and liver cancer are prevalent [34,35,36].

Q-3S: Often women who have painful menstrual cycles are placed on OCPs. Are there medical alternatives with less risks than the OCP?

Menstrual cramps can be controlled by other less harmful drugs called non-steroidals such as naproxen or ibuprofen, alone, or in combination with acetominophen.* Other doctors treat cramps by encouraging women to take 1,000 mg of calcium and the RDA (recommended daily allowance) of magnesium directly before and during menstruation. Conversely, The Journal of Adolescent Medicine published a case report of a young lady who experienced a 90% reduction in her cramping symptoms when taking Nicardipine after her menstrual cramps had begun [37]. Nicardipine is a type of calcium channel blocker that is used for treating hypertension.

Q-3T: What about the risk of "low dose" progestin containing contraceptives such as "the minipill," or long-acting progestins such as Norplant or Depo-Provera?

Skegg et al [38] pooled the data from the World Health Organization (WHO) and New Zealand studies, the two largest studies that looked at women who took Depo-Provera (active ingredient is DMPA: depot-medroxyprogesterone acetate) for long periods of time. He found that women who had taken DMPA for between two and three years before age 25 had a 310% statistically significant risk of getting breast cancer [RR=4.1: (1.6-10.90)] while women who had taken DMPA for more than 3 years prior to age 25 had at least a 190% increased risk, that was also significant [RR=2.9: (1.2-7.1)]. The risks for long-term Norplant use in young women could be just as high as for Depo-Provera users, although widespread tests have not been done because Norplant was developed later than Depo-Provera. In regard to the progestin containing "minipill," the Oxford study noted an overall increased risk of 19% (ie, RR=1.19 [0.89-1.49]) in women who had taken minipills for four or more years, but they said nothing about extended use in young women, especially women who took them prior to first term pregnancy [17, p986]. The latter group of women might be at an especially increased risk.

Q-3U: How do the natural means of regulating birth compare to the artificial means?

Several well-designed trials by the World Health Organization have shown that Natural Family Planning (NFP) (ie, a method for determining when a woman is most fertile or infertile, based on qualitative observations of cervical mucus and, for some NFP users, measuring basal body temperature) has had an effectiveness rate when used correctly that is better than OCPs, that is, less than 3% pregnancies per year. These trials have been done in both modern and less advanced countries and have shown low annual pregnancy rates: the United Kingdom -- 2.7% [39], Germany -- 2.3% [40], Belgium -- 1.7% [41] , and India -- 2.0% [42]. One of the largest trials (of 19,843 women performed by the World Health Organization in India) showed the failure rate to be 0.2 pregnancies per 100 women yearly -- a rate that is significantly better than almost all artificial methods of contraception [43]. (For more information regarding NFP see end of bibliography).

Q-3V: How can I verify the above noted information?

Go to your nearest medical library -- nearly every hospital has one -- and ask the librarian to help you look up the medical references that interest you.

Q-3W: What are the three questions never answered by the Harvard study?

The researchers at Harvard have never answered the following simple questions:

1) How many women were there in the group who were under age 45 and who used oral contraceptives for 5 years or more prior to first full term pregnancy (see page 69, Table 3 of your paper [ie, the women who were followed for 9,741 person-years]). What was the mean age for the women in this group?
2) How many women were there in the group who were under age 45 and never used the pill? (see Table 2 page 68, these women were followed for 176,306 person-years). What was their mean age?
3) How many women were in the group who were under age 45 and had used the pill for 10 years or more of total duration? (see Table 2, page 68, the group that had 21,760 person-years of follow-up)

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