Breast Cancer and the Pill: Other Questions


Q-9W: Do women with breast cancer who took OCPs at an early age have a worse prognosis than those who never took them or who took them at a late age?

It would appear that they do. Ranstam et al [51] noted that "cases" who used OCPs before the age of 20 had a 62% 5-year survival rate, whereas "cases" who had never used them or took them after the age of 25 had an 86% 5-year survival rate [51, p.2043].

Q-9X: Do women who have the BRCAI or BRCA2 oncogene and have taken OCPs have a greater risk of getting breast cancer than women who have the oncogene but have never taken OCPs?

Ursin et al [55] have noted that "Long-term OC use (>48 months) before a FFTP was associated with an elevated risk of being classified as a mutBRCA carrier," (odds ratio 7.8, p=0.004). In other words, if two groups of women both had a mutation of the BRCA gene, then if one group used OCPs for 4 years or more before their FFTP, that group would have a 680% increased risk of getting breast cancer. This is important for Jewish women who have a far higher frequency of carrying a defective BRCA1 gene.

Q-9Y: In light of all the evidence presented, why has the Food and Drug Administration (FDA) continued to allow OCPs to be sold with very little warning, and why do most physicians and pharmacists rarely stress the risk of the OCP causing breast cancer?

The FDA is usually extremely conservative as concerns the approval of new drugs and warnings of their dangers, yet it has failed to pull OCPs off the market despite the evidence. Perhaps the FDA will reconsider this in light of testimony this author recently presented* and the fact that this book has been submitted to the FDA as part of the public record.

*Proceedings of the FDA: Over-The-Counter Products. Gaithersburg, Maryland; June 28, 2000. Presenter: Chris Kahlenborn, M.D.: The Pill and Breast Cancer.

Physicians and pharmacists should certainly warn their patients about the increased risk of breast cancer. Both financial incentives and an attitude of "medical correctness" may contribute to the failure of physicians, pharmacists, and drug companies to adequately warn their patients. This is unfortunate in light of the proven effectiveness of natural methods of child spacing. (See question 9Z). Until these groups are effectively confronted by the laity or start to lose law suits, little will change. The only way to promote positive change is to present them with the evidence.

Q-9Z: Why have so few couples used Natural Family Planning?

Natural Family Planning (NFP) - methods of family planning based on measurements of cervical mucus viscosity (and basal body temperature for some methods) - has been criticized widely, probably more out of bias and ignorance than an informed opinion. Several good trials have shown that NFP has an effectiveness rate that is on par with OCPs - that is, less than a 3% rate of pregnancies per year. These trials have been done in both industrialized and less advanced countries and have shown low annual pregnancy rates: the United Kingdom - 2.7% [56]; Germany - 2.3% [57]; Belgium - 1.7% [58]; India - 2.0% [59]; Liberia - 4.3% [60]; and China - 4.4% [61]. In addition, "the largest natural family planning study combined effective teaching with high motivation and showed that natural family planning can be extremely effective in the Third World. The study was of 19,843 predominantly poor women in Calcutta, 52% Hindu, 27% Muslim, and 21% Christian. Because of poverty, motivation was high both among the users and among the well trained teachers of natural family planning. The failure rate was similar to

that with the combined oral contraceptive pill - 0.2 pregnancy per 100 woman yearly." [62]. (Note: The recent review study by Potter noted a typical failure rate of 7% for women who take OCPs [63]). Perhaps the greatest reason that so few know of or have used NFP is that there is no economic force behind it. If couples were to use NFP, drug companies, physicians, pharmacists, and family planning agents such as Planned Parenthood would all suffer financially. Why NFP use in countries such as China, Brazil and other developing countries is not more common, especially given its lack of side effects and monetary advantages over conventional contraception, remains a mystery.


Addendum 9A:

[The following questions have answers that contain more complex material and may be omitted without a loss of continuity]

Q-9AI: Does use of oral contraceptives which contain a higher amount of the estrogen hormone have a higher propensity to cause breast cancer?

No one is sure, but so far only a few studies point to an increased risk with higher estrogen or progestin doses, and a number of studies actually show the reverse trend. Most oral contraceptives contained 50 micrograms of ethinyl estradiol in the 1970s, but in the 1980s the "low dose" brands that contained 35 micrograms were increasingly used. Today both types are used, in addition to the more recent "super-low" OCPs which contain 20 micrograms of synthetic estrogen. Although researchers originally claimed that use of the higher dose OCPs caused more breast cancer, several studies since then have contradicted this. Rookus and Leeuwen [17] noted that women who took OCPs for more than 12 years had a 1.2 RR if their brand of OCP contained more than 50 micrograms of estrogen and a 2.9 RR if the OCP had less than 50 micrograms. Thomas et al [64] noted that women who took low dose OCPs for more than 5 years had a 1.69 RR (1.20-2.38) compared to a 1.32 RR (0.96-1.84) for those women who had taken high dose OCPs. Ursin et al [45] noted that women who used OCPs with a low mestranol content (ie, a type of estrogen) had more than twice the risk of those who used OCPs with the medium-dose mestranol content.

The strongest evidence, however, comes from the Oxford study, the largest meta-analysis to date concerning OCPs. Surprisingly, it showed a small, non-statistically significant increase in risk as the estrogen content of an OCP was decreased in women who had taken OCPs more than 10 years ago [34, p.94S]. It also showed an increased risk (non-significant) for women who took the lower dose triphasic pills compared to those who took the conventional higher dose monophasic pills in the group of women who had taken them more than 10 years ago [34, p.87S]. Women who had taken high dose OCPs more than 10 years ago had less metastatic breast cancer than women who had used low-dose OCPs more than 10 years ago [34, p.96S].

Q-9A2: Will the dose of estrogen in the OCP affect the results of future studies?

No one knows if the lower dose OCPs will be more or less dangerous than higher dose OCPs in the long run. It was noted that some authors have actually found an increased risk for breast cancer in women who used the lower dose estrogen pill and that the Oxford meta-analysis supported this finding in certain subgroups. Brinton's findings also lend support to the finding that low dose OCPs appear to carry a significant risk. In her study, which showed a calculated odds ratio of 42% for women who had used OCPs prior to their FFTP, she noted: "It is doubtful, however, that the relationship will be explained by use of higher dose preparations, since the majority of these younger women would have initiated pill use during an era when both estrogen and progestin doses would have been reduced."[3, p.834]. As the low dose OCPs' estrogen content drops even lower (ie, some now contain 20 micrograms of estrogen), OCPs will cause an even higher number of early abortions because the rate of breakthrough ovulation will increase. Whether a very early abortion could affect the risk of breast cancer will not be known until the physiology of very early pregnancy is understood better, as was noted in the answer to question 8D.

Q-9A3: Are OCPs which contain a potent progestin more dangerous than those with a low potency progestin?

Many studies are finding that the progestin component may actually be the main factor in breast cancer formation, either through a compound effect with estrogen or by an independent process. OCPs contain more modern and potent progestins today and no one really knows if they will be more dangerous, although two studies raise exactly that suspicion. White et al noted that women who took OCPs with a high potency progestin had a 50% increased risk of breast cancer compared to women who took OCPs that contained a low potency progestin. [21, p.509]. Pike et al [65] noted that women who took high potency progestin OCPs before the age of 25 had a far greater risk (ie, infinite risk [2.0 - infinity]) of developing breast cancer than those who took the low potency progestin OCPs [RR=4.9 (1.9-13.4)]. This is especially significant in that the most common types of OCPs used to date, according to information from the Oxford meta-analysis [34, p.88S], use the combination of estradiol and a very high potency progestin (according to Pike [65] named norgestrel (eg, Ovral).

Q-9A4: What about the risks for developing breast cancer in women who took higher vs. lower dose progestins IO years ago?

The Oxford study showed no difference in women who had taken a high versus a low dose progestin called norethisterone when they had used it more than 10 years ago [34, p.92S].

Q-9A5: In addition to possibly causing a higher rate of breast cancer, does use of OCPs which contain high dose progestins cause a more aggressive type of breast cancer?

Several studies support this statement. "Recent or current use (at time of diagnosis), use of progestin-predominant oral contraceptives, or use before age 20 may increase risk of estrogen receptor negative tumors." [66, p.1118]. (Estrogen receptor negative tumors generally have a worse prognosis than estrogen positive tumors). In addition, Olsson has noted that these same type of progestin OCPs lead to tumors which have much higher INT2 levels than tumors in women who did not take these OCPs [53, p.1486]. A breast cell's INT2 level is felt to be of prognostic importance; in general, the higher it is, the poorer the patient's prognosis.

Q-9A6: Until this point, retrospective studies have been analyzed. Why did this author separate the prospective studies from the retrospective?

The Oxford study gives a complete list of the ten prospective studies which had been done before 1996. In general, these studies cannot be easily analyzed in regard to the OCP/breast cancer link for several reasons: 1) they examine older patients - that is, they rarely subdivide their data into age groups that look specifically at those women who are less than the age of 45 on or before 1995. Including older women means that they would have had little access to early OCP use, which makes it almost impossible to measure this variable; 2) a high drop-out rate. It is not unusual for a prospective study to lose thousands of participants along the way, due either to apathy or patients moving away, or due to the death of the patients from disease including breast cancer; 3) a short follow-up period. Often a prospective study will allow 10 years or less of follow-up time, such as Calle's study [67]. This is hardly enough of a latent period to show much effect. 4) In addition, prospective studies may suffer from "follow-up differentiation." in which the "cohort" (ie, the women who have either had an abortion or have taken the OCP) are followed up for far shorter periods of time than the "controls" as is noted in Appendix 1: Q-A1B. A prospective study starts out with thousands of women but only a small percent ever develop breast cancer. Vessey et al studied 17,032 women, 72 of whom developed breast cancer in the 35 to 47 year-old age group [68]. It is obviously difficult to make conclusions based on such a small study size; 5) a post-menopausal population. Several of the prospective studies looked at hormone use in post-menopausal women. Because this population involves older women, most of whom are far older than the age of 45, it has little relevance to the question of OCP risk in women under the age of 45; and 6) a failure to adjust for other variables. Many prospective studies do not ask their participants about their history of abortion, alcohol use, or even family history. This certainly reduces the accuracy of a study, especially when one notes that all three of the former variables are important risk factors.

Q-9A7: What did the prospective studies show?

Several of the studies confined themselves to the population of post-menopausal women (Hiatt [69], Mills [70], and Schuurman [71]). Two of the studies made no mention of OCP risk at all (Miller [12], Hiatt [69]). The remaining six studies usually showed non-specific risks due to limitations of the study. Some of the relevant findings include: 1) Calle et al [67]: In their cohort of 676,530 several hundred developed breast cancer. It was noted that women who had a family history of breast cancer and used OCP's had a relative risk of 2.82 - this was statistically significant although no age group was given; 2) Vessey et al [68] found no specific relationship between OCP use and breast cancer but only studied 72 women between the ages of 25 and 44 years old; 3) Alexander [72] noted a 4.83 relative risk (1.97-11.87) to women aged 45 to 54 years old who took OCPs for more than 1 year versus women who took it for less than 1 year; 4) In a study of Seventh Day Adventists, Mills [70] found that women who used OCPs postmenopausally had a relative risk of 1.54 (0.94-2.53) compared to nonusers; 5) Kay et al [73] found a 3.33 RR in "ever" versus "never" use in women aged 30 to 34 years old who had breast cancer; and 6) Romieu [74] found a RR of 1.06 (0.96-1.18) for all users of OCPs, noting that the average age of the patients was well over 45. She also noted that patients who were taking OCPs "currently" had a 1.53 (1.06-2.19) increased risk. The Oxford meta-analysis found a 1.15 relative risk in its summary of all the prospective studies for women who used OCPs within 5 years of having their breast cancer diagnosed [34, p.44S].

Q-9A8: Can you summarize the results of the prospective studies?

Yes. In general, the information that can be gathered from prospective studies in regard to early OCP use and the risk of breast cancer before the age of 45 is very limited due to the reasons given. Several of the studies do show increased risks in specific categories, but this is usually in slightly older women. One study [ie, Kay et al, 73] did show a specific statistically significant risk in a specific age group - women aged 30 to 34 with breast cancer.


Addendum:

Rosenberg calculated risks for women who took OCPs for at least 4 years:

"Cases" and "controls" aged 25-44 who had more than 5 years of OCP use were 23+21+34+85=163, and 30+47+39+149=265 respectively, versus 547 "cases" and 1014 "controls" who had less than 1 year's use of OCPs. The OR (odds ratio) is therefore: 163/547 divided by 265/1014, yielding a 1.14 or 14% increased risk for women who took OCPs for 5 or more years despite a severe stack effect.

Calculation of OR for OCP use after a FFTP for the Brinton [3] and Rosenberg studies [18]:

Brinton noted that 82+45+38+75=240 "cases" and 69+50+35+92=246 "controls" used OCPs for at least 6 months or more after a FFTP, whereas 389 "cases" and 431 "controls" had less than 6 months of OCP use prior to the age of 25. The OR would be:

240/389 divided by 246/431=1.08 or an 8% increased risk.

In the Rosenberg study, the number of women aged 25 to 44 years old with and without breast cancer who used OCPs for more than 1 year after a FFTP was 36+21+134+85=276 (ie, "cases") and 102+47+186+149=484 (ie, "controls"), whereas 547 "cases" and 1014"controls" used OCPs for less than 1 year. The estimated relative risk is therefore: 276/547 divided by 484/1014 which yield an OR of 1.06 (ie, a 6% increased risk).


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1, 2, 3,