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Overview: Breast Cancer And The Pill

Chris Kahlenborn, MD

Q-2A: What is an oral contraceptive?

An oral contraceptive is usually a combination of synthetic estrogen and progestin (the two major types of female hormones) which women take for 21 days out of a 28-day cycle. These hormones work by suppressing but not eliminating ovulation, thickening cervical mucus, and changing the lining of the uterus.

Q-2B: Is there any evidence that the OCP (oral contraceptive pill) causes breast cancer in animals?

Yes. Concerns were raised in 1972 when it was noted that an oral contraceptive pill containing the artificial hormones mestranol and norethynodrel appeared to cause a case of metastatic breast cancer in a group of six female rhesus monkeys [1]. This was especially worrisome since rhesus monkeys rarely develop breast cancer. Until that time, only three cases of breast cancer in rhesus monkeys were reported. Although some argued that this was simply a "chance finding," concern grew further when it was noted that both beagles and rodents developed breast cancer when exposed to the hormones contained in today’s OCPs [2, 3, 4, 5, 6].

Q-2C: How might OCPs cause breast cancer in humans?

In 1989, Anderson et al [7] published a classic paper regarding the influence of the OCPs on the rate of breast cell division. They found that nulliparous women (women who have not had children) who took OCPs had a significantly higher rate of breast cell division than nulliparous women who did not take them. This was especially important since it is known that in general, cells that divide more rapidly are more vulnerable to carcinogens (cancer producing agents) and thus more likely to become cancerous.

Q-2D: Do oral contraceptives cause an early abortion and if so, could this also be playing a role in the increased risk of breast cancer?

Both pro-life and pro-abortion groups openly admit that OCPs cause early abortions, with the latter doing so publicly in testimony before the Supreme Court in 1989 [8]. Induced abortion before a woman’s first-term pregnancy has been noted to increase a woman’s risk of breast cancer by 50% [9]. Could an abortion (defined to be the death of the zygote, embryo or fetus after conception has occurred) within the first week after conception have a deleterious effect as concerns breast cancer? The hormonal physiology of early pregnancy is difficult to measure but Stewart et al [10] and Norman et al [11] have shown that estradiol and progesterone levels (the female hormones) start to rise above baseline levels within four days of conception, ie, prior to implantation and before hCG levels begin to rise. An early abortion would cause a sudden fall in the levels of these hormones. Could this early "hormonal blow" be playing a role? To this author's knowledge, no one has studied this question.

Q-2E: Can you give a brief history of the studies that showed a link between OCP use prior to first term pregnancy and increased risk of breast cancer? In 1981, Pike et al [12] found that women who took OCPs for four years before their first term pregnancy had at least a 2.25 fold (125% increased) risk of developing breast cancer before age 32. This startled the research world and led to additional studies, including a very large American trial called the CASH study (ie, Cancer And Steroid Hormone study). In 1993, the CASH study showed that women who took OCPs prior to first term pregnancy and were under 44 years of age had a 40% increased risk of breast cancer, which reached statistical significance in the 35-44 age group [13]. Later, in England, Chilvers et al [14] published the results of another large study called the United Kingdom National Study. She showed that young women under the age of 36 who had used oral contraceptives for at least 4 years before their first term pregnancy had at least a 44% increased risk of breast cancer. Another large study was performed in 1995 by Brinton et al [15]. It showed a 42% increased risk for women who used OCPs for more than 6 months prior to having a full term pregnancy.

* Chapter 2 of Breast Cancer, Its Link with Abortion and the Birth Control Pill

Q-2F: If the major studies showed the risks that have been mentioned, why do doctors and pharmacists fail to inform their patients of those risks?

That is a good question. Major journals and major medical associations (eg, the AMA {American Medical Association}, ACOG {American College of Obstetricians and Gynecologists}, and the AAP {American Academy of Pediatrics}) have failed to stress or properly note this risk. Part of the problem is that, because the OCP/breast cancer debate is complicated, most lay people have to rely on what "the experts" tell them. A good example of this occurred recently in the Oxford study reported in condensed version in The Lancet [16] and in complete form in Contraception [17]. This study was and remains the largest meta-analysis (ie, a synthesis of all the major studies done in a particular field, concluding in an overall risk for the pooled studies) regarding the studies of OCPs and breast cancer. Researchers from around the world studied and combined the data from 54 studies, involving 25 countries and 53,297 women who had breast cancer. It concluded that: "Women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed, although the additional cancers tend to be localized to the breast. There is no evidence of an increase in the risk of having breast cancer diagnosed 10 or more years after cessation of use..." Unfortunately, this study is known more for what it did say, than what it did not say! There were several major weaknesses of the study.

Q-2G: What are the weaknesses of the Oxford study and what implications do they have?

The main weakness was the failure to report any evidence of what the pooled risk of oral contraceptive use before a first term pregnancy was in women less than 45 years old. Another major weakness is that the Oxford study pooled data from studies which looked at women with breast cancer from the early and mid 1970s [17, p5S]. A woman's breast is especially sensitive to carcinogenic influence (ie, cancer producing influence) before she has her first child since the breast undergoes a maturing process throughout a woman's first pregnancy. By failing to measure the effect of OCP use before a woman's first term pregnancy (FTP), the Oxford study failed to give data on the one group of women who are most likely to get breast cancer from oral contraceptives, namely, those women who used them before their first term pregnancy (eg, many teenagers and women in their twenties). The second weakness is that the Oxford study used data from older studies which took some of their data from the mid and early 1970s. This does not leave a long enough latent period. A latent period is the time between exposure to a suspected risk factor (eg, early OCP use) and the cancer which it increases (eg, breast cancer). Often the latent period between a risk factor and a cancer is 15 to 20 years or more (eg, cigarettes and lung cancer). Although women in the US began taking OCPs in the 1960s, they began taking them for longer periods of time at younger ages in the 1970s. Thus, only studies which include data from the 1980s and 1990s or beyond would allow a long enough latent period to pick up the influence of early OCP use.

Q-2H: 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 woman 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-2I: 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)?

Table 2A: Risk Of Breast Cancer In Women With Ocp Use Prior To First Birth

Author

Years Studied

 Size Of Study Findings
Wingo [13] Cash Study 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 X {Parous women} 50% increase: for use within 5 years of menarche
Brinton [15] 5/90-12/92 1648 less than age 45 42% increased risk*

*Computed from study data; increase reflects the odds .

The four largest retrospective studies (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.) of women under the age of 45 all show at least a 40% increased risk for women who took OCPs prior to their FTP or within five years of menarche. Two studies (Rosenberg [18] and Brinton [15]) did not list a formal risk but it was calculated from the data in their paper.

Q-2J: 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 42% increased risk [20]. In a more refined meta-analysis in 1990, Romieu et al restricted their analysis to studies done after 1980. The study showed that women under age 45 who had taken OCPs for four or more years prior to FTP had a 72% increased incidence [RR=1.72 (1.36-2.19)] of breast cancer [21] .

Q-2K: 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-2L: 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, p 9S; 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-2M: Is there any way that the public will gain access to the critical data not presented in the Harvard study?

I am not sure. This author tried in vain for six months to obtain the answers to three basic questions 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 researchers at Harvard make their data available for all to see, the study’s conclusions must remain suspect.

Q-2N: Have 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. 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.

Q-2O: 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 first baby, she suffers at least a 72% increased risk of developing breast cancer.

Q-2P: 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, Brinton’s study [15] is significant because 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-2Q: 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 that no one knows how dangerous OCP use will be for women as they grow older.

Q-2R: 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 2300 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 mentioned cancers combined, making this the most dangerous risk in western countries. Oral contraceptive use may be particularly risky in Asian and African countries where cervical and liver cancer are prevalent [35, 36].

Q-2S: 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 acetaminophen.(The non-steroidals may have to be taken in higher doses to be effective and should then be used only under a physician’s guidance.) 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. Also, 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 for relief of her menstrual cramps [37]. Nicardipine is a type of calcium channel blocker that is used for treating hypertension.

Q-2T: 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. Regarding the progestin containing "minipill," the Oxford study noted an overall increased risk of 19% (ie, 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, p98]. The latter group of women might be at especially increased risk.

Q-2U: 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 all artificial methods of contraception [43]. (For more information on NFP, contact the organizations listed after the References.)Q-2V: How can I verify the above 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-2W: What are the questions never answered by the Harvard study?

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

References

  1. Kirschstein RL et al. Infiltrating duct carcinoma of the mammary gland of a Rhesus monkey after administration of an oral contraceptive: a preliminary report. JNCI. 1972; 48: 551-553.
  2. Geil et al FDA studies of estrogen, progestogens, and estrogen/ progesterone combinations in the dog and monkey. J Tox. Env. Health. 3: 1979.
  3. Shubik P. Oral contraceptives and breast cancer: laboratory evidence. In: Interpretation of Negative Epidemiological Evidence for Carcinogenicity. IARC Sci. Publ. 1985: 65; 33.
  4. Kahn RH et al. Effect of long-term treatment with norethynodrel on A/J and C3H/Hej mice. Endocrinology 1969; 84: 661.
  5. Weisburger JH et al. Reduction in Carcinogen Induced Breast Cancer in rats by an anti-fertility drug. Life Sci. 1968; 7: 259.
  6. Welsch CW et al. 17B-Estradiol and enovid mammary tumorogenesis in C3H/HeJ female mice: counteraction by concurrent 2-bromo-ergo cryptine. Br. J. Cancer. 1977; 35: 322
  7. Anderson T, Battersby S, et al. Oral contraceptive use influences resting breast proliferation. Hum. Pathol. 1989; 20: 1139-1144.
  8. Alderson Reporting Company. Transcripts of oral arguments before court on abortion case. New York Times. April 27, 1989; B12.
  9. Brind J, Chinchilli M, Severs W, Summer-Long J. Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis. J. Epi. and Comm. Health. 10/ 1996; 50: 481-496.
  10. Stewart DR, Overstreet JW et al. Enhanced ovarian steroid secretion before implantation in early human pregnancy. J. of Endo. and Met. 1993; 76: 1470-1476.
  11. Norman RJ et al. Inhibin and relaxin concentration in early singleton, multiple, and failing pregnancy: relationship to gonadotropin and steroid profiles. Fertility and Sterility. 1993; 59: 130-137.
  12. Pike MC, Henderson BE et al. Oral contraceptive use and early abortion as risk factors for breast cancer in young women. British Journal of Cancer. 1981; 43: 72-76.
  13. Wingo PA, Lee NC et al. Age-specific differences in the relationship between oral contraceptives use and breast cancer. Cancer (supplement). 1993; 71: 1506-17
  14. Chilvers C, McPherson K, et al. Oral contraceptive use and breast cancer risk in young women {UK National Case-Control Study Group}. The Lancet. May 6, 1989: 973-982.
  15. Brinton LA, Daling JR et al. Oral contraceptives and breast cancer risk among younger women. JNCI. 6/7/1995; 87: 827-35.
  16. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. The Lancet 1996; 347: 1713-1727.
  17. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996; 34: S1-S106.
  18. Rosenberg L, Palmer JR, et al. Case-control study of oral contraceptive use and risk of breast cancer. American Journal of Epidemiology. 1996; 143: 25-37.
  19. White E, Malone K, Weiss N, Daling J. Breast cancer among young US women in relation to oral contraceptive use. JNCI. 1994; 86: 505-514.
  20. Thomas DB. Oral contraceptives and breast cancer: review of the epidemiological literature. Contraception. 1991; 43: 597-642
  21. Romieu I, Berlin J, et al. Oral contraceptives and breast cancer. Cancer. 1990; 66: 2253-2263
  22. Hankinson SE et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses Health Study, United States). Cancer Causes and Control. 1997; 8: 65-72.
  23. Beral V et al. Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46,000 women from Royal College of General Practitioners’ oral contraception study. BMJ. 318. 1/99; 96-99.
  24. Rookus MA, Leeuwen FE. Oral contraceptives and risk of breast cancer in women ages 20-54 years. Lancet. 1994; 344: 844-851.
  25. Weinstein A, Mahoney M, et al. Breast cancer risk and oral contraceptive use: results from a large case-control study. Epidemiology. 1991; 2: 353-358.
  26. Palmer J, Rosenberg L, et al. Oral contraceptives use and breast cancer risk among African-American women. Cancer Causes and Control. 1995; 6: 321-331.
  27. Thomas DB, Noonan EA. Breast cancer and combined oral contraceptives: results from a multinational study [The WHO collaborative study of Neoplasia and steroid contraceptives]. Br. J of Cancer. 1990; 61: 110-119.
  28. Wang Q, Ross R, et al. A case-control study of breast cancer in Tianjin, China. Cancer Epidemiology. 1992; 1: 435-439.
  29. Miller D, Rosenberg L, et al. Breast cancer before age 45 and oral contraceptive use: new findings. American Journal of Epidemiology. 1989; 129: 269-279.
  30. Colton T, Greenberg ER, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. JAMA, 1993; 269: 2096-3000.
  31. Thomas DB et al. Oral contraceptives and invasive adenocarcinomas and adenosquamos carcinomas of the uterine cervix. American J. of Epidemiology. 1996; 144: 281-289.
  32. Ebeling K. et al. Use of oral contraceptives and risk of invasive cervical cancer in previously screened women. Int J. of Cancer. 1987; 39: 427-430.
  33. Kenya PR. Oral contraceptive use and liver tumours: a review. East African Medical Journal. 1990. 67:146-153.
  34. Thomas DB et al. Invasive squamos-cell cervical carcinoma and combined oral contraceptives: Results from a multinational study. Int. J of Cancer. 1993. 53; 228-236.
  35. Parkin et al. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int. J of Cancer. 1988. 41: 184-197.
  36. Fauci AS et al. Harrison's: Principle of Internal Medicine 14th edition. McGraw Hill Inc. NY.(C) 1998.
  37. Earl DT, et al. Calcium channel blockers and dysmenorrhea. Journal of Adolescent Medicine. 1992; 13: 107-108.
  38. Skegg DCG, Noonan EA, et al. Depot medroxyprogesterone acetate and breast cancer [A pooled analysis of the World Health Organization and New Zealand studies]. 1995; JAMA: 799-804.
  39. Clubb EM et al. A pilot study on teaching NFP in general practice: current knowledge and new strategies for the 1990s. Washington, DC Georgetown University, 1990: 130-132.
  40. Frank-Hermann P et al Effectiveness and acceptability of the symptothermal method of NFP in Germany. Am. J. of Obstet. Gyn. 1991; 165: 2052-45.
  41. Liezola MA. De premiere d'une etude prospecive d'efficacite du planning famillial naturel realisee en Belgique francophone. J. Gyncol. Obstet. Biol. Rev. 1994, 23: 359-364.
  42. Dorairaj K. The modification mucus method in India. Am. J. Ob. Gyn. 1991; 165: 2066-67.
  43. Ryder RE. "Natural Family Planning": Effective birth control supported by the Catholic Church. BMJ. 1993; 307: 723-6.

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