The complex answer to this can be found in Appendix 4 (Commentary on the Oxford Oral Contraceptive Study). In short, Table 9E shows the results of the studies which limit their focus to women who were less than 45 years old and obtained the bulk of their data after 1980. The Oxford study combined the data from old studies (ie, before 1980 with data from new ones. The pattern of OCP use was far different in older studies: Women in the 1960s and early 1970s often took OCPs after their FFTP, whereas women in the late 1970s and 1980s started taking them earlier and for longer periods of time [34, p.9S]. In addition, studies before 1980 fail to allow an adequate latent period. Until a meta-analysis is done on the newer studies, the reader might be best served by making his or her own conclusions after reviewing Table 9E.
| Table 9F: | ||||
|---|---|---|---|---|
| Breast Cancer Risk To Women Who Took OCPS For At Least 4 Years Prior To The Age Of 45 | ||||
| Author | Percent Change | Year | Study Size |
Findings (RR) or
Odds Ratio (OR) |
| Brinton et al [3] | 27% increase* | 1990-1992 | 1648< 45 years old |
1.27 (1.0-1.6)
> or = 5 yrs of use |
| Chie et al [5] | 250% increase* | 1993-1994 | about 80 less than 45 |
OR=3.5 (0.9-14.3)>
or = to 5 yrs of use |
|
Chilvers [1]
United Kingdom Study |
43-74% increase | 1/82-12/85 | 755 less than 36 |
1.43 (0.97-2.12)
4-8 yrs; 1.74 (1.15-2.62) for > 8 yrs of use |
| La Vecchia [25] | 30-60% increase | 1991-1993 | 454 less than 45 |
OR = 1.3 (0.9-2.0)
> 10 yrs use age <35; OR = 1.6 (0.4-6.0) > 10 yrs of use ages 35-44 |
|
McCredie RE
et al [9] |
16% increase | 1992-1995 | 467 under 40 |
OR = 1.16 for
> 5 yrs of use |
| McPherson et al [15] | 20-78% increase* | 1980-1984 | 351 < 45 |
1.20 (0.78-1.84)
4-12 yrs of use; 1.78 (0.82-3.87) for > 12 yrs of use |
| Meirik et al [11] | 20-120% increase | 1984-1985 | 422 less than 45 |
1.2 (0.8-1.0) 4-7 yrs;
1.4 (0.8-2.3) 8-11 yrs; 2.2 (1.2-4.0) > 12 yrs of use |
| Miller et al [12] | 90-310% increase | 1983-1986 | 407 less than 45 |
1.9 (1.1-3.3) 5-9
yrs use; 4.1 (1.8- 9.3) for more than 10 yrs of use |
| Olsson [13] | 100-110% increase | 1979-1985 | 174 premenopausal |
2.1 (1.1-3.8) 4-7 yrs pFFTP; 2.0 (0.8-4.7) > 8 yrs pFFTP |
| Paul et al [15] | 0-130% increase* | 1983-1987 | 388 less than 45 |
1.3 (0.41-4.0) 6-
9 yrs in ages 25-34; 2.3 (0.67-7.8) 10- 13 yrs ages 25-34; 1.0 (0.62-1.8) 6- 9 yrs ages 35-44; 1.0 (0.59-1.8) 10- 13 yrs ages 35-44 |
| Rookus et al [17] | 110% increase* | 1986-1989 | 132 less than 36 |
2.1 (1.0-4.5) for
4 or more yrs |
| Rosenberg [18] | 14% increase** | 1977-1992 | 1427 less than 45 |
OR=1.14**
raw for 5 or more years |
| Ursin et al [19] |
29% decrease
to 40% increase |
1983-1988 | 742 less than age 40 |
OR= 0.71 (0.49-1.02)
4-8 yrs; 0.79 (0.52- 1.18) 8-12 yrs; 1.40 (0.81-2.40) > 12 yrs |
| Weinstein et al [20] | 78% increase | 1984-1986 |
about 326 less than
or equal to 49 |
OR=1.78 (1.09-
2.93) > 4 yrs |
| White et al [21] | 32% increase* | 1983-1990 | 747 < than 45 |
1.32 (0.92-1.88)
for > 10 yrs use |
|
* This result reflects a trend toward an increased or decreased risk but does not attain statistical significance.
|
||||
Table 9F clearly shows that when one reviews the studies whose data come predominantly after 1980, every one shows an increased trend or an actual statistically significant risk. Many of the studies, including Meirik et al [11], Paul et al [15], Rookus et al [17], and Miller et al [12] point to an increase of over 100% risk when OCPs were taken for a total of 10 to 12 years. The Oxford study did not reflect this risk because of its inclusion of older data that did not allow for a sufficient latent period.
Most studies show a trend toward an increased risk of developing breast cancer. Paul et al's study results must be interpreted in light of both a severe stack effect and the death effect [15, p.367-8] rendering the results of this study extremely questionable.
| Table 9G: | ||||
|---|---|---|---|---|
| Breast Cancer Risk From OCP Use In Nulliparous Women under The Age of 45 | ||||
| Author | Percent Change | Year | Study Size | Findings (RR) |
| Chilvers [1] |
2% decrease to
130% increase |
1982-1985 | 755 less than 36 |
0.98 for 0-4 yrs
1.37 for 4-8 yrs 2.30 for > 8 yrs |
| Ewertz [7] | 25% increase* | 1983-1984 | 203 less than 40 | 1.25 (0.46-3.38) |
| Lund et al [27] | 142% increase | 1984-1985 | 422 less than 45 |
OR = 2.42
(calculated) |
| Miller et al [12] | 60% increase* | 1983-1986 | 407 less than 45 | 1.6 (0.8-3.1) |
| Palmer [14] | 150-210% increase* | 1977-1992 |
524 less than 45
(black women) |
2.5 (0.5-13) 1-
2 yrs; 3.1 (0.5- 17) 3-4 yrs; 2.7 (0.8-8.9) > 5 yrs |
| Paul et al [15] | 43% (decrease) | 1983-1987 |
345 less than 45
(comment: large stack effect) |
0.57 (0.25-1.3) |
| Rosenberg [18] | 12% increase* | 1977-1992 | 1427 less than 45 |
OR=1.12
(calculated) |
| Ursin et al [19] |
43% decrease
to 20% increase |
1983-1988 | 742 less than age 40 |
0.82 (0.5-1.33)
1-4 yrs; 0.57 (0.32-1.02) 4-8 yrs; 0.58 (0.31- 1.08) 8-12 yrs; 1.20 (0.58- 2.48) > 12 yrs |
| Wingo [22] | 0-50% increase* | 12/80-82 |
2089 less than
age 45 |
1.5 (0.8-2.7) ages
20-34; 1.0 (0.7- 1.6) ages 35-44 |
|
* This result reflects a trend toward an increased or decreased risk but does not attain statistical significance. |
||||
The increased overall risk shown by the remaining studies is especially significant for another reason. When a study such as that of Chilvers [1] notes an increased risk of 130% for nulliparous women who have taken OCPs for more than 8 years, this represents the increased risk of these women compared to other nulliparous women and not the female population in general. In other words, women who are nulliparous and have used OCPs for more than 8 years would experience a 2.3-fold risk compared to other nulliparous women, but an even higher risk when compared to the general population because nulliparity itself is a risk factor which confers about a 2-fold risk [35]. The combination of nulliparity and an 8-year length of exposure would result in an estimated increase of 4.6 (ie, 2.3 x 2.0) which is a 360% increased risk of developing breast cancer compared to the general population. This phenomenon was also supported by the finding of another author of CASH, Bruce Stadel [36, p.288], who pointed out that nulliparous women aged 20 to 44 who had menarche before age 13 and had used OCPs for 8 to 11 years had a 170% increased risk of developing breast cancer, and if they used them for 12 or more years they had a 1080% increased risk! In addition, special note should be taken of Palmer's study [14] which pointed to a very high risk for black nulliparous women.
Table 9H shows that every study which looked at late OCP use (ie, after the age of 25) showed an elevated trend or risk, which increased markedly as the length of time of total OCP use increased. Although Table 9H lists only a few studies, the reader will note that in general the degree of increased risk is not small by any means, with some of them showing over a 140% increase.
| Table 9H: | ||||
|---|---|---|---|---|
| Breast Cancer Risk To Women Who Took OCPS After The Age of 25 | ||||
| Author | Percent Change | Year |
Study Size
(RR) or Odds Ratio (OR) |
Findings |
| Lund et al [27] | 50% increase | 1984-1985 | 422 less than 45 |
OR = 1.50 (calculated) |
| Noonan et al [30] | 42% increase | 1979-1984 |
Estimate 600 under age 45 |
1.42 (1.04-1.58) use after age 35 |
| Olsson [13] | 60% increase | 1979-1985 | 174 premenopausal | 1.6 (0.9-2.7) |
| Palmer [14] | 0-140% increase | 1977-1992 |
524 less than 45
(black women) |
1.0 (0.4-2.5) < 3
yrs; 2.4 (1.3-4.6) > 3 yrs after age 25 |
| Paul et al [37] | 170% increase* | 1983-1987 |
891 women
aged 25-54* |
2.7 (0.97-7.5) for
10 yrs use after age 40 |
| Rosenberg [18] | 14% increase* | 1977-1992 | 1427 less than 45 |
OR = 1.14
(calculated) |
| Rosenberg [32] | no change | 1982-1986 |
79 less than 40
(Canadian women) |
OR=1.00
(calculated) |
| Wang et al [38] | 160-300% increase | 1985-1986 | 300 aged 20-55 |
2.6 (1.2-5.8) <
2 yrs after 35; 4.0 (1.1-15.1) > 2 yrs after 35 |
| Weinstein et al [20] | 32% increase | 1984-1986 |
about 326 less than
or equal to 49 |
OR=1.32
(0.87-2.00) |
| Yuan et al [39] | 300% increase | 1984-1985 |
about 200 less than 45 |
4.0 (1.15-16.59)
for use after age 45 |
|
* This result reflects a trend toward an increased or decreased risk but does not attain statistical significance. |
||||
Most patients get their information on oral contraceptive pill risks from four main sources: 1) their physician, 2) their pharmacist, 3) the drug insert (ie, from the pharmaceutical company), and 4) from the lay press.
The average physician is often very busy, and he or she often relies on conferences and/or the most popular journal articles to keep him or her updated. Unfortunately, as you may have noticed, information regarding the field of OCP use and its link to breast cancer is found in literally hundreds of medical journal articles and is a complex area. So, although individual physicians should know about this link, most do not. Of course, that does not excuse physicians because any physician ought to be familiar with the dangers of any hormones he/she prescribes. The excuse that "I just followed the practices of my colleagues" will become unacceptable as patients become familiar with the information contained in this book and present it to their physicians and nurses.
Pharmacists have routinely failed to inform patients about the link between OCP use and breast cancer. Part of the reason is that no pharmacist can tell every patient about every side effect. However, this does not mean they should be ignorant of the risks of OCP use, especially in young women. Perhaps this will change as people bring this to their pharmacist's attention.
Pharmaceutical companies do include a drug insert with every drug they manufacture and they do state that: "Some studies have reported an increased relative risk of developing breast cancer particularly at a young age. This increased relative risk appears to be related to duration of use" [40]. This, however, is hopelessly inadequate because few patients ever read the fine print of their drug inserts and the drug companies know it. Drug companies have a responsibility to print this birth control risk information in large bold print. Until now, they have been grossly negligent in adequately stressing the danger of early OCP use.
The lay press has also paid little attention to this issue but cannot be totally accountable because they literally must rely on the words of "the experts." Unfortunately, many of today's "research experts" are hopelessly dependent on and/or fearful of the biases of their financial supporters (ie, usually the federal government) who cannot be presumed to be unbiased. At the very least, and especially in light of the millions of lives at stake, the scientific community should respond aggressively and candidly to the concerns documented in this book. The evidence can no longer be ignored.
| Table 9I: | ||||
|---|---|---|---|---|
| Breast Cancer Risk From OCPS Use 15-20 Years Since First Use | ||||
| Study--> |
Brinton [3]
Women Less Than Age 35 |
Palmer [14]*
Black Women Less Than 45 |
Miller [12]**
Women Less Than 45 |
Rosenberg [18]
Women Aged 25-34 |
| Year of Interview | 1990-1992 | 1977-1992 | 1983-1986 | 1977-1992 |
|
Interval Since First
Use of OCP |
||||
| < 10 Years | 1.6 (1.1-2.3) = 60% | |||
| 10-14 Years | 1.63 (1.1-2.5)=63% | 1.8 (1.3-2.6) = 80% | ||
| 15-19 Years | 2.02 (1.2-3.4)=102% | 2.6 (1.5-4.6) = 160% | 1.9 (1.0-3.5) = 90% | |
| >= 20 Years |
3.01 (0.3-34.9)
= 201%*** |
2.0 (1.0-4.3)
= 100%*** |
6.0 (1.6-22) = 500% | |
|
* In women who used OCPs for more than 3 years.
|
||||
Brinton et al [3] noted that young women have a 63-102% statistically significant increased risk of developing breast cancer 14 to 19 years after first OCP use, and a 201% statistically insignificant risk 20 or more years after original OCP use. Rosenberg [18] et al noted similar risks in young women up to 19 years after first OCP use. Miller et al [12] noted an even higher risk 20 years after first use of OCPs and Palmer [14] reported that black women also have elevated risks. In summary, these results give doctors who gave their patients OCPs reason to be extremely concerned, because every one of the four studies pointed to at least a 90% increased risk of developing breast cancer as one approaches a 20-year latent period.
As you will note, the information from the Brinton and Rosenberg studies was confined to women under the age of 35. The trend toward an increased risk 16 years after first use is not as strong in the older age groups in these two studies. There is a good reason for this. Women who were the age of 35 or less in the late 1980s or early 1990s (when the latter two studies obtained their data) would have been far more likely to have used OCPs prior to their FFTP than women in their mid to late forties. The young women under the age of 35 represent a group of women who statistically had far higher and longer OCP use prior to their FFTP than older women. In addition, one must also note that both Miller and Palmer did study women under the age of 45 and found statistically significant elevated risks.
At this point doctors need to inform their patients that the studies which looked at the risk of OCP use in young women after almost 20 years since their first use, found statistically significant increases in breast cancer risk of 90% or higher.
This author found no study on this specific group of women although there is every reason to suspect that OCPs would raise the risk of breast and cervical cancer in this group of women as much as it does in other women. However, Dr. Grimes [41] did note that women who took OCPs to regulate their cycles had an increased risk of pituitary adenoma (ie, specifically "prolactinomas" - a type of tumor of the pituitary gland). For example, Shy et al [42] noted that women who took OCPs for irregular cycles had a 670% increased risk of developing prolactinomas: [RR= 7.7: (3.7-17.0)]. This should be taken seriously because at least one progestin has been noted to cause growth of the pituitary gland in rats [43]. Young women frequently have irregular cycles and do not necessarily require medical treatment.
Menstrual cramps can be controlled by less harmful drugs than OCPs. For example, taking 1,000 mg of Calcium and 399 mg of Magnesium around the time of a woman's onset of menstrual bleeding appears to help with menstrual cramps and migraine headaches. In addition, taking high dose anti-inflammatory agents (eg, ibuprofen) after one's menstrual flow has started (and under a doctor's care) will often give relief. Also, the Journal of Adolescent Medicine [44] 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.
Ursin et al [45] studied this specific question. They studied 144 "cases" and noted that women who had taken OCPs for more than 1 year had a 70% trend toward an increased risk of developing bilateral breast cancer [1.7 (1.02.9)]. When this analysis was restricted to parous women only, the trend toward an increased risk rose to 110% [RR = 2.1 (1.0-4.4)].
When two factors can both influence the same effect (ie, breast cancer), one must be careful to distinguish between them. Fortunately, almost every major study since the late 1970s has adjusted for age at first birth, thus, clearly separating its effect and the effect of early OCP use.
The converse situation exists with OCP use and the risk factor of family history. Because women with very strong family histories of breast cancer might be less likely to use OCPs - and thus underestimate the relative risk for OCP use - one might think that these risks would be difficult to distinguish. Almost every good study adjusts for the risk factors of family history, except for certain prospective studies [eg, 46, 47].
No one is really sure, although these pills often contain norgestrel (eg, Ovrette) and therefore could carry similar risks. The Oxford study noted an overall increased trend of 19% (ie, 1.19 [0.89-1.49]) in women who had taken progestin-only OCPs for 4 or more years, but this says little about extended use in young women, especially before their FFTP [34, p.98S]. Analysis from the New Zealand study [48] noted that women who had taken progestin only OCPs before age 25 had a 1.5-fold risk (0.73-2.9), although the result did not achieve statistical significance. It must again be noted that the risks for early use prior to a FFTP are most likely quite a bit higher, and as of today, there is no good reason to believe that the oral progestins are any less dangerous than the combination OCPs.
Yes, as noted earlier by Olsson: "these results indicate that the rate of tumor cell proliferation is higher in patients with breast cancer who have used oral contraceptives at an early age or who at a young age have had an abortion performed early in the woman's reproductive life. . ." [49, p.1288-9]. Schonborn et al [50] observed that women who took OCPs had a higher percentage of poorly differentiated tumors. Ranstam et al have also noted that the survival rate of women who have used oral contraceptives - especially at an early age - was less than those who did not use OCPs or used them at later ages [51, p.2044]. It was also noted that women who used OCPs early in their reproductive lives had larger tumors than women who did not use OCPs [52, 267]. The same study found that women who had used OCPs early in life had a significantly lower concentration of estrogen and progesterone receptors on their tumor cells [In general, the lower the concentration of estrogen and progesterone receptors of a breast cancer cell, the worse the prognosis and response to treatment. The converse is also true - the higher the concentration of estrogen or progesterone receptors, the better the prognosis]. "The studies suggest that hormone receptors of the primary tumor are permanently reduced after early OCP use in a dose-dependent manner (the earlier the use, the lower the receptor)." [52, p.1991]. Olsson et al [53] also noted that women who had used OCPs at an early age (ie, on or before the age of 20) had a 5.3-fold risk of having "amplification of Her-2/neu." Her-2/neu is a type of oncogene that is associated with larger tumors, high tumor grade, advanced tumor stage, and an absence of steroid receptors [53, p.1483].
Kooy et al [54] noted that women who used oral contraceptives for more than 9 years had a 2.5-fold (1.4-4.4) increased risk for developing p53+ tumors. Over expression of the p53 gene is commonly regarded as evidence of the presence of a p53 mutation which has been associated with breast cancer. Therefore the question to be answered is: Does long-term use of OCPs act as an oncogene activator by causing over expression of the p53 gene?
Other evidence comes from the Oxford study which found that women who took OCPs before the age of 20 and had used them within the last 5 years had a higher incidence of local and distal breast cancer. (Local [regional] breast cancer is cancer that is confined to the breast, whereas distal breast cancer means cancer that has spread from its original site. Distal breast cancer is also 168 Breast Cancer, Its Link to Abortion and the Birth Control Pill called metastatic breast cancer). They also noted that women who took OCPs after the age of 20 had a slightly higher risk of regional breast cancer and a slightly lower risk of distal breast cancer [34, p.83S]. Of course this is a critical difference, especially when one notes that most of today's young women are taking OCPs before their FFTP, which is precisely the time interval that correlates with an increased risk of both local and distal breast cancer.
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