The Harvard Medical School Family Health Guide

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Oral contraceptives and breast cancer risk

Researchers continue to unravel the web concerning the use of oral contraceptives and the risk of breast cancer. A study published in June 2002 indicated that birth control pills don't increase the risk of breast cancer for women in the general population (see August update). But a new study published in the December 4, 2002, issue of the Journal of the National Cancer Institute shows oral contraceptives can increase the risk of breast cancer in women with a particular genetic mutation.

The study examined whether the use of oral contraceptives increased the risk of breast cancer in women with a mutation in the BRCA1 or BRCA2 gene. Women who have such a mutation are already known to have a high risk of developing breast cancer and ovarian cancer. A person inherits these types of gene mutations.

The study involved 1,311 pairs of women who have the BRCA1 mutation, BRCA2 mutation, or both. Each pair of women shared certain characteristics, including mutation type, age, country, and history of ovarian cancer. Each pair included one woman who had been diagnosed with breast cancer and one who had not. Participants completed a questionnaire regarding their use of oral contraceptives based on their memory.

The researchers discovered that the use of oral contraceptives by women with the BRCA2 mutation was not associated with an increased risk of breast cancer compared to women who had not used the pill. For women with the BRCA1 mutation, use of the pill was associated with a modest increase in risk. However, women with the BRCA1 mutation and certain other characteristics had a significant increase in risk. For example, BRCA1 carriers who used oral contraceptives for five or more years had a 33% increase in risk of breast cancer compared to BRCA1 carriers who did not use oral contraceptives. In addition, women with the BRCA1 mutation who used the pill before 1975, when estrogen levels in the pill were higher, had a 42% increase in risk. Use of oral contraceptives before the age of 30 was associated with a 29% increase in risk for these women.

These findings apply only to women with the BRCA1 gene mutation, which can be detected through genetic testing. In light of this study, women who know they have this genetic mutation should discuss the pros and cons of birth control pills with their doctors. One benefit of taking the pill may be a decrease in the risk of ovarian cancer. A study published in the New England Journal of Medicine in 1998 showed women with either the BRCA1 mutation, the BRCA2 mutation, or both who took oral contraceptives for 5 years had a 60% decrease in risk of developing ovarian cancer compared to women who did not take the pill.

A woman’s age and how long she plans to use the pill should also be considered; use after the age of 30 and for fewer than five years was not associated with a significant increase in risk of breast cancer.

January 2003 Update

Mammograms: To screen or not to screen?

The mammography debate rages on, newly fueled by results from a Canadian trial published in the Sept. 3, 2002, Annals of Internal Medicine.

The Canadian National Breast Screening Study (CNBSS) is the first trial designed specifically to assess screening mammography in women ages 40–49. In the early 1980s, the CNBSS recruited 50,430 women in this age group with no history of breast cancer. Half were assigned to receive annual mammograms; the other half, to receive “usual care,” meaning that mammograms were done only if a patient’s doctor recommended them.

After an average of 13 years, there were 105 breast cancer deaths in the mammography group and 108 in the usual care group — not statistically significant difference. The researchers concluded that mammograms are not justified for breast cancer screening in women under age 50.

Critics of the CNBSS trial said the data came from older technology, before improved imaging was available. The women who took part enrolled 20 years ago, when mammography images were less clear and radiologists weren’t as proficient at reading them.

But the American Cancer Society, the Centers for Disease Control and Prevention, and the National Cancer Institute advise women to get annual mammograms starting at age 40.

To further muddy the waters, the same issue of Annals of Internal Medicine that carried the CNBSS results published new guidelines for breast cancer screening from the U.S. Preventive Services Task Force (USPSTF). The USPSTF is a panel of health experts that analyzes published research and makes suggestions about preventive health care.

The group recommends having a mammogram every one to two years, starting at age 40. The authors assert that there is no convincing evidence to support the theory that starting annual screening at age 40 exposes women to undue harm, with minimal chances of finding cancer.

On the other hand, if mammograms can find breast cancer, why not start at age 40? For one, the screening test may adversely affect some women. False-positive results (which flag a problem when none exists) can lead to anxiety and further testing.

In defense of its recommendations, however, the USPSTF says that anxiety usually disintegrates after cancer is ruled out. And even when it doesn’t go away, anxiety doesn’t seem to discourage women from continuing their screening regimen.

If you have a family history of breast cancer or other risk factors, it makes sense to start mammograms at age 40 (perhaps earlier, depending upon your level of risk). For everyone else, a discussion with your doctor is the most sensible first step. If she or he feels annual mammograms are unnecessary for you, and you’re comfortable with the decision, waiting until you’re 50 should be fine.

November 2002 Update

Chemotherapy not needed for all breast cancers

Chemotherapy may not be necessary for all breast cancer patients. A study published in the July 17, 2002, issue of the Journal of the National Cancer Institute indicated that postmenopausal women whose breast cancer is sensitive to estrogen may not benefit from adding chemotherapy to the estrogen-blocking drug tamoxifen.

The International Breast Cancer Study Group’s Trial IX looked at 1,669 women whose breast cancer had not spread to their lymph nodes. After being grouped according to their cancer’s estrogen sensitivity — estrogen receptor-positive or -negative — half of the women received chemotherapy followed by five years of tamoxifen, while the other half received only tamoxifen.

Those with ER-negative breast cancer enjoyed a statistically significant benefit in terms of disease-free survival (time before relapse; appearance of another cancer; or death) and overall survival when treated with chemotherapy followed by tamoxifen. But for those in the ER-positive group there was no difference in disease-free survival or overall survival when treated with the combined therapy.

Chemotherapy, in addition to tamoxifen, is regularly prescribed for the majority of postmenopausal patients with lymph-node negative, ER-positive breast cancer. The researchers hope that results from this and similar studies will encourage clinicians to treat postmenopausal women with a more individualized program, one that takes the estrogen sensitivity of their cancers into account.

September 2002 Update

Birth Control Pills and Breast Cancer

Good news for women who take the Pill — a new study, published in the June 27, 2002, issue of the New England Journal of Medicine, shows that current or former use of oral contraceptives does not increase the risk of breast cancer later in life.

Previous research indicated women who use or had used oral contraceptives in the past ten years were at an increased risk for breast cancer compared to women who had never used the Pill or had used it less recently. The new study was necessary now because the first generation of women to use the Pill at a younger age is reaching the period in their lives when the risk for breast cancer is greatest.

The study, conducted in Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle, involved 4,575 women with breast cancer and 4,682 without. Study participants were between the ages of 35 and 64. Seventy-seven percent of the women with breast cancer and 79% of the women with no personal history of breast cancer had used oral contraceptives in their lives. The results were analyzed according to race, age, family history of breast cancer, and type of oral contraceptive used.

According to the results, women who took the Pill were as likely to have breast cancer as those who had never taken it. The results also showed the risk for breast cancer did not increase with longer periods of use or with higher doses of estrogen. Age, race, weight, and family history did not affect the risk of breast cancer in women using the Pill compared to women who did not.

Researchers interviewed only Caucasian and African American women. They also evaluated the risk of breast cancer in relation to a family history in first-degree relatives only (not including grandmothers, aunts, and cousins). Regardless, the results of this study should allay the fear that breast cancer may be related to use of the Pill.

August 2002 Update

New Developments in Hormone Replacement Therapy

In July 2002, the government halted a major study of hormone therapy three years early because of a slight but significant increase in the risk of invasive breast cancer. Researchers concluded that the long-term risks of taking hormones outweigh the benefits for a woman who still has her uterus.

More than 16,000 women took part in the study, known as the Women's Health Initiative, the largest to compare postmenopausal hormones with a placebo. The therapy was a combination of estrogen and progestin (Prempro), a treatment used by an estimated six million women to replace the declining levels of hormones at menopause.

The study sought to determine whether this combination hormone therapy could prevent such ailments as osteoporosis and heart disease. But while there were small decreases in hip fractures and colorectal cancer, the increases in breast cancer, heart attacks, strokes, and blood clots were too unsettling.

The data suggested that for every 10,000 women on the estrogen-progestin combination, an additional 8 will develop invasive breast cancer, when compared with women not taking the therapy. An additional 7 will have cardiovascular disease, 8 will have a stroke, and 8 will have blood clots in the lungs (pulmonary embolism).

In the aftermath of the trial, it seems that many doctors will be reconsidering prescribing estrogen and progestin. Some women may want to lower their doses or limit the duration of the use of these combinations, while others will elect to try other treatments to combat their hot flashes, vaginal dryness, and other menopausal symptoms.

However, it is important for women already on hormone replacement therapy (HRT) to know that there is no urgency to stop, and waiting until an annual exam to discuss it with a doctor is fine. There is also no harm in stopping immediately, if a woman is more comfortable doing so.

It's important to remember that only combination therapy appears to have these effects. Estrogen alone taken by women who have had a hysterectomy has not displayed such risks. A separate trial, with 10,000 women who have had a hysterectomy randomly assigned to either estrogen or a placebo, has not indicated an increased breast cancer risk. The trial is scheduled to go until 2005.

The full report on the Women's Health Initiative appeared in the Journal of the American Medical Association on July 17, 2002.

July 2002 Update

Hormonal Therapy Recommended for All Hormone-Receptor-Positive Breast Cancers

In a statement issued late last year, the National Institutes of Health recommended that all women who have hormone-receptor-positive breast cancer receive hormonal therapy in addition to their primary treatment (surgery alone or surgery plus chemotherapy). This recommendation holds regardless of a woman's age, menopausal status, tumor size, or whether the cancer has spread to the lymph nodes.

Hormone-receptor-positive cancers grow in response to the hormone estrogen, which is produced by the ovaries. Tamoxifen (Nolvadex, Tamoplex), the most widely used hormonal therapy, works by blocking estrogen receptors on breast cancer cells. It is used to halt, slow, or prevent tumor growth. Studies have shown that women who take tamoxifen for five years reduce their annual risk of a recurrence of breast cancer by 40%. Taking the drug for more than five years offers no additional advantage, and it increases the risk of toxic effects.

Premenopausal breast cancer patients under the age of 50 reap a significant benefit from adjuvant tamoxifen therapy. Results from a small study show that women under 50 who received tamoxifen in addition to chemotherapy had a 40% reduction in recurrence and a 39% reduction in death compared with women who had chemotherapy alone. These results are not conclusive, however, because of the small trial size. A study currently underway in Canada may provide more reliable results.

Postmenopausal women with very small, low-grade tumors, however, may experience only a small overall benefit from tamoxifen. After menopause, women have lower levels of estrogen in their bodies. Studies have shown that women in this group who undergo chemotherapy but do not take tamoxifen may live as long as women of the same age with no history of breast cancer. Because tamoxifen can cause rare, serious side effects such as blood clotting and endometrial cancer, postmenopausal women and their physicians should weigh the benefits of taking the drug against the risks.
May 2001 Update

FDA Approves Femara as First-Line Breast Cancer Treatment

On January 10, 2001, the U.S. Food and Drug Administration (FDA) approved Femara (letrozole) as a first-line treatment for postmenopausal women with advanced breast cancer. Femara was originally approved in 1997 to treat advanced breast cancer in women who did not respond to standard antiestrogen drugs such as tamoxifen.

The hormone estrogen stimulates the growth of about half of all breast cancers, known as hormone-receptor-positive breast cancers. Femara, which works by blocking the production of estrogen, can now be used as a principal therapy for these and hormone-receptor-unknown advanced breast cancers. For 20 years, tamoxifen, which blocks estrogen from binding to an estrogen receptor on cancer cells, has been used as a first-line treatment in early and advanced breast cancer patients with hormone-receptor-positive or hormone-receptor-unknown cancer. It has also been used to slow the progress of tumor growth of breast cancers that have metastasized, or spread to other parts of the body.

The recent FDA approval of Femara was based on the results of a randomized, double-blinded, multinational clinical trial comparing Femara and tamoxifen. It involved more than 900 postmenopausal women with locally advanced breast cancer, breast cancer that had spread to other parts of the body, or recurring breast cancer that could not be treated with surgery or radiation. The trial showed that Femara increased time to progression of the disease to 9.4 months, compared to 6 months for tamoxifen. The gain is considerable for late-stage cancer, and it allows women to delay more toxic chemotherapy. The side effects for both drugs were comparable and included back, joint, and bone pain, nausea, and hot flashes.

What is not known at this point is whether Femara will have any role in the prevention of breast cancer. Tamoxifen is often given to hormone-receptor-positive breast cancer patients after surgery, to prevent tumors from recurring and to women with a strong family history of breast cancer to prevent the disease from developing in the first place. Femara has not yet been approved for either of these purposes.
January 2001 Update

More News and Less Clarity on Hormone-Replacement Therapy and Breast Cancer

Menopausal and postmenopausal women might choose to take hormone (estrogen)- replacement therapy for a number of reasons. Short-term HRT can help relieve discomforts associated with menopause, for example, hot flashes. Longer-term HRT may help ward off osteoporosis and also has been associated with a lower risk of heart disease. Estrogen taken alone greatly increases the risk of developing cancer of the uterine lining (endometrial cancer). If a woman has not had her uterus removed, typically progesterone is also taken as part of the hormone-replacement therapy and brings the risk of endometrial cancer back to baseline. Another potential downside of HRT is the possible increase in breast cancer risk associated with this therapy, which scientists believe may be related to estrogen's effect on breast tissue. Recent analysis of a large body of epidemiological data suggests that having used HRT recently and for a longer time increased breast cancer risk, particularly among leaner women. Having taken HRT in the past did not seem to influence this risk.

A recent study conducted at the National Cancer Institute (NCI) set out to examine whether combined therapy (estrogen and progesterone) affected breast cancer risk beyond what one might expect from estrogen alone. Study investigators followed 46,355 postmenopausal women for an average of 10 years. The study volunteers' average age was 58 years old at the start of the study. Based upon the number of breast cancer cases during follow-up, researchers calculated that taking estrogen alone increased breast cancer risk by 1% per year for each year a woman takes HRT. Taking combined estrogen and progesterone raised that risk considerably to 8% per year. Calculated out over several years, that prospect can be terrifying for many women. This conclusion does not come totally out of the blue for researchers. For example, the Harvard Nurses' Health Study data also have shown an association between combined therapy and increased breast cancer risk when compared with estrogen taken alone.

However, as with all clinical studies, there are factors in the NCI study that make it hard to tease out firm conclusions from this research. First, there are several ways to take combined therapy. A woman might take estrogen every day and progesterone only some days of the month, mimicking the menstrual cycle and producing a "period" each month. In fact, most of the women in this study followed this regimen. However, women can also choose to take both hormones every day to avoid monthly bleeding. It is hard to say if the results of this study apply equally to this method of combination HRT. Another interesting aspect of this research was that investigators sorted results by the women's body mass index (BMI) (a woman was considered overweight if her BMI was above 24.4). This threw another wrench into the conventional wisdom. Being overweight is generally associated with a higher breast cancer risk. The theory is that fat tissue produces a weak form of estrogen that may affect breast tissue. However, data from this study suggested that for the women who were overweight HRT of any type did not increase breast cancer risk: and even more strangely, that estrogen taken alone reduces that risk in overweight women. It is difficult to say whether this is due to biology or simply because their risk was higher to begin with. Similarly, the increased breast cancer risk found for thinner women could be due to some biological aspect of body weight, or perhaps because slim women often have smaller breasts and it may be easier to catch breast cancer when breast tissue is less dense.

Rather than offer enlightenment to women facing the HRT decision, this research has muddied the waters further. An editorial written by Harvard Medical School doctors that accompanied the publication of this study makes the following suggestions. Given what we know now, short-term HRT (two to three years) taken to alleviate menopausal symptoms is very unlikely to alter breast cancer risk. Women thinking of HRT for this purpose should not be discouraged by this new study. Women who do not have a uterus do not need progesterone along with estrogen and should not take combination therapy. Women who do have a uterus and are thinking about long-term HRT to reduce the risk of osteoporosis or heart disease should carefully weigh the potential risks and benefits of HRT for this purpose. There are new drugs available to treat and help prevent osteoporosis, and recent data on hormone replacement and heart disease suggest that cholesterol-lowering drugs (statins) can do as good a job as HRT without many of the risks. And no matter what a woman decides about HRT, there is no substitute for careful attention to a healthy diet, adequate exercise, and following her doctor's recommendations for screening tests and physical exams.

Osteoporosis Drug May Offer Protection Against Breast Cancer

A drug designed to combat osteoporosis greatly reduced the risk of some forms of breast cancer in a study of postmenopausal women. Researchers from the University of California at San Francisco were originally testing Raloxifene's ability to reduce bone fractures in postmenopausal women with osteoporosis. Women with osteoporosis are particularly vulnerable to bone fractures because estrogen production drops sharply after menopause. The 7,705 participants were also monitored for breast cancer, and it was this secondary purpose that revealed the drug's effects on breast cancer risk.

Raloxifene reduced the overall risk of breast cancer by 76%, and estrogen receptor-positive breast cancer by 90% in the three-year study. Estrogen receptor-positive is the most common form of breast cancer in older women. However, Raloxifene did increase the chance of venous thromboembolic disease, a rare disorder that causes blood clots in the veins, but it did not increase the risk of endometrial cancer, which is cancer of the uterine lining.

Raloxifene's side effects included hot flashes, leg cramps, and sinusitis, but fewer than 1% of the subjects dropped out because of them. Researchers caution against euphoria. The original intent of the study was Raloxifene's effect on osteoporosis, not breast cancer and neither the long-term benefits, nor the long-term risks of the drug are known. However, Raloxifene offers hope for a way to reduce the risk of breast cancer.

New Information on Hormone-Replacement Therapy and Breast Cancers

Menopausal women deciding about whether to start hormone-replacement therapy (HRT) must weigh the potential benefits, which include a reduced risk for heart disease and osteoporosis, against the potential risks — the most serious being an increased risk of breast cancer. A 1995 analysis of 51 combined studies did show an increase in breast cancer risk for women taking HRT for five or more years when compared to women who had never taken HRT. The researchers who performed this analysis, however, also proposed that HRT exposure promotes the growth of less aggressive, slower-growing forms of breast cancer.

A recent report from the Iowa Women's Health Study appears to support this hypothesis. For the purposes of this report, study investigators followed the health of 37,105 women who were 55 to 69 years old in 1986 for 11 years. Over this period, 1,520 of the women developed breast cancer. Researchers found that while postmenopausal use of hormone-replacement therapy may increase the risk of breast cancer by 15%-30%, HRT use was most strongly associated with breast cancers with a favorable prognosis.

This information may help women better weigh their health concerns and personal preferences when deciding whether or not postmenopausal hormone-replacement therapy is right for them. For more information on postmenopausal hormone-replacement therapy, see page 1049 in the Family Health Guide.

High-Dose Chemotherapy and Stem Cell Transplantation for Breast Cancer

Most women with metastatic breast cancer respond to conventional doses of chemotherapy. 10 years after their disease is detected, fewer than 5% of these women are still alive. This sobering statistic was the impetus for research into more effective treatments. In the late 1980s, initial studies on patients with metastatic breast cancer treated with high doses of chemotherapy and stem cell transplantation yielded some promising results. Stem cells are the immature cells that form all blood cells. The therapy involved harvesting and preserving stem cells from the breast cancer patient prior to treatment with high doses of chemotherapy (which destroys bone marrow as well as the cancer cells). Following chemotherapy the stem cells were transplanted back into the patient. The treatment became popular for women with metastatic or high-risk breast cancer (which has spread to the lymph nodes but not other organs), despite the lack of solid evidence from randomized clinical trials.

Now, results from a clinical trial show that this grueling therapy does not improve survival in women with metastatic breast cancer. The study, which began in 1990 in Philadelphia, compared the effect of high-dose chemotherapy and stem cell transplantation with conventional doses of chemotherapy. Researchers initially treated 553 metastatic breast cancer patients with standard doses of chemotherapy. The 199 women who responded to this treatment were then randomly assigned to receive either the experimental treatment or conventional doses of chemotherapy. Researchers analyzed each therapy by length of survival, time to disease progression, and toxic effects.

Women receiving the experimental therapy had a three-year survival rate of 32%, while women receiving conventional chemotherapy had a slightly higher three-year survival of 38%. The median time to disease progression was similar among both groups; 9.6 months for the experimental group and 9.0 months for the conventional treatment group. These results suggest that high-dose chemotherapy combined with stem cell transplantation offers no advantage over conventional therapy in terms of survival rate and time to progression. Furthermore, the incidence of serious adverse effects was greater among women treated with the experimental therapy.

These data contradict a previous study that reported that high-dose chemotherapy combined with stem cell transplantation significantly improved the survival of women with high-risk breast cancer. This was the only randomized study that reported positive results with the therapy.The study has been discredited due to scientific misconduct. Researchers also believe that selection bias toward healthier and younger women may have played a role in the positive results seen in the initial studies from the 1980s.

Results of further studies on women with metastatic or high-risk breast cancer may clarify approaches to the most effective treatment for this disease. For the time being, however, high-dose chemotherapy with stem cell transplantation is not recommended for women with metastatic breast cancer outside of clinical trials.

Clonidine for Tamoxifen-Induced Hot Flashes

Hot flashes are a common side effect in postmenopausal women taking tamoxifen for breast cancer. While many of these women are able to keep their hot flashes from interfering with their daily activities, others are not. Even though low doses of megestrol, and other progestational agents, have been found to control hot flashes, doctors are reluctant to prescribe them for women taking tamoxifen because both progestational agents and tamoxifen can cause side effects, including blood clots.

A recent report suggests that clonidine, a nonhormonal drug, appears to be effective in reducing the frequency of hot flashes in this group of women. During this study, participants who took 0.1 mg of clonidine at bedtime for eight weeks reported a significant reduction in the number of hot flashes they experienced and a small beneficial effect on the severity and duration of these episodes. Women in the group taking clonidine had been experiencing an average of eight hot flashes a day at the start of the research. After eight weeks of taking clonidine daily, these women experienced an average of 2.2 fewer hot flashes per day.

While clonidine showed significant benefit for most of the women taking it in the study, it should be noted that some women experienced no benefit. Only one major side effect, difficulty sleeping, was reported by 41% of the women taking clonidine. Though the study did not evaluate clonidine’s long-term benefits, the researchers involved believe that its continued use would prove valuable.


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