Prospects have improved with the development of new drugs that interfere with unique biochemical pathways driven by cancer-causing mutations. The translation of molecular findings into practical treatments is exemplified by the recent approval and acceptance of Herceptin® in clinical practice.This antibody targets the cell surface marker for a particularly lethal subtype of breast cancer, and is active only in patients carrying that marker. Identifying patients likely to benefit was a major challenge, solved by rigorous testing of large populations in early clinical trials. Recent randomized studies prove that carefully selected patients enjoy markedly improved outcomes if Herceptin is combined with standard chemotherapy at the time of original diagnosis. Other new US Food and Drug Administration (FDA)- approved biologic agents, (Avastin®, Tarceva®, and Erbitux®) cannot be prescribed with confidence (or insurance coverage) until the logistical hurdles of patient selection and definition of optimal combinations are solved. Similarly, investigational agents such as sorafenib and lapatinib are poised for approval but will not be used widely until the same barriers are breached.
Another area of hot research is the genotyping of cancer cells to determine whether a patient will or will not benefit from specific treatments, including standard hormone or chemotherapy, or new biologics. In particular, the OncotypeDX® assay of 21 cancer-related genes predicts patient outcome, and can guide the drug therapy of post-menopausal women at the time of initial diagnosis. In a perfect future, effective therapies will cure rather than palliate, and they will be used only on those patients who will benefit from them. This is known as the testicular cancer paradigm treatment can cure, even if used in advanced disease. Currently, medical treatments extend the lives of breast cancer patients by approximately five years beyond that expected with only surgery or radiation. New treatments will buy even more survival time, but no cures are on the horizon. Side effects of current cancer therapies range from none to debilitating, and individual patient costs can exceed US$100,000 per year.
Screening is widely accepted, despite remaining doubts about overall benefit and cost-effectiveness. Strong opinions promote its use, based on the assumption that cancers discovered early can be excised and cured. Randomized trials encompassing half a million women have the statistical power to demonstrate a relative benefit for screened versus unscreened women. However, in absolute terms, only six per 10,000 women benefit from regular screening, whereas several thousand will undergo additional tests and biopsies. A recent comparison of women diagnosed with either early or advanced breast cancers found that similar proportions had participated in screening.
The notion that timely surgery can cure is becoming outdated as it ignores two important bodies of knowledge. Firstly, most screen-detected breast cancers are slow-growing, with a low likelihood for harm. Finding and excising these low-risk cancers, many of which are destined to remain dormant, makes only a small impact in overall cancer mortality, while committing a large number of women to treatment. In addition, pre-cancerous tissue, which is often found via screening, is frequently over-treated, as a clear consensus on optimal management is lacking. Ironically, screened populations have approximately 50% more breast cancers than unscreened populations, because screening detects so many low-risk cases that would never become clinically significant. Consequently, many healthy women are labeled cancer patients. Meanwhile, the most lethal cancers are often missed by screening mammograms either because they cannot be differentiated from surrounding normal tissue, or because they grow quickly in the interval between screening examinations. Despite the promise of digital mammography, it has not been proven to be better than standard technology. A screening test that preferentially finds lethal cancers is needed.The second area of research arguing against a strategy of early detection is the discovery that breast cancer cells often disperse early in the course of the disease.With new pathologic technologies, they can be seen in the bloodstream, lymph nodes (LNs), bone marrow and elsewhere, even in women thought to be cured by surgery.Whether the cells remain dormant for decades, or grow rapidly, the cat is out of the bag. Early detection, to accomplish a surgical cure, will probably not work.These cases need medication that works throughout the entire body, to suppress or eliminate the disseminated cells.
Societally, population-based screening is now being committed to, despite the associated burdens of downstream testing, over-diagnosis, and over-treatment. No significant improvements in mammography are on the horizon, although alternative screening tests (magnetic resonance imaging (MRI), ultrasound, and ductal lavage) are being evaluated. Current costs are very high, estimated to be several hundred dollars per woman per year, for every woman who chooses to be screened.
Ideally, prevention would be the best solution. Breast cancer is caused by multiple mutations in normal breast tissue, and preferential growth of those mutated cells. Mutations can be congenital, like inherited breast cancer mutations, or acquired, with ionizing radiation the only proven culprit. Growth of breast tissue, normal or abnormal, is stimulated by hormones and perhaps by other growth factors as well. If a woman is born with a breast cancer gene mutation, she can consider prophylactic mastectomies or hormone suppression, via removal of the ovaries or anti-hormone medications. Women at high risk for breast cancer because of prior radiotherapy for childhood cancer or lymphoma can reduce their risk by the same means. These circumstances are rare, but they offer insight into prevention strategies for the more common, sporadic breast cancers.
Regardless of causation, the mutations that lead to breast cancers accumulate during a woman’s lifetime. Older women are therefore much more likely to develop breast cancer than younger women. Besides age, factors that increase risk are those associated with increased exposure to uninterrupted estrogen—early menarche, late pregnancies, low parity, late menopause, and supplemental hormones. Until recently, the negative impact of post-menopausal hormones was underestimated and thought to be a fair trade-off for their presumed cardiac benefits. However, results from the Women’s Health Initiative (WHI) were reported in 2002. Post-menopausal women were randomized to receive hormone therapy or placebo, with a primary end-point of cardiac disease. The study was stopped early because of an increased incidence of cardiac and thrombo-embolic events, as well as breast cancer, in women receiving both estrogen and progesterone.
In the UK, the Million Women Study (MWS) obtained detailed information about the use of hormone replacement therapy (HRT), and confirmed the findings of the WHI. These studies resulted in most public health advisory committees withdrawing their previous recommendations for menopausal hormone therapy. Interestingly, when the study drugs were stopped abruptly in the WHI, 67% of women receiving hormones, and 40% of women receiving placebo experienced moderate or severe side effects, demonstrating the suggestibility of health-conscious women and their beliefs about the subjective benefits of hormone therapy. It is interesting to speculate how much the use of post-menopausal hormones has contributed to the increasing incidence of breast cancer over the past 25 years.
Besides avoiding cancer-promoting hormones, a woman can take medications to reduce the hormone stimulation of her breasts. Two classes of anti-cancer hormones exist—selective estrogen receptor modifiers, (SERMs), which include tamoxifen (Nolvadex®) and raloxifene (Evista®), and Aromatase inhibitors (AIs), which include anastrazole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®).For 40 years, the SERM tamoxifen has been a mainstay in the treatment of metastatic breast cancer and as adjuvant therapy to prevent recurrence after surgery for 25 years. It only works in hormone-sensitive breast cancers, which comprise approximately two-thirds of all breast cancers. Tamoxifen and another SERM (raloxifene) have been proven to prevent one-half of new breast cancers in women at moderate to high risk. Precancers are also reduced. These drugs affect all bodily tissues influenced by estrogen. Like estrogen, they improve bone mineral density (BMD), cause blood clots, and stimulate proliferation of the uterine lining, even leading to cancer. However, they have an anti-estrogen effect on the breast, decreasing tissue density and reversing proliferative activity, and they cause hot flashes.
AIs are a new class of drugs for hormone-sensitive breast cancer. These drugs block the estrogenproducing enzyme aromatase and are effective against metastatic breast cancer resistant to SERMs. More recently they have been recommended for adjuvant treatment to prevent recurrence after initial breast cancer surgery in this context they are roughly equivalent to SERMs in reducing cancer mortality. The AI side effect profile is attractive no blood clots or uterine cancer, and fewer hot flashes; however, they may weaken bones, and women have more fractures. Bone-strengthening drugs can reverse the AI effect on BMD, but they do not prevent the increased risk of falling, also seen with AIs. Impaired cognition has also been documented.
The inadequately studied neurologic effects of AIs could limit their use as cancer prevention agents where the tolerance for side effects is low; however, benefits and risks must be weighed up. These drugs appear to prevent breast cancer very effectively. Testing of AIs versus SERMs in women with newly diagnosed breast cancer reveals a greater reduction in new breast cancers with AIs. This finding has led to several small AI prevention trials in the US, targeting women at high risk because of increased breast density or high serum estrogen levels. In addition, two large randomized controlled trials, each accruing several thousand postmenopausal women, are also under way. An international trial sponsored by Pfizer compares exemestane with placebo, with early results anticipated in 2010.A similar trial, sponsored by AstraZeneca in the UK, compares anastrazole with placebo.
These trials are extremely likely to yield positive results, and widespread adoption by women at moderate or high risk could reduce breast cancer incidence by 50%. Ultimately, the acceptance of these drugs will depend on their side effects and price,which currently stands at more than US$100 per month. By contrast, tamoxifen has just lost patent protection and is inexpensive (under US$10 per month), but is still not widely used for cancer prevention because of the potential side effects.
Besides hormone therapies, there is little on the horizon. Hormone-resistant cancer, which preferentially affects younger women, grows rapidly and has poor outcomes, can be successfully treated with chemotherapy and, in appropriate cases, Herceptin. Neither can be used for prevention, and at-risk women cannot be identified. Causation and evolution are poorly understood, so there are no effective methods to prevent it.
Other than hormones, proven risk factors for breast cancer are obesity, a sedentary lifestyle, and alcohol consumption. A common mechanism to explain these findings (insulin-related growth factor) has been proposed, but not confirmed. Lifestyle changes are the only proposed intervention. Many theories about breast cancer causation have been disproven, including breast trauma, underarm deodorants, abortion, organochlorides, magnetic fields, and high-voltage power lines. Other drugs proposed for the prevention of breast and other cancers include the cyclo-oxygenase (COX)-2 inhibitors recently withdrawn from the market because of cardiac toxicities and dietary supplements that are in early stages of development. Vitamins do not prevent cancer, and some may increase incidence and mortality. Regular aspirin use has been associated with decreased breast cancer incidence, but has not been tested prospectively.
The most promising interventions to control breast cancer lie in hormone manipulation for prevention and treatment. In the future, new drugs effective enough to cure may be found.With careful research molecular mechanisms may eventually be understood well enough to tailor treatment to each patient s individual cancer, although that goal is in the distant future. Recognizing that it took Herceptin 20 years from first proposal until its use as adjuvant therapy, patience should be expressed. Each new drug will require similarly rigorous testing, to determine which cancers may benefit and which treatment regimens will work. Despite calls from investors for rapid drug approval, shortcuts in drug development will not bring the desired results, but may endanger patients, delay or obscure important clinical findings or allow potentially useful agents to be overlooked.Translation of molecular findings into clinical practice will only work if treatment results are analyzed and compared with proven standards. Well-designed clinical trials will always be needed, and must be granted the time and money required for their performance. ■