The Global Breast Cancer Disparity: Title and subTitle BreakStrategies for Bridging the Gap

It is estimated that, by the year 2020, 70% of patients with cancer will live in countries that have less than 5% of the resources available for care of patients with cancer.¹ Breast cancer is the most common malignancy in women worldwide and is a prototype of global cancer disparity. While breast cancer mortality is decreasing in developed countries, it continues to increase in low- and middle-income countries (LMCs). The age-adjusted survival rate from breast cancer ranges from 32% in sub-Saharan Africa to 81% in the United States.¹ This disparity results from several factors, mostly related to disease biology and access to screening and effective treatments.¹

Selective aromatase inhibitors, the taxanes, and targeted therapies (trastuzumab, lapatinib) are pharmacological treatments that have been proven effective and are widely available in developed nations. These novel agents carry substantial price tags and are mostly cost-prohibitive in LMCs. While these scientific breakthroughs should be acclaimed and propagated, they must be applied in an equitable and cost-effective way. Several strategies have been proposed by working groups, such as the Breast Health Global Initiative,^{2 - 3} with the goal of improving health care in LMCs.

Targeting the estrogen receptor has been the most important breakthrough in tailoring treatment for breast cancer. A few trials have shown the value of extended therapy with an aromatase inhibitor after 5 years of adjuvant therapy with tamoxifen. Based on the hypothesis that intermittent doses of aromatase inhibitors may cause estrogen stimulation and enhance response of residual resistant cells, an ongoing trial (NCT00553410) is comparing continuous vs intermittent treatment with letrozole as extended adjuvant therapy. Intermittent aromatase inhibitor therapy would result in reduced treatment costs.

The next milestone in breast cancer therapy was the development of therapies targeting the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2, formerly HER2/neu) receptor. In the FinHER trial, the outcomes of 9 weeks of trastuzumab in women with amplified ERBB2 gene were similar to outcomes in other trials with 52 weeks of treatment. Despite a much smaller sample size, the results were encouraging and should be confirmed in larger studies. Three European trials comparing 52 weeks of trastuzumab with 9 weeks (NCT00593697), 3 months (NCT00629278), and 6 months (NCT00381901) are in progress.

Lapatinib is an oral dual tyrosine kinase inhibitor of both epidermal growth factor receptor and ERBB2, approved for advanced ERBB2-positive breast cancer after failure of trastuzumab treatment. Recent pharmacokinetic data showed that lapatinib plasma concentrations increase when the drug is taken with food, particularly with fat, allowing the administration of reduced doses of the drug.⁴ Nevertheless, the label advises that lapatinib should be taken on an empty stomach. Additionally, a phase 2 trial comparing 2 schedules of lapatinib treatment (500 mg twice daily and 1500 mg once daily) showed no difference in efficacy with the lower dose.⁵

In the advanced as well as the early stage of disease, limiting use of trastuzumab to women with known ERBB2-positive status is a cost-effective measure, even with the additional associated testing costs. Nevertheless, in the United States, a recent study revealed that up to 20% of patients receiving trastuzumab were neither tested nor had any documentation of a positive test result.⁶

Pharmacogenetics has also played a role in the effort to increase drug efficacy. Patients can be classified as decreased, intermediate, or extensive metabolizers according to the genetic variation in CYP2D6, a key enzyme in tamoxifen metabolism. A recent modeling analysis suggested that the benefit of 5 years of adjuvant tamoxifen therapy in patients who were carriers of the wild-type CYP2D6 (the extensive metabolizers) was similar or perhaps superior when compared with aromatase inhibitor therapy.⁷ Thus, a one-time test for CYP2D6 genotype has the potential to make the patient eligible for 5 years of savings by allowing for the use of tamoxifen, the less expensive agent. However, CYP2D6 genotyping has not been routinely incorporated into clinical practice, and prospective studies are needed to corroborate these data.

Multigene arrays can be used to classify tumors into low, intermediate, and high risk of recurrence. These arrays may reduce cost by identifying a large number of patients in the low-risk group, which does not need adjuvant chemotherapy in addition to tamoxifen; these arrays also can turn conventional cytotoxic regimens into targeted treatment for high-risk patients. Although more than 90% of US health insurers cover these tests, the hefty price tag (approximately $4000 for some tests) makes the test cost-prohibitive in many LMCs. The development and validation of less expensive prognostic tools⁸ are attractive alternatives in LMCs.

The poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors are potentially practice-changing and are the newest examples of personalized therapy in metastatic breast cancer. Recent studies have shown that PARP inhibitors are active against breast cancer gene (BRCA)–associated malignancies, either as single agents or in combination with cytotoxic drugs. They are potentially better tolerated and at least as effective as cisplatin but represent another example of a drug that would likely be cost-prohibitive in LMCs.

Interest in older and less expensive drugs has also been renewed. Cisplatin has been found to be effective in vivo in BRCA1-mutant cells and is currently being tested in triple-negative, basal-like breast cancers. In contrast to the PARP inhibitors, cisplatin is much less expensive and is readily available in most LMCs. In a pilot study with 25 women with BRCA1 mutations, after 4 cycles of neoadjuvant cisplatin therapy, 18 of 25 women (72%) had a pathologic complete response in breast and lymph nodes.⁹

In the pre-tamoxifen era, synthetic estrogens constituted one of the few nonsurgical options for breast cancer. Toxicities resulting from high-dose estrogens and the development of the better-tolerated tamoxifen have led to the current rare use of synthetic estrogens. A recent phase 2 trial in postmenopausal women with metastatic breast cancer and acquired resistance to aromatase inhibitors showed a clinical benefit for 28% of patients treated with high-dose (30 mg) estradiol therapy and for 29% of those treated with a lower dose (6 mg).¹⁰ Fewer serious adverse events were reported in the lower-dose group. Larger clinical trials are warranted to determine the efficacy of the less expensive and better tolerated lower-dose estradiol and cisplatin from a targeted perspective.

Especially in a limited-budget scenario, choices must be based on cost and effectiveness. The LMCs have a disproportionately high burden of deaths from breast cancer and could derive the most benefit from validation of the aforementioned strategies. However, although potentially cost-effective, some of these measures are expensive enough to limit their use in many LMCs.

While LMCs face great challenges, they have the unique opportunity to learn from the successes as well as the errors of wealthier countries. Acknowledging that the development of novel technologies does not always result in improved effectiveness or reduced costs is mandatory. Furthermore, the barriers for LMCs to close the gap involve 4 intertwined challenges: investing in human capital; developing and validating less expensive technologies, through comparative effectiveness studies, that apply locally to varying budgets and cost restraints; improving access to treatment through publicly funded health care systems; and financing policies that facilitate these initiatives.

These initiatives for improving health care in LMCs represent valuable opportunities for research in global cancer disparities, comparative effectiveness, and pharmacoeconomics. These initiatives may be promoted and facilitated by international cooperation.