Broadening Our Perspective on Breast Cancer

April 1, 2007

Several issues raised in the article by Cianfrocca and Wolff and the accompanying reviews in the January issue of ONCOLOGY (21:63-80, 2007) deserve further comment. First, all authors address American resource-rich patient populations only. According to data from Parkin et al, nearly two-thirds of all new cases of breast cancer globally (a total of 1 million cases) occur among poor women. Half of these (500,000 cases) are in premenopausal women with hormone-receptor-positive tumors.[1] We need to broaden our horizons to consider these much larger populations whenever we discuss breast cancer therapies.

Several issues raised in the article by Cianfrocca and Wolff and the accompanying reviews in the January issue of ONCOLOGY (21:63-80, 2007) deserve further comment. First, all authors address American resource-rich patient populations only. According to data from Parkin et al, nearly two-thirds of all new cases of breast cancer globally (a total of 1 million cases) occur among poor women. Half of these (500,000 cases) are in premenopausal women with hormone-receptor-positive tumors.[1] We need to broaden our horizons to consider these much larger populations whenever we discuss breast cancer therapies.

Second, some discussion of emerging thinking about disease growth models seems appropriate. The authors mostly describe but do not evaluate currently available results. Breast cancer stem cell hypotheses, for example, warrant comments in light of population statistics, combined clinical trial data, and MA.17 trial results, all of which show significant rates of "late" recurrence despite 5 years of adjuvant hormonal therapies.[2-4] Uncertainties about the optimal duration of hormonal therapies must be considered in light of these data.

It is troubling to acknowledge that for prostate cancer (also apparently with limited data), there is considerably greater unwillingness to stop lutenizing hormone-releasing hormone (LHRH) agonist therapy even with the progression of disease considered "hormone-refractory." In the discussions about the superiority of adjuvant aromatase inhibitors over tamoxifen, I miss thoughts about why this makes biologic sense.

Third, the limited references to emerging data showing differences in the frequency of side effects and in rates of efficacy with tamoxifen therapy according to host genotype (for critical metabolizing enzymes) or use of selective serotonin-reuptake inhibitor (SSRI) drugs, suggest discomfort with the way we have promoted SSRI use, and limited sensitivity to how big these issues may be in some populations.[5,6]

Finally, I understand the uncertainty about "optimal" hormonal therapies being addressed by the Suppression of Ovarian Function Trial (SOFT), Tamoxifen and Exemestane Trial (TEXT), and Premenopausal Endocrine-Responsive Chemotherapy Trial (PERCHE), but I find the enthusiasm for these trials disturbing. Results will be a long time in coming, and the differences among therapies tested are likely to be small. We need to be proposing and testing bolder hypotheses and strategies. One such approach follows from our observation that the timing of surgical oophorectomy may have a significant impact on long-term outcomes.[7]

Richard R. Love, MD
Professor of Medicine
Hematology/Oncology
Professor of Public Health
Epidemiology/Biometrics
Director of International Oncology
Comprehensive Cancer Center
The Ohio State University
Columbus, Ohio

References

1. Parkin DM, Pisani P, Bray F, et al: Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 83:18-29, 1999.

2. Yakovlev A, Tsodikov AD, Boucher K, et al: The shape of the hazard function in breast carcinoma: Curability of the disease revisited. Cancer 85:1789-1798, 1999.

3. Saphner T, Tormey DC, Gray R: Annual hazard rates recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996.

4. Goss P, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early stage breast cancer. N Engl J Med 349:1793-1802, 2003.

5. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005.

6. Lim H, Lee K, Lee E, et al: CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer (abstract 634). J Clin Oncol 24(18S):36s, 2006.

7. Love RR, Duc NB, Dinh NV, et al: Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 94:662-669, 2002.


The Authors Respond

In his Letter to the Editor, Dr. Love discusses several important points including the need to address the impact of breast cancer outside the developed world, uncertainties about the optimal duration of adjuvant endocrine therapy in hormone-receptor-positive disease, how to optimally integrate aromatase inhibitors (AIs) and tamoxifen, the growing (though yet limited) body of evidence on the importance of host characteristics regarding drug metabolism, and the discomfort expressed by many regarding an excessive enthusiasm for the ongoing generation of randomized adjuvant endocrine trials for premenopausal women such as those currently being led by the International Breast Cancer Study Group (IBCSG).

We agree that late recurrences pose a significant risk for women with hormone-receptor-positive breast cancer.[1] The results from MA.17[2] strongly suggest that extended adjuvant endocrine therapy can decrease this risk of recurrence in postmenopausal women, and this concern has led many clinicians to consider extending endocrine therapy with an AI after 5 years of upfront AI therapy, even in the absence of safety and efficacy data. Results from the second AI randomization of MA.17—as well as from the crossover arms of Breast International Group (BIG) 1-98 testing an AI upfront vs crossover strategies—are eagerly anticipated. Unfortunately, even less is known about the safety and efficacy of extending adjuvant endocrine therapy (including ovarian suppression) beyond 5 years in premenopausal women. Consequently, clinicians should exercise caution and disclose the uncertainty about these various approaches when counseling their patients.

We share similar concerns about the long life cycle of large randomized trials, and about the generalizability of their findings beyond a relatively homogeneous group of research subjects. We agree that innovative trial designs exploring the identification of robust intermediate biomarkers will hopefully allow us to address questions that are relevant to a smaller patient subgroup, and also generate useful data more rapidly. For now, disease-free and overall survival remain the gold-standard metrics in the adjuvant setting, but we are hopeful that the improved characterization of various tumor phenotypes and the identification of more accurate predictors of therapeutic benefit will generate more meaningful data for the individual patients seen in our clinical practices.

We enthusiastically support the conduct of trials testing bolder hypotheses and strategies, many of which will subsequently require confirmatory studies. In the meantime, more traditional randomized efficacy trials (like those being conducted by the IBCSG) will continue to play an important role in our efforts to refine the optimal use of ovarian function suppression strategies in premenopausal women with hormone-receptor-positive breast cancer.

Mary E. Cianfrocca, DO
Assistant Professor
Division of Hematology/Oncology
Northwestern University Feinberg School of Medicine
Robert H. Lurie Comprehensive Cancer Center
Chicago, Illinois

Antonio C. Wolff, MD, FACP
Associate Professor of Oncology
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland

References

1. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14: 2738-2746, 1996.

2. Goss PE, Ingle, JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005.