Hormone Receptor–Positive Breast Cancer: The Known and the Unknown

Over the last decade, retrospective and prospective studies, as well as multiple editorials expressing various expert opinions, have been published that explore different aspects of the subtypes of breast cancer that we know to exist. Interestingly, with each piece of data and viewpoint published, we acknowledge the fact that breast cancer is a heterogeneous disease, comprising multiple subtypes about which there are myriad questions. The review by Lim and colleagues, on the natural history of hormone receptor–positive breast cancer, is timely as it gives us a comprehensive overview of the most important data on the subject published to date. It takes us through a proposed natural history of this disease derived from the existing data, and examines some of the interesting questions that have arisen.

What do we know about hormone receptor–positive disease? We know it has a known target for treatment with endocrine therapy; it is more chemotherapy-resistant compared with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer; it tends to recur late, possibly after completion of endocrine therapy; and like every other subtype identified, it, too, is heterogeneous. Yet has any of this knowledge changed the way we treat a woman with hormone receptor–positive cancer today, compared with a decade ago? The answer is probably both yes and no.

Consider a typical case of a postmenopausal woman with a T2N1M0 hormone receptor–positive HER2-negative breast cancer. The question that frequently arises is: Does this type of patient require chemotherapy? Berry et al[1] showed in a retrospective analysis of three prospective trials that the addition of chemotherapy resulted in an absolute improvement in 5-year disease-free survival of 22.8% and 7% in women with estrogen receptor–negative and estrogen receptor–positive disease, respectively. This indicates that a benefit exists, but not as much as that for women with hormone receptor–negative disease. How can we truly know the benefit of subjecting a patient to the potential toxicities of chemotherapy? The answer may come from genomic risk assessments of breast tumor tissues.

The recurrence score derived from Oncotype DX (Genomic Health, Inc) is able to categorize hormone receptor–positive, node-negative tumors into high and low risk groups that do and do not benefit from the addition of chemotherapy, respectively. Oncotype DX has been validated in multiple datasets, leading to its incorporation into practice guidelines. Its role in patients with node-positive disease is currently being investigated. Albain et al[2] used the recurrence score to determine the benefit of the addition of chemotherapy in patients with node-positive disease who were enrolled in the Southwest Oncology Group (SWOG) 8814 trial (which randomized women to endocrine therapy alone or to endocrine therapy and chemotherapy), demonstrating no benefit for the addition of chemotherapy in women with a recurrence score of less than 18 and a significant benefit in those with a recurrence score greater than or equal to 31. RxPONDER is a large prospective planned trial whose objective is to determine the benefit of chemotherapy among women with hormone receptor–positive breast cancer, one to three positive nodes, and a recurrence score less than or equal to 25. Thus, until the results are available, the standard would be to add chemotherapy to this patient’s treatment regimen.

Despite having mechanisms in place to determine chemotherapy benefit in this cohort, unfortunately there is no precise way at prsent to determine the degree of benefit and resistance to endocrine therapy at the individual level of the patient with hormone receptor–positive breast cancer. Lim et al describe various mechanisms that could be potentially responsible for de novo and acquired endocrine resistance. The most studied of these mechanisms is the activated PI3 kinase pathway that confers resistance to endocrine therapy. One way to overcome this resistance is to combine endocrine therapy with an mTOR inhibitor such as everolimus (Afinitor), the benefit of which has been demonstrated in patients with hormone receptor–positive breast cancer who have progressed on endocrine therapy. Whether we can use this upfront in the adjuvant setting is a question that is being studied. Such agents are not without toxicity, however, and this warrants the development of methods that would allow up-front determination of specific tumors inherently resistant to endocrine therapy. Tumors that co-express HER2 are also known to be less responsive to endocrine therapy in the absence of an anti-HER2 agent, which raises the question of whether 1 year of adjuvant trastuzumab (Herceptin) is enough in women whose tumors co-express both receptors. The arm of the HERA (Herceptin Adjuvant) trial that is investigating 2 years of trastuzumab may shed some light on this issue. Another explanation for lack of response to endocrine therapy may simply be the inaccurate measurement of estrogen and progesterone receptor levels using immunohistochemistry, with studies indicating that the inaccuracy rate could be as high as 20%.[3] Although the multitude of resistance mechanisms appears daunting, the ability to accurately determine up-front resistance to endocrine therapy is an active area of research. Recent and interesting work comes from Symmans e al,[4] who developed the sensitivity to endocrine therapy (SET) index that assesses the expression of genes correlated with estrogen to better predict outcome in response to endocrine therapy.

The questions of how long to give adjuvant endocrine therapy, and how much of a role resistance mechanisms play in women with hormone receptor–positive breast cancer who recur upon completion of 5 years of adjuvant endocrine therapy are currently the focus of multiple clinical trials. Prospective studies have demonstrated the continued benefit of endocrine therapy, in postmenopausal women, in the form of an aromatase inhibitor following completion of 5 years of tamoxifen. Whether postmenopausal women who get up-front aromatase inhibitors will benefit from more than 5 years of endocrine therapy is a question currently under investigation. Such strategies are designed to reduce the late recurrence known to be associated with hormone receptor–positive disease. Accurately identifying women at risk for a late recurrence (who will specifically require continued suppression of the estrogen receptor pathway) will be important if we are to spare those who do not need it from the long-term effects of estrogen-deprivation therapy.

Three decades ago, data from prospective clinical trials revealed the benefit of endocrine therapy among women with hormone receptor–positive breast cancer. Three decades later, we have come a long way in understanding the biology of this disease and developing strategies to improve outcomes. No doubt molecular profiling will continue to play a crucial role in allowing individualization of treatment strategies. We still have a long way to go, however. The time ahead is an exciting one, with results of a number of clinical trials eagerly anticipated. Given the current rate of progress in this field, it may not be completely unlikely that women with hormone receptor–positive breast cancer will be cured of this disease in the foreseeable future.

Financial Disclosure:Dr. Dawood has received an honorarium in the past year from GlaxoSmithKline. Dr. Gonzalez-Angulo has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. 2006;295:1658-67.

2. Albain KS, Barlow WE, Ravdin PM, et al. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374(9707):2055-63.

3. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784-95.

4. Symanns WF, Hatzis C, Sotiriou C, et al. Genomic index of sensitivity to endocrine therapy for breast cancer. J Clin Oncol. 2010;28:4111-19.