Historical and Cultural Determinants in the Evolution of Adjuvant Endocrine Therapy

The direction of research into adjuvant systemic therapy for breast cancer has been determined in large part by historical and cultural differences between Europe and the United States. As is often the case, the truth has eventually come to rest somewhere in the mid-Atlantic-not sunk like the Titanic, but sailing in ever tighter circles, not quite sure in which direction it should head next.

George Beatson, a Scottish surgeon, in 1896 described the first systemic therapy for breast cancer: surgical castration.[1] Beatson was able to recognize the benefits of this approach, although since hormones had yet to be discovered, the reasons he proposed for its success were incorrect. The first trials of adjuvant ovarian ablation were carried out in Manchester and Norway about 60 years later.[2,3]

Prior to the discovery of tamoxifen by Walpole in the late 1960s,[4] the only endocrine therapies available were surgical or radiation ablation of the ovaries, the adrenal glands, and the pituitary gland. Because these modalities were controlled by surgeons (initially including radiotherapy), the tradition in the United Kingdom has been for surgeons to take the lead in this area. In addition, the most important endocrine therapies that replaced the removal of the ovaries and the barbarity of adrenalectomy and hypophysectomy-ie, tamoxifen, anastrozole (Arimidex), and the luteinizing hormone–releasing hormone (LHRH) agonist goserelin (Zoladex)-were the inventions of British scientists working for Imperial Chemical Industries (later AstraZeneca).[4-6] Thus it is not surprising that at least in one area, Europe led America. (I can't resist remarking that parts of this history have been rewritten, and that the first-ever randomized controlled trial showing the advantage of adjuvant tamoxifen[7] almost never appears in American literature, including this otherwise masterful review of the subject by Rao and Cobleigh).

On the other hand, an American visionary, Bernard Fisher of the University of Pittsburgh, is largely responsible for the conceptual revolution that occurred in the treatment of breast cancer, as well as for the gestation of a research program that continues to flourish after nearly 50 years.[8] Furthermore, while medical oncology as a speciality languished in the UK, the subject took off like a rocket in the United States when Nixon, with his declaration of a “war on cancer” in 1971, tried to outdo Kennedy's NASA program and its boast of the first man on the moon. It is no surprise, therefore, that the Americans, with a little help from our friends in Milan,[9] led the way in pioneering adjuvant chemotherapy.

Although ultimately this twin-track approach was a great success, in the early days it actually acted as a barrier to progress.

If you'll forgive the cultural stereotyping for a moment, the American frontier spirit (“no gain without pain,” “the bigger the better”) resulted in the dismissal of “soft” remedies such as the hormone therapy advocated by the decadent Europeans, in favor of big, complex approaches that at one point resulted in the abomination of high-dose chemotherapy and bone marrow grafting (the less said about that the better). In addition, there was a subtler fall-out regarding adjuvant endocrine therapy that has yet to be adequately resolved.

Rao and Cobleigh start the section of their very comprehensive review that deals with the management of premenopausal women as follows:

“The 2010 ASCO guidelines recommend tamoxifen for premenopausal women…. These guidelines state that, currently, the benefit of ovarian suppression . . . is not known... .”

What? Still not known after more than 40 years of effort? How can that be?

I believe there are two reasons to explain this paradox. First, the early trials in Manchester, Oslo, and Edinburgh were hopelessly underpowered.[2,3,10] Furthermore, because these studies were conducted before the hormone receptor mechanisms had been described, they were hampered by the failure to stratify cases by HR status. By the time we woke up to the importance of statistical power and the beta error, and before patients in trials of endocrine modalities were selected by HR status, the chemotherapy battalions were off and conquering the world.

Without question, adjuvant chemotherapy offers the best chance yet for many younger women with early breast cancer, but it also has the unfortunate (or maybe fortunate) side effect of rendering these women amenorrheic.[11] There can be little doubt that part of the benefit of adjuvant chemotherapy in younger women is mediated by chemical ovarian suppression. Still, from the first Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview in 1988[12] until today we have been trying to untangle this knotty issue. At times the debate has been acrimonious, and it almost led to a new Anglo-American war of independence (this time with the Anglos seeking independence from the Yankees); but now, all is sweetness and light, with many multinational groups finally working together to resolve the problem once and for all.

The situation with tamoxifen, however, is clear. Assuming a patient's tumor is hormone receptor (HR)-positive, then both pre- and postmenopausal women benefit from this agent-and within reason, the longer their exposure the better, although 5 years is a reasonable compromise.[13] I think that the absolute risk of endometrial cancer has been exaggerated because of ascertainment bias. Most women on tamoxifen develop subendometrial edema that on ultrasound scanning cannot be easily distinguished from endometrial thickening.[14] These indeterminate findings then lead to endometrial biopsy and the occasional random detection of early endometrial cancer (EC). Remembering that most symptomatic cases of EC are cured by hysterectomy, my advice would be not to monitor the poor woman's womb even if there is reimbursement for this futile activity! Many women complain of hot flushes on tamoxifen, but closer consideration of patient histories suggests that in many cases the problem is the withdrawal of a concomitant prescription for hormone replacement therapy or the onset of menopause provoked by the diagnosis and treatment of the breast cancer.

With regard to aromatase inhibitors (AIs), I share the authors' view that these demonstrate a class effect, although there is a tantalizing suggestion that the steroidal AI, exemestane (Aromasin), has a slightly different spectrum of activity from that of the two nonsteroidal drugs, anastrozole and letrozole (Femara).[15]

Because the AIs are only active in postmenopausal women, it was reasonable for trials in premenopausal women to combine ovarian suppression with an LHRH agonist and an AI; however, the results so far are a little disappointing.

In contrast, the trials comparing monotherapy with tamoxifen to monotherapy with an AI have produced an unequivocal answer, with a small (~3%) absolute improvement in disease-free survival (DFS).[16] As the original principal investigator on the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, I can speak with some authority on the subject. Because of the favorable side-effect profile of anastrozole, the ATAC study was powered for “noninferiority”; thus, we considered the improved outcome in DFS an added bonus.

I remain disappointed that the improvement in DFS has yet to be translated into a gain in overall survival. However, having lived with the data since 2001, I have a hunch why this might be. There are many elderly women in the ATAC trial, some even recruited in their 80s, and recent papers have shown that the older patients are at diagnosis, the more likely they are to die of comorbid conditions.[17] I believe such non–breast cancer–related deaths in older patients might have diluted a real survival advantage for, say, women under 65, and I hope that the guardians of the data set will get around to looking at that possibility. The side effect of polyarthralgia can be severe in a small percentage of cases, but the problem of loss of bone mineral density is relatively easy to manage. After all, we don't avoid the use of cytotoxic drugs for fear of bone marrow suppression; we merely monitor the patient's white blood cell count. The same approach should apply to women taking an AI who need regular bone mineral density scans.

In many ways the advent of adjuvant endocrine therapy can be considered one of the greatest advances in the history of cancer therapy. Mortality from breast cancer has been falling rapidly since the publication of the first EBCTCG overview in 1988,[12] and it is estimated that close to two-thirds of this decline can be attributed to the rapid adoption of adjuvant endocrine therapy.

Envoi

It is said that 50% of global expenditures for cancer treatment occur in the United States, a country that carries only 5% of the global tumor burden. Anti-American rhetoric would have it that US hegemony and solipsistic attitudes have led to increasingly expensive therapies that are unaffordable in resource-poor countries. I would counter that the United States is the global engine and powerhouse that has kept the pharmaceutical industry in business and that has indirectly paid the salaries of most of the best basic scientists in drug discovery programs around the world.

Patents aren't forever. Tamoxifen is now widely available in cheap and effective generic form, and anastrozole has recently come off patent as well (in June 2010). Thus, effective endocrine therapy should soon become affordable in those parts of the developing world that carry the greatest tumor burden- and the resource-rich countries in both our hemispheres can take pride in that.

So in which direction should this good ship sail in the future? Mechanisms of endocrine resistance in HR-positive tumors are being intensely scrutinized. However, it shouldn't be beyond the wit of man to engineer the conversion of HR-negative tumors into HR-positive phenotypes. It's quite simple, really. Just get the pluripotent stem cells in the cancer to repopulate the tumor with ER-positive cells.[18]

Financial Disclosure:The author 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. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;2:104-7.

2. Patterson R, Russell MH. Clinical trials in malignant disease: part II.

Breast cancer: value of irradiation of the ovaries. J Fac Radiol. 1959;10:130-33.

3. Nissen-Meyer R. Castration as part of the primary treatment for operable female breast cancer. Acta Radiologica. 1965;(Suppl 249).

4. Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethenes. Nature. 1966; 212:87-9.

5. Yates RA, Dowsett M, Fisher GV, et al. Arimidex (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal female volunteers. Br J Cancer. 1996;73:543-8.

6. Nicholson RI, Finney EJ, Maynard PV. Activity of a new analogue of luteinizing releasing hormone analogue, ICI 118630, on the growth of rat mammary tumours. J Endocrinol. 1978;79:51P-52P.

7. Baum M, Brinkley DM, Dossett JA, et al. Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet. 1983;2:450-4.

8. Fisher B. The surgical dilemma in the primary therapy of invasive breast cancer: a critical appraisal. Current problems in surgery. Chicago: Year Book Medical Publishers;1970.

9. Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405-10.

10. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast cancer: The Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Lancet. 1993;344:1293-8.

11. Rose DP, Davis TE. Ovarian function in women receiving chemotherapy for breast cancer. Lancet. 1977; 1:1174-6.

12. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. Early Breast Cancer Trialists' Collaborative Group (EBCTG). N Engl J Med.1988;319:1681-92.

13. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996;88:1529-42.

14. Jackson TL, Duffy SRG, on behalf of the ATAC Trialists' Group (Endometrial Sub-Protocol). The ATAC (‘Arimidex', Tamoxifen, Alone or in Combination) Trial: transvaginal ultrasound scan findings overestimate observed pathological findings in postmenopausal gynaecologically asymptomatic women before treatment. Breast Cancer Res Treat. 2000; 64:64. (Abstract 233)

15. Smith I E, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-42.

16. Thürlimann B, Keshaviah A, Coates AS, et al; for the Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747-57.

17. Schairer C, Mink PJ, Carroll L, et al. Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst. 2004;96:1311-21.

18. Buckley NE, Mullan PB. BRCA1-conductor of the breast stem cell orchestra: the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer. Buckley NE, Mullan PB. Stem Cell Rev. 2012 Mar 17. [Epub ahead of print]