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The Role of Chemotherapy in Advanced Estrogen Receptor Positive Breast Cancer

Tamer M. Fouad, M.D.

Tamer M. Fouad, M.D.'s avatar

Published online: September 03, 2009

Disclosures of potential conflicts of interest and author contributions are found at the end of this article.

BACKGROUND:

Estrogen receptor positive (ER-positive) breast tumors account for approximately three-quarters of all new cases. Patients with advanced tumors are treated based on the presence of risk factors such as the presence of visceral metastasis, short disease free interval are traditionally treated with chemotherapy regardless of ER status. In a recent review article published in the Annals of Oncology, the authors identified a category of patients with advanced breast cancer and poor prognostic features that can benefit from endocrine therapy.

In a recent issue of Annals of Oncology, Barrios et al1 reviewed the current options available for the management of estrogen receptor positive (ER-positive) advanced breast cancer. The authors identified a category of patients with advanced breast cancer and poor prognostic features that can benefit from endocrine therapy.1

Breast cancer is more common in postmenopausal women which account for approximately 75% of cases.2 Eighty percent of postmenopausal breast cancers are ER-positive, while approximately 65% of premenopausal women express ER-positivity.2, 3 This, according to the article, roughly suggests that ER-positive tumors account for three-quarters of cases overall.1

Treatment of metastatic breast cancer is essentially palliative.4, 5 The challenge is to weigh the likelihood of achieving effective palliation against the burden of toxicity. Certain prognostic factors can assist in the decision making. A long relapse free interval is more favorable than a shorter period6-8; the number of sites of involved with metastasis is also an important prognostic indicator, with patients presenting with isolated metastasis faring better than those with extensive spread.6, 7 In addition, the presence of visceral metastasis confers a degree of urgency which is typically treated with chemotherapy with its more rapid response rate. Other factors include poor performance status 9; ER status 8, 10; HER-2 positivity 11-13; and high tumor grade.8, 10, 14

Visceral metastasis is defined in CALGB studies as lymphangitis carcinomatosa of the lungs, bone marrow infiltration, carcinomatous meningitis or widespread liver metastatasis.15, 16 While non-visceral metastasis that may benefit from endocrine therapy include soft tissue metastasis and bone metastasis.5, 17

Generally speaking, advanced breast cancer patients are broken down into: (1) ER-negative cases that receive chemotherapy 17; (2) HER-2 positive patients who receive trastuzumab combined with chemotherapy, especially since they tend to be less responsive to endocrine therapy 17, 18; (3) ER-positive patients that do not show any poor prognostic features who are given endocrine therapy upfront 5, 17; (4) ER-positive patients with poor prognostic factors that receive chemotherapy upfront.17

In clinical practice, visceral metastasis is usually the decision point in the management of metastatic breast cancer. Barrios et al identify a category of patients with poor prognostic factors that may benefit from first line endocrine therapy. Interestingly, this would include patients with visceral metastasis but not as he names it, visceral crisis, such as those with small volume liver or lung disease and patients with few or no symptoms. The rationale being that chemotherapy does not seem to influence overall survival in these patients and treatment-related toxicity is unwarranted.1

I personally recall treating a 50 year old breast cancer patient presenting radiologically with multiple liver metastases but without any symptoms. Initially she was given the appropriate chemotherapy regimen but failed to show a radiological response after four cycles. Given her relatively long history, we felt we had run out of chemotherapy options and the decision was to give letrozole a chance. Letrozole was a relatively new drug at the time, not yet approved in the adjuvant setting; therefore, the patient had not received the drug previously. She underwent a dramatic response which was both rapid and durable with a better quality of life when compared to her previous course of chemotherapy. It’s not every day that you get a nice surprise in the practice of oncology and this one was particularly memorable.

Not all ER-positive patients respond so completely, but this story emphasizes the need to justify prescribing chemotherapy in asymptomatic patients when a clear benefit in outcome is doubtful. This brings to mind the recent discovery that endocrine positive tumors can belong to one of two genetic categories (luminal A or luminal B)19, 20, which have different prognostic implications, and would explain why some ER positive patients respond to endocrine therapy more dramatically than others.19, 20

At this stage I would like to emphasize a point that’s not always mentioned in conferences or apparent in Kaplan–Meier survival curves. While only a handful of agents have shown a survival benefit for metastatic breast cancer21, for the patient with life threatening visceral crisis the story is very different. For these individual patients there is a survival benefit. The rapid regression that may be observed with successful chemotherapy could be a life saving decision. A long time ago some colleagues used the term “emergency chemotherapy” to refer to chemotherapy that is administered in an emergency situation aimed at saving lives.22 This is clinically significant, for the individual patient who can tolerate a chemotherapy regimen that is expected to incur a rapid tumor regression and alleviate potentially fatal symptoms. One such example would be the treatment of lymphangitis carcinomatosa, where therapy is a race against time.

Another important point that should be mentioned here is the recent discovery that ER positive tumors have a reduced sensitivity to chemotherapy in both the adjuvant23-26 and neoadjuvant settings.27-30 This article elegantly casts doubt on the evidence that these findings may be extrapolated to the metastatic setting, citing the inadequacy of available trials comparing chemotherapy outcome in ER positive versus ER negative disease.1

Conclusion

This article touches on some very important aspects in our understanding of the role played by chemotherapy and endocrine therapy in the treatment of endocrine positive advanced breast cancer. Clearly, chemotherapy is not for everyone especially asymptomatic patients. In some patients endocrine therapy is associated with similar therapeutic responses compared to chemotherapy and is associated with a better Quality of Life (QoL). Traditionally advanced breast cancer patients with visceral metastasis, shorter time to progression and symptoms are treated with chemotherapy regardless of ER status. The authors of this article identified a category of patients with advanced breast cancer and poor prognostic features that can benefit from endocrine therapy.

Conflict of interest statement

None to declare.

CITE THIS ARTICLE:
Tamer M. Fouad, M.D.. The Role of Chemotherapy in Advanced Estrogen Receptor Positive Breast Cancer. Doctors Lounge. Available at: https://www.doctorslounge.com/index.php/articles/page/297. Accessed August 16 2017.

References

1. Barrios CH, Sampaio C, Vinholes J, Caponero R. What is the role of chemotherapy in estrogen receptor-positive, advanced breast cancer? Ann Oncol. Jul 2009;20(7):1157-1162.

2. Hankey BF, Miller B, Curtis R, Kosary C. Trends in breast cancer in younger women in contrast to older women. J Natl Cancer Inst Monogr. 1994(16):7-14.

3. Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. Nov 2002;76(1):27-36.

4. Miller KD, Sledge GW, Jr. The role of chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am. Apr 1999;13(2):415-434.

5. Hortobagyi GN. Treatment of breast cancer. N Engl J Med. Oct 1 1998;339(14):974-984.

6. Swenerton KD, Legha SS, Smith T, et al. Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res. May 1979;39(5):1552-1562.

7. Hortobagyi GN, Smith TL, Legha SS, et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol. Dec 1983;1(12):776-786.

8. Clark GM, Sledge GW, Jr., Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol. Jan 1987;5(1):55-61.

9. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. J Clin Oncol. Feb 1986;4(2):186-193.

10. Vogel CL, Azevedo S, Hilsenbeck S, East DR, Ayub J. Survival after first recurrence of breast cancer. The Miami experience. Cancer. Jul 1 1992;70(1):129-135.

11. Gusterson BA, Gelber RD, Goldhirsch A, et al. Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol. Jul 1992;10(7):1049-1056.

12. Muss HB, Thor AD, Berry DA, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. May 5 1994;330(18):1260-1266.

13. Paik S, Bryant J, Park C, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst. Sep 16 1998;90(18):1361-1370.

14. Leivonen MK, Kalima TV. Prognostic factors associated with survival after breast cancer recurrence. Acta Oncol. 1991;30(5):583-586.

15. Costanza ME, Berry D, Henderson IC, et al. Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642). Clin Cancer Res. Jul 1995;1(7):699-704.

16. Parnes HL, Cirrincione C, Aisner J, et al. Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140. J Clin Oncol. May 1 2003;21(9):1819-1824.

17. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology - v.2.2007. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed October 5, 2007.

18. De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. Jul 1 2005;11(13):4741-4748.

19. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. Sep 11 2001;98(19):10869-10874.

20. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. Jul 8 2003;100(14):8418-8423.

21. Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP. Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst. Dec 17 2008;100(24):1780-1791.

22. Zona G, de Tribolet N, Pizzolato G, Dietrich PY. Etoposide-carboplatin association as 'emergency' up-front chemotherapy in a case of life-threatening adult medulloblastoma. J Neurooncol. Sep 1998;39(3):253-259.

23. International Breast Cancer Study Group (IBCSG). Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst. Jul 17 2002;94(14):1054-1065.

24. Albain KS, Green SJ, Ravdin PM. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol. Vol 21. 2002:37a.

25. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. Aug 10 2006;24(23):3726-3734.

26. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. Apr 12 2006;295(14):1658-1667.

27. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. Nov 15 2003;21(22):4165-4174.

28. Ring AE, Smith IE, Ashley S, Fulford LG, Lakhani SR. Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer. Dec 13 2004;91(12):2012-2017.

29. von Minckwitz G, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. Apr 20 2005;23(12):2676-2685.

30. Guarneri V, Broglio K, Kau SW, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol. Mar 1 2006;24(7):1037-1044.


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October 10, 2009 11:23 PM

Dear Dr.Tamer,
I must commend you for the very prompt and succinct explanation.

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October 10, 2009 08:04 PM

Great question Dr. Aroon. The controversies surrounding this topic are endless and have been going on for a very long time. It is clear that our understanding of the predictive power of PR receptor expression in breast cancer is incomplete.

Your statement is absolutely correct for breast cancer in the metastatic setting. Indeed, measurement of PR improves the predictive power for obtaining a response in ER positive tumors. Metastatic patients that express both ER and PR are associated with a 70% response rate to hormonal therapy. While ER+/PR- or ER-/PR+ have a 40% chance of response. Those with both ER and PR negativity respond in less than 10% of cases. There is also some evidence that HER2 positivity may affect hormonal response in ER/PR positive patients.

It’s a different story when we discuss PR status in the adjuvant setting. Initial reports from the ATAC trial (9366 patients) which randomized patients to receive either initial tamoxifen or anastrazole, suggested better outcome in ER+/PR- as compared to ER+/PR+. This benefit was not confirmed in follow up data or in another important trial, the BIG 1-98, which tested a different aromatase inhibitor (letrozole) against standard tamoxifen. Here there was clearly no difference between ER+/PR- and ER+/PR+ groups.

Again, you are right in saying that the PR status has been overshadowed by ER status. This was later overshadowed by the role that HER-2 status played in modulating response to hormonal therapy. Currently, the focus is on genetic profiling, with Luminal A patients showing superior responses compared to Luminal B hormone positive tumors, which is probably why your point is not mentioned in this review.

Thanks again for this important question.


October 09, 2009 01:11 PM

Dear Dr.Tamer,
Went through the very informative and thought provoking article of yours on the role of chemotherapy in advanced estrogen receptor positive breast cancer.I just thought i should make a mention the importance of the progesterone receptors-PR(PgR) in relation to this topic.Generally the role progesterone receptors tends to be overshadowed by that of the estrogen receptors. A low level of PgR’s is sited as one of the reasons for a poor response to hormonal manipulation. Does the study that you have sited make any mention of the PgR levels in the patients studied?
Thank you again Dr.Tamer,

Dr.M.Aroon kamath.


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