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The Role of Chemotherapy in Advanced Estrogen Receptor Positive Breast Cancer

Tamer M. Fouad, M.D. | Published: September 03, 2009. Updated: September 26, 2009.

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

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

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


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.

Tamer M. Fouad, M.D.. The Role of Chemotherapy in Advanced Estrogen Receptor Positive Breast Cancer. Doctors Lounge Website. Available at: Accessed March 29 2017.


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October 10, 2009 11:23 PM

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


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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