H. Lee Moffitt Cancer Center & Research Institute

Search Moffitt.org

Can Metastatic Breast Cancer Be Cured or Controlled by Chemotherapy?

Gabriel N. Hortobagyi, MD

A proportion of patient populations that received standard-dose chemotherapy
experience very long survival.

Introduction

I would first like to discuss the concept of cure, because we tend to use "cure" as a general term for a variety of diseases, and I suspect that we mean different things in different situations. For example, a pneumococcal pneumonia cure is an entirely different concept from a cure in childhood acute lymphocytic leukemia, which also differs from a metastatic breast cancer cure. I believe that a cure is possible in all three of these diseases, but it may mean something different in each. If one reviews the existing literature and evaluates cure of primary breast cancer, one sees that while most recurrences occur during the first few years after initial diagnosis, there are actually documented cases of first metastasis or relapse between 10 and 40 years after diagnosis.1,2 Thus, one could make a case that it is impossible to decrease the hazard rate to zero in primary breast cancer. Does this mean that no patient is cured? Of course not. It simply means that we cannot establish an arbitrary number of months or years at which time all of those who remain free of recurrence are cured.

In breast cancer, many use a definition for cure that has been termed "personal cure." In other words, a person with long-term disease-free survival after treatment for breast cancer is considered cured if she dies of some other cause, including old age, but without a recurrence. Alternatively, if that person develops recurrent breast cancer before her timely death from other causes, she is considered not cured. In this context, I believe that both primary and metastatic breast cancer can be cured.

The data on metastatic breast cancer that I will discuss should be considered in the context of additional information. Oncologists who have practiced in a cancer center for many years have likely encountered an occasional patient who underwent surgical resection or radiation therapy for an isolated metastatic breast cancer lesion and remains progression free without additional treatment two to four decades later.1,3-9 This suggests that metastatic breast cancer occasionally can be cured with local therapy.

The University of Texas M.D. Anderson Cancer Center has maintained a large database of patients with metastatic breast cancer since the early 1970s. Some years ago, we reported on the short-term prognosis of a subgroup of these patients who achieved a complete remission after initial chemotherapy (ie, stage IV metastatic breast cancer).1,10,11 Over the past decades, we have also treated several hundred patients in this category who presented with a solitary metastatic lesion or limited metastatic disease following curative therapy of their primary tumor. The metastatic disease was addressed locally or regionally, usually with surgical resection or biopsy followed by radiation therapy and adjuvant chemotherapy (stage IV, no evident disease). For comparison, we identified a small group of historic controls who had biopsy-proven metastases and were treated with surgical resection or radiation therapy after biopsy but did not receive subsequent adjuvant chemotherapy. Although this comparison group was small, a limited number of those patients remain progression free many years later. Overall, the group that received adjuvant chemotherapy in addition to local or regional treatment had a somewhat higher long-term progression-free survival curve compared with patients who did not receive adjuvant therapy, although both survival curves plateaued.

I mention these two issues as anecdotes, because in the absence of a simultaneous control population, it is difficult to assess the magnitude of benefit from adjuvant therapy. However, these two examples demonstrate that metastatic breast cancer can be treated successfully and result in personal cure.

The larger database that I will now discuss includes patients with demonstrated metastatic breast cancer. It includes patients enrolled in prospective clinical trials designed to develop regimens to manage metastatic breast cancer. All patients received an anthracycline (doxorubicin), an alkylating agent (usually cyclophosphamide or ifosfamide), and usually a fluoropyrimidine (either fluorouracil [5-FU] or ftorafur [Tegafur]). Recently, we reanalyzed information from the database to describe the long-term outcome for patients who demonstrated a complete response (CR) to systemic chemotherapy with or without hormonal manipulation.12

Of 1,581 patients with metastatic breast cancer included in this database, most received 5-FU, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy. Of the total population, 263 patients (16.6%) achieved a complete remission as defined by most clinical investigators. Of these patients, 49 remained progression free more than five years after chemotherapy (Figure).12 We now have a median follow-up on these patients of 191 months (15.9 years), and 30 (11.4% of CR, 2% of total) patients remain progression free. Four of these patients died of intercurrent disease but without evidence of metastatic disease.

Overall, these data demonstrate that a fraction of patients with definite metastatic breast cancer can survive progression free following a finite chemotherapy regimen. The question now becomes what fraction of patients with metastatic disease can be cured. Unfortunately, few databases in the literature describe prolonged metastatic breast cancer patient follow-up. Most studies, whether single institution or cooperative group, present follow-up data of less than two years. A few reports describe CR in metastatic breast cancer following cyclophosphamide, methotrexate, and 5-FU (CMF) therapy in which there do not appear to be long-term progression-free survivors.13-15 These reports are supported by unpublished observations from the European Organization for Research and Treatment of Cancer (EORTC) (personal communication, M. Piccart, MD, January 1996) and the Cancer and Leukemia Group B (CALGB) breast cancer group (personal communication, J. Aisner, MD, March 1996).

Obviously, these observations also mean that 97% of patients with metastatic breast cancer remained uncured. In our retrospective analysis, we looked at prognostic characteristics of the long-term survivors and found, not unexpectedly, that patients with the best prognoses were those with a good performance status, limited or no comorbid conditions, and metastatic disease of very limited extent or volume.12 In addition, patients who were younger and had a slightly shorter disease-free interval also had better prognoses. These results are very similar to those reported in patients receiving high-dose chemotherapy regimens and who go on to receive autologous bone marrow transplantation or peripheral blood stem cell transplantation.16 These findings suggest that we know which patients are most likely to benefit from therapy. Thus, in this setting, I believe chemotherapy can cure a fraction of patients. Further, a number of new agents currently available or under development may improve the efficacy of currently used cytotoxic regimens in terms of response rate and duration as well as long-term survival.

Subset Analysis

There is a subgroup of women with metastatic breast cancer who are premenopausal and estrogen receptor-positive who received ovariectomy plus FAC-type chemotherapy and had a median 59-month overall survival rate.17 However, this type of subgroup analysis reiterates the importance of being aware of selection bias and carefully evaluating any study of a new modality with this reservation.

DR HORTON

Oncologists have been taught that young women with breast cancer have a poor prognosis. Dr Hortobagyi, what is your experience?

DR HORTOBAGYI

I think women between 40 and 50 years of age have the best prognosis. Historic data suggest that patients who are premenopausal at the time of their primary diagnosis and develop metastasis after menopause have the best response to therapy and longest survival. This is likely because they have an endogenous hormonal manipulation (ie, menopause) that alters their disease course. These are also the patients who gain the greatest benefit from ovariectomy as well as chemotherapy.

Hormone Replacement Therapy

DR HORTON

What is your perspective on hormone replacement therapy (HRT) for patients treated for breast cancer in long-term follow-up who go through menopause?

DR HORTOBAGYI

At M.D. Anderson, we are conducting the only controlled trials evaluating HRT in breast cancer. We have approximately 180 patients enrolled thus far; accrual is continuing. However, outside of this trial, I discuss the options with my patients, and together we decide whether to initiate HRT, depending on the severity of their symptoms, risk factors for cardiovascular disease or osteoporosis, and perception of risk of recurrence.

Adjuvant Therapy: Influence on Outcomes in Metastatic Disease

DR HORTON

Currently, the majority of patients diagnosed with stage IV breast cancer will have received some kind of adjuvant therapy before they developed metastatic disease. How do you think this influences outcomes?

DR HORTOBAGYI

If we agree that all patients have some degree of micrometastatic or metastatic disease, we can expect that the fraction of patients who have a complete remission following adjuvant therapy will decrease the fraction of patients who can achieve complete remission following overt metastatic disease. The reason is that those who relapse after adjuvant therapy will have partial or complete drug resistance and be less amenable to a successful therapeutic intervention.

We are currently evaluating a group of patients who received FAC adjuvant therapy and have subsequently relapsed. The difficulty is that their treatment for overt metastatic disease is much more heterogeneous. However, the fraction of this group that remains progression free beyond five years is much smaller than the fraction of the untreated group I discussed earlier. The other drawback is that most of those patients were treated in the pre-taxane era. I think we have to reset the target now with the newer drugs, because I am convinced that some of these newer drugs are more effective than previously used agents.

References

  1. Legha SS, Buzdar AU, Smith TL, et al. Complete remissions in metastatic breast cancer treated with combination drug therapy. Ann Intern Med. 1979;91:847-852.
  2. Harris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita T Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology, 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997:1557-1616.
  3. Ross MB, Buzdar AU, Smith TL, et al. Improved survival of patients with metastatic breast cancer receiving combination chemotherapy. comparison of consecutive series of patients in 1950s, 1960s, and 1970s. Cancer. 1985;55:341-346.
  4. Todd M, Shoag M, Cadman E. Survival of women with metastatic breast cancer at Yale from 1920 to 1980. J Clin Oncol. 1983;1:403-408.
  5. Cold S, Jensen NV, Brincker H, et al. The influence of chemotherapy on survival after recurrence in breast cancer: a population-based study of patients treated in the 1950s, 1960s and 1970s. Eur J Cancer. 1993;29A:1146-1152.
  6. Brinkley D, Haybittle JL. The curability of breast cancer. Lancet. 1975;2:95.
  7. Brinkley D, Haybittle JL. Long-term survival of women with breast cancer. Lancet. 1984;1:1118.
  8. Brinkley D, Haybittle JL. The curability of breast cancer. World J Surg. 1977;1:287-289.
  9. Rutqvist LE, Wallgren A. Long-term survival of 458 young breast cancer patients. Cancer. 1985;55:658-665.
  10. Swenerton KD, Legha SS, Smith T, et al. Prognostic factors in metastatic breast cancer treated with combination chemotherapy. Cancer Res. 1979;29:1552-1562.
  11. Hortobagyi GN, Smith TL, Legha SS, et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol. 1983;1:776-786.
  12. Greenberg PAC, Hortobagyi GN, Smith TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol. 1996;14:2197-2205.
  13. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901-906.
  14. Pedrazzini A, Cavalli F, Brunner KW, et al. Complete remission following endocrine or combined cytotoxic and hormonal treatment in advanced breast cancer. A retrospective analysis. Oncology. 1987;44:51-59.
  15. Decker DA, Ahmann DL, Bisel HF, et al. Complete responders to chemotherapy in metastatic breast cancer: characterization and analysis. JAMA. 1979;242:2075-2079.
  16. Dunphy FR, Spitzer G, Fornoff JE, et al. Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support [published erratum in Cancer. 1994;74:773]. Cancer. 1994;73:2157-2167.
  17. Falkson G, Holcroft C, Gelman RS, et al. Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1995;13:1453-1458.

  Back to Cancer Control Journal Supplement Volume 4 Number 3 

© Copyright 1996 - 2009 H. Lee Moffitt Cancer Center & Research Institute