CORRESPONDENCE

RESPONSE: Re: Prognosis and Treatment of Patients With Breast Tumors of One Centimeter or Less and Negative Axillary Lymph Nodes

Bernard Fisher, James J. Dignam

Affiliations of authors: B. Fisher, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; J. J. Dignam, Department of Health Studies, University of Chicago, IL.

Correspondence to: Bernard Fisher, M.D., Scientific Director, National Surgical Adjuvant Breast and Bowel Project, 4 Allegheny Center, Suite 602, Pittsburgh, PA 15212–5234 (e-mail: bernard.fisher{at}nsabp.org).

We concur with Benson and della Rovere's statement that "an emerging dilemma is addressed in the article by Fisher et al." (1). We believe, however, that their perspective with regard to our findings is too narrow. So, too, is the view of others, including that of Mirchandani and Muggia, involved in the dialectic that has ensued with regard to our article on the prognosis and treatment of patients with tumors of 1 cm or less. Along with the findings reported from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Prevention Study (P-1) (2) and from our trials aimed at preventing invasive cancer in women with ductal carcinoma in situ (3,4), our article must be viewed as part of an overall effort that is aimed at eradicating breast cancer closer to its phenotypic expression. All of those studies have, paradoxically, demonstrated benefits from therapies that have resulted in controversy with regard to the clinical application of the findings, not with the data itself. It is evident that we have embarked on an era of medicine in which success results in the genesis of difficult problems. When a group of breast cancer patients with an increasingly better prognosis is defined and when evidence of a therapeutic benefit among the few in the group who are likely to have a tumor recurrence is demonstrated, treatment decisions become more difficult. When there is no discriminant to indicate with precision who is likely to have a treatment failure, the question arises as to what risk of recurrence may be deemed low enough to preclude treating the entire group.

We have never stated that all patients with a "good prognosis" should receive chemotherapy, tamoxifen, or radiation therapy after lumpectomy for invasive or noninvasive breast cancer. We do contend, however, that, because the odds of another breast cancer event in patients with tumors 1 cm or less can be altered by systemic therapy, the use of therapeutic agents of proven benefit should receive consideration in that group. Patients and physicians should consider the merits of using such therapy on the basis of data rather than on personal bias. Our studies have provided such data. Although we support the need for "cost-benefit" consideration when therapeutic decisions are made, in patients such as those who participated in our studies, such estimates attain credibility only when they are made after a long follow-up period; e.g., the conclusions from such estimates made after 5 years might be invalid after more prolonged follow-up time, during which more breast cancer events could occur.

In their letter, Benson and della Rovere have expressed concern about several aspects of our article. Although they indicate that no significant differences in the outcomes examined were noted in most comparisons, Fig. 1 of our paper does demonstrate a benefit with respect to recurrence-free survival for both estrogen receptor (ER)-negative and ER-positive patients who received systemic adjuvant therapy, i.e., chemotherapy in the case of ER-negative patients and tamoxifen alone or tamoxifen and chemotherapy in the case of ER-positive patients. Although relative risk estimates were consistent with those observed among patients with larger tumors, results did not achieve conventional statistical significance, since statistical power was inadequate to do so. For survival (Fig. 4), the essentially overlaid curves among ER-negative patients suggest no survival difference, whereas, among ER-positive patients, a survival advantage is apparent, although the absolute magnitude of this difference is small.

We did not examine results for patients who underwent mastectomy and breast-conserving surgery separately, as Benson and della Rovere would have desired, mainly because of the size of the patient cohort. We did, however, note the percentages of breast cancer recurrence events by site, and, in all treatment groups, at least 50% of such events were tumors at sites other than in the ipsilateral breast. All patients who underwent breast conservation received radiotherapy; thus, as was expected, local recurrence was low.

Because they were not uniformly available for all patients, tumor grade and lymphovascular invasion were not reported. Tumor nuclear grade was examined but did not emerge as a significant prognostic factor. However, tumor type was a significant prognostic factor; tumors other than invasive ductal or lobular carcinoma indicated lower failure risk. Consequently, this characteristic might be used to make decisions with regard to selection of systemic adjuvant therapy.

Another point raised by Benson and della Rovere is the potential for micrometastatic disease to provide information about tumor cell dissemination and, thus, aid in determining whether or not systemic adjuvant therapy should be used. They suggest that there is an increased risk of failure for those patients with localized disease who exhibit bone marrow micrometastases. The most reliable information about the potential clinical implications of both lymph node (LN) and bone marrow (BM) micrometastases will come from ongoing prospective studies that evaluate sentinel lymph node biopsy, in particular, the ancillary studies associated with randomized trials of the American College of Surgeons Oncology Group (LN and BM) and the NSABP (LN).

Finally, with regard to the establishment of risk gradients for patients with tumors under 1 cm, referred to in the editorial by Lippman and Hayes (5), it is unlikely that a determination of risk on a millimeter-by-millimeter basis could satisfactorily be evaluated in existing databases. Except in large, carefully defined cohorts, of which we are not aware, there would be inadequate statistical power to discern between a linear risk extending from 10 mm to zero versus another functional form, such as some threshold, e.g., 5 mm, below which risk might be even lower. While risk differentials between T1a and T1b tumors are plausible, our study was unable to provide such information.

REFERENCES

1 Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, et al. Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 2001;93:112–20.[Abstract/Free Full Text]

2 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

3 Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J, Poller W, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998;16:441–52.[Abstract]

4 Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000.[Medline]

5 Lippman ME, Hayes DF. Adjuvant therapy for all patients with breast cancer? [editorial]. J Natl Cancer Inst 2001;93:80–2.[Free Full Text]



             
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