Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.

Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials.

OBJECTIVE: To determine whether in the previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies of node-negative breast cancer there were either cohorts of patients with a prognosis favorable enough to preclude using systemic therapy or subsets of patients who failed to benefit from the treatments. DESIGN: Randomized clinical trials with stratification after surgery. SETTING: NSABP trials at institutions in the United States and Canada. PATIENTS: Data were collected on 731 eligible patients (Protocol B-13) with estrogen-receptor-negative tumors who randomly received either no therapy after surgery or sequential methotrexate and fluorouracil (M----F) followed by leucovorin. Data were also collected on 2834 patients (Protocol B-14) with estrogen-receptor-positive tumors who randomly received either placebo or tamoxifen treatment. The percentage of patients surviving disease-free was determined through 4 years of follow-up using life-table estimates. INTERVENTIONS: Protocol B-13 patients received 12 courses of M----F given intravenously on days 1 and 8 every 4 weeks. Leucovorin therapy was begun 24 hours after M----F administration. Protocol B-14 patients received 5-year treatment with either tamoxifen (10 mg twice daily by mouth) or placebo. RESULTS: When the outcome of untreated patients in either trial was related to the stratification variables, women were found to have a disease-free survival of less than 80% through 4 years of follow-up. This percentage is apt to decrease because the probability of treatment failure increases with time. In both trials, all subsets of women benefited from M----F or tamoxifen therapy. CONCLUSIONS: The disease-free survival of all cohorts of node-negative patients with estrogen-receptor-negative or estrogen-receptor-positive tumors was poor enough to justify systemic treatment. The benefits of the therapies used are insufficient to eliminate the need for assessing putatively better regimens.

Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience.

Despite numerous reports of findings obtained following the use of doxorubicin (Adriamycin [A]; Adria Laboratories, Columbus, OH) for the postoperative treatment of patients with primary breast cancer and positive axillary nodes, no clear consensus exists regarding its worth when used in that setting. In June 1981, the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented two randomized clinical trials aimed at evaluating the worth of doxorubicin when administered in conjunction with melphalan (L-PAM) and fluorouracil (5-FU) (PF). A prior NSABP study identified cohorts of patients who did or did not benefit from tamoxifen (TAM, T) when used with chemotherapy. That information was employed in the design of the present studies. Women considered responsive to TAM (1,106) were randomized between PFT and PAFT, and those nonresponsive to TAM (707) were randomized between PF and PAF. Findings through 6 years of follow-up (mean duration of potential time on study, 64 months and 63 months, respectively) indicate that non-TAM-responsive patients who received PAF had a significantly better disease-free survival (DFS) (P = .003) and survival (P = .05) than did those receiving PF. By contrast, there was no significant difference in DFS (P = .6) or survival (P = .7) between PFT- and PAFT-treated patients. No disparity in the amount of drug received, whether related to the median amount or to dose-intensity, is present to account for the difference in findings between the studies. Aside from alopecia and emesis, the toxicity from the doxorubicin-containing regimens was similar to those in which doxorubicin was omitted. Cardiomyopathy was not a significant finding; there were no deaths from cardiac toxicity. The incidence of arterial and venous complications in patients receiving TAM was less than reported by others.

A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors.

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

Isolation of the human anionic glutathione S-transferase cDNA and the relation of its gene expression to estrogen-receptor content in primary breast cancer.

The development of multidrug resistance in MCF7 human breast cancer cells is associated with overexpression of P-glycoprotein, changes in activities of several detoxication enzymes, and loss of hormone sensitivity and estrogen receptors (ERs). We have cloned the cDNA for one of the drug-detoxifying enzymes overexpressed in multidrug-resistant MCF7 cells (AdrR MCF7), the anionic isozyme of glutathione S-transferase (GST pi). Hybridization with this GST pi cDNA, GST pi-1, demonstrated that increased GST pi activity in AdrR MCF7 cells is associated with overexpression but not with amplification of the gene. We mapped the GST pi gene to human chromosome 11q13 by in situ hybridization. Since multidrug resistance and GST pi overexpression are associated with the loss of ERs in AdrR MCF7 cells, we examined several other breast cancer cell lines that were not selected for drug resistance. In each of these cell lines we found an inverse association between GST pi expression and ER content. We also examined RNA from 21 primary breast cancers and found a similar association between GST pi expression and ER content in vivo. GST pi mRNA content in 11 ER-positive tumors (less than or equal to 10 fmol/mg of protein) was significantly different from the GST pi content of 10 ER-negative tumors (P = 0.002; Mann-Whitney Wilcoxon test for two independent samples). The finding of similar patterns of expression of a drug-detoxifying enzyme and of ERs in vitro as well as in vivo suggests that ER-negative breast cancer cells may have greater protection against antineoplastic agents conferred by GST pi than ER-positive tumors.

Prolonging tamoxifen therapy for primary breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial.

OBJECTIVE: To determine whether prolonging the duration of tamoxifen administration beyond the cessation of a combined chemotherapy regimen benefits patients with primary breast cancer with positive findings in axillary nodes who benefit initially from the combined regimen. DESIGN: Nonrandomized, nonconcurrent cohort study. SETTING: National Surgical Adjuvant Breast and Bowel Project, conducted in 68 institutions in North America. PATIENTS: Women were included if they had breast cancer with positive nodes and were aged 49 years or less with both estrogen and progesterone receptor levels of 10 fmol or more, aged 50 to 59 years with progesterone receptor levels of 10 fmol or more, or aged 60 to 69 years. Two cohorts were compared: patients who were randomly assigned to the tamoxifen arm of the adjuvant chemotherapy trial (randomized patients) and women who were added to this arm after randomization had ceased (registered patients). Three hundred seventy-seven women in each group who were disease free at the end of the initial 2-year treatment period were followed for an additional 3 years. INTERVENTIONS: All received melphalan, fluorouracil, and tamoxifen (10 mg twice daily by mouth) for 2 years. Registered patients (but not randomized patients) were offered tamoxifen for a third year after the initial 2-year treatment period, and 273 (72%) agreed. MEASUREMENTS AND MAIN RESULTS: Women receiving a third year of tamoxifen had a better disease-free survival rate (odds ratio, 1.54; 95% confidence interval, 1.14 to 2.07; p = 0.004) and survival rate (odds ratio, 1.56; 95% Cl, 1.02 to 2.37; p = 0.04) through their fifth postoperative year. Women aged 50 years or more benefited, but those aged 49 years or less did not. CONCLUSIONS: The benefit of tamoxifen given to tamoxifen-responsive patients in conjunction with melphalan and fluorouracil appears to be enhanced when the tamoxifen treatment is continued beyond cessation of treatment with these agents.

Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial.

In this National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial, 1,891 women with primary operable breast cancer and positive axillary nodes were randomized between Jan, 1977 and May 1980 to receive L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) either with or without tamoxifen (TAM)-PFT. This report presents life table probabilities, cumulative odds ratios, and P values for disease-free survival (DFS) and survival at yearly intervals through 5 years of observation (mean time on study, 72 months). When patients were examined overall without regard for any discriminant associated with outcome, ie, age, number of positive nodes, or tumor receptor status, there was a significant prolongation of DFS (P = .002), but not survival through the fifth postoperative year. The benefit was almost entirely restricted to those greater than or equal to 50 years with greater than or equal to 4 positive nodes. In that group there was a 66% greater chance of remaining disease free if PFT was received (P less than .001), and there was also a significant survival benefit (P = .02). The advantage from PFT was found to be associated with tumor estrogen receptor (ER) and progesterone receptor (PR) as well as patient age and nodal status. Overall there was a significant improvement in DFS from PFT in those having tumors with an ER or PR level greater than or equal to 10 femtomole (fmol) (P = .01 and .009, respectively). No significant benefit in DFS or survival has been observed in patients less than or equal to 49 years old related either to nodes or tumor receptor status. Survival continues to be adversely affected by TAM in those patients (less than or equal to 49 years old), particularly when their tumors have a PR of 0 to 9 fmol (P = .007). In patients greater than or equal to 50 years old with four or more positive nodes, a significant DFS benefit persisted through the fifth year of observation in those having tumor ER or PR levels greater than 10 fmol (P less than .001 and .002). The advantage was observed in patients 50 to 59 years old as well as those 60 to 70. Women in the older decade demonstrated some advantage from PFT when their tumor ER or PR was 0 to 9 fmol. The most likely explanation for this finding is analytical error in receptor analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

The prognostic significance of preoperative carcinoembryonic antigen levels in colorectal cancer. Results from NSABP (National Surgical Adjuvant Breast and Bowel Project) clinical trials.

This analysis explores the prognostic significance of preoperative carcinoembryonic antigen (CEA) levels in patients with colorectal cancer. The data were derived from 945 patients entered into two randomized prospective clinical trials of the National Surgical Adjuvant Breast and Bowel Project. A strong correlation was evident between preoperative CEA level and Dukes class. The mean CEA progressively increased with each Dukes category and the mean value for each of the four classes was significantly different. This relationship was prevalent whether the data were analyzed for all colorectal lesions regardless of location or specifically for right-sided colon tumors. The prognostic function of preoperative CEA level was independent of the number of positive histologic nodes. Preoperative CEA level correlated with the degree of lumen encirclement by tumor. Tumors that did not encircle more than one half the lumen were associated with significantly lower preoperative CEA levels than those that did. The presence or absence of lumen obstruction was unrelated to the preoperative CEA level. The relative risk of developing a treatment failure was associated with preoperative CEA, in both Dukes B and C patients, demonstrating that the prognostic significance of preoperative CEA was independent of Dukes class.

Biological markers and breast cancer. A multiparametric study. II. Depressed immune competence.

Immune functions were evaluated in 207 carefully staged breast cancer patients, 54 patients with benign breast diseases and 152 normal controls. All patients were followed for at least five years and the prognostic significance of immune competence determined at diagnosis was established. The parameters employed were dermal hypersensitivity to four skin test antigens and to 2,4-dinitrochlorobenzene (DNCB), blastogenic responses to PHA (phytohemagglutinin), ConA (Concanavalin A), and PW (Pokeweed mitogen) mitogens and percentage of T- and B-lymphocytes. A significant degree of impairment of immune functions was found in breast cancer patients when compared to controls; this was illustrated by depressed T-cell counts and low responses to PHA, ConA and PW mitogens and by depressed responses to recall antigens. However, only lymphocyte stimulation with PHA, percentage of T-cells and dermal hypersensitivity tests showed a continued decrease with advancing stages of the disease. Moreover, among cancer patients with low responses to recall antigens, 61% died before five years, 16% showed progressive disease and only 22% were disease-free after five years of follow-up; compared to 30, 18 and 52%, respectively, in patients with normal responses to recall Ags (overall P value less than or equal to 0.005). A similar relation could be illustrated in patents with low PHA responses as 42% of these patients died before five years, 19% showed progressive disease and 39% were disease-free compared to 26, 19, and 54%, respectively. In patients with normal PHA responses (overall P value less than or equal to .05). It is concluded that initial immunocompetence, determined by parameters of cell-mediated immunity, could be significantly depressed in patients with localized or even premalignant breast disease as well as in advanced cancer. Depressed responses to PHA and dermal hypersensitivity to recall antigens seem to indicate a poorer prognosis. There is no single ideal biological marker as yet. Combined with our previous results on serum proteins, this current study may help us, at the time of initial treatment, in the identification of a subset of Stage I breast cancer patients likely to do poorly.

Biologic markers and breast cancer: a multiparametric study--1. Increased serum protein levels.

From early 1972 to the end of 1976, the profiles of several serum protein were used to monitor disease stage and prognosis of 207 patients with breast cancer. Six of these proteins, alpha 1-antitrypsin (alpha-AT), alpha 2-ceruloplasmin (Cp), beta 1-transferrin, IgA, C4, and C5, were significantly elevated in these cancer patients and were used as biologic markers in a multiparametric study. Among these breast cancer patients, 72% had at least two of these protein levels elevated, of which alpha-AT (55%), C5 (38%), and IgA (36%) levels were most commonly raised. The number of elevated proteins was parallel to disease progression as 61% (Group 1) and 74% (Group 2) of the patients with operable breast cancer and 90% of patients with metastatic disease showed an elevation of two or more of these nonspecific proteins. There was also a positive correlation between the number of elevated proteins and prognosis; of the 26 patients who died during the five-year follow-up, only four (15%) had no more than one protein level elevated, and 22 (85%) had two or more protein levels elevated. On the other hand, when considered as a group, patients with no or only one protein level elevated had a better prognosis than patients with two or more levels elevated (P less than 0.03). This multiparametric study tends to indicate that the high level of these serum proteins, reflecting an abnormal biochemical profile, provides valuable information that relates to the stage of the disease and patients' prognosis. Results also suggest that these proteins may aid in differentiating the group with high recurrent risks from that with a more favorable prognosis for a given clinical and pathologic stage, illustrating their importance as biologic markers in breast cancer.

Tamoxifen-induced tumor stimulation and withdrawal response.

A postmenopausal breast cancer patient with a measurable lung metastasis was treated with tamoxifen. The tumor doubling time of the pulmonary lesion was 140 days during spontaneous growth and 52 days during tamoxifen therapy, an almost threefold increase in tumor growth rate. This stimulation persisted fro 1 month after discontinuation of tamoxifen and was followed thereafter by a withdrawal regression lasting greater than 6 months. Awareness of the possible tumor growth enhancement with tamoxifen is of importance especially in view of its prolonged activity. Hormone withdrawal regression may occur following tamoxifen therapy, and a sufficient time interval should therefore elapse between cessation of tamoxifen and initiation of other therapeutic modalities.