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Purpose: In preclinical models, established molecular determinants of cellular sensitivity to cyclophosphamide, long a mainstay of chemotherapeutic regimens used to treat breast cancers, include the aldehyde dehydrogenases that catalyze the detoxification of this agent, namely, ALDH1A1 and ALDH3A1. As judged by bulk quantification of relevant catalytic activities, as well as of relevant proteins (ELISAs), tissue levels of these enzymes vary widely in primary and metastatic breast malignancies. Thus, interindividual variation in the activity of either of these enzymes in breast cancers could contribute to the wide variation in clinical responses obtained when such regimens are used to treat these malignancies. Direct evidence for this notion was sought in the present investigation. Methods: Cellular levels of ALDH1A1 and ALDH3A1 in 171 repository human breast tumor (122 primary and 49 metastatic) samples were semiquantified using immunocytochemical staining. Clinical responses were retrieved from the archived medical records of each of 48 metastatic breast cancer sample donors, 26 of whom had been treated with a cyclophosphamide-based chemotherapeutic regimen subsequent to tumor sampling and 22 of whom had not. The premise that cellular levels of ALDH1A1 and/or ALDH3A1 predict clinical responses to cyclophosphamide-based chemotherapeutic regimens was submitted to statistical analysis. Results: Confirming an earlier report, ALDH1A1 and ALDH3A1 levels varied widely in both primary and metastatic breast tumor cells. When measurably present, each of the enzymes appeared to be evenly distributed throughout a given tumor cell population. Retrospective analysis indicated that cellular levels of ALDH1A1, but not those of ALDH3A1, were (1) significantly higher in metastatic tumor cells that had survived exposure to cyclophosphamide than in those that had not been exposed to this drug, and (2) significantly higher in metastatic tumors that did not respond (tumor size did not decrease or even increased) to subsequent treatment with cyclophosphamide-based chemotherapeutic regimens than in those that did respond (tumor size decreased) to such regimens. The therapeutic outcome of cyclophosphamide-based chemotherapy corresponded to cellular ALDH1A1 levels in 77% of cases. The frequencies of false-positives (cyclophosphamide-based chemotherapy not effective when a low level of ALDH1A1 predicted it would be) and false-negatives (cyclophosphamide-based chemotherapy effective when a high level of ALDH1A1 predicted it would not be) were 0.00 and 0.43, respectively. Thus, partial or complete responses to cyclophosphamide-based chemotherapy occurred 2.3 times more often when the ALDH1A1 level was low than when it was high. Conclusions: Given (1) the wide range of ALDH1A1 levels observed in malignant breast tissues, (2) that ALDH1A1 levels in primary breast tumor tissue, as well as those in normal breast tissue, directly reflect ALDH1A1 levels in metastatic breast tumor cells derived therefrom, and (3) the findings reported here, measurement of ALDH1A1 levels in primary breast malignancies and/or normal breast tissue prior to the initiation of chemotherapy is likely to be of value in predicting the therapeutic potential, or lack of potential, of cyclophosphamide and other oxazaphosphorines, e.g. ifosfamide, in the treatment of primary, as well as metastatic, breast cancer, thus providing a rational basis for the design of individualized therapeutic regimens for this disease. Failure to observe the expected inverse relationship between clinical responses to cyclophosphamide-based chemotherapeutic regimens and ALDH3A1 levels was probably because even the highest breast tumor tissue ALDH3A1 level thus far reported appears to be below the threshold level at which ALDH3A1-catalyzed detoxification of oxazaphosphorines becomes pharmacologically meaningful. However, ALDH3A1 levels in certain other malignancies, e.g. those of the alimentary tract and lung, may be of a sufficient magnitude in that regard.

Background : The possible link between psychological factors and length of cancer survival has generated a literature of contradictory findings. Associations usually have not been found when general psychological symptoms are assessed. Associations usually have been found for predictors related to expressive versus repressive emotional coping (e.g., depression, fighting spirit, hostility, and type C personality) ; however, even these associations have been relatively small, when compared with those for medical factors. Yet few studies have adequately controlled for medical and treatment-related factors. Purpose : Within a Cancer and Leukemia Group B (CALGB) national clinical trial of four adjuvant therapy regimens for stage II breast cancer (CALGB 8082), this study prospectively examined the contribution of potential psychological predictors to length of disease-free and overall survival over a 15-year period. Methods : Subjects were 280 women with stage II breast cancer, out of a total of 899, who were randomly assigned to receive CMFVP (cyclophosphamide-methotrexate-fluorouracil-vincristine-pred -nisone) for two 6-week cycles or six 4-week cycles, then subsequently randomly assigned to receive or not to receive VATH (vinblastine-doxorubicin-thiotepa-fluoxymesterone). Subjects were recruited during the period between October 1980 and August 1984, inclusive, and followed until January 1996. Prior to chemotherapy, psychological symptoms were assessed using the Symptom Check List-90-Revised (SCL-90-R). SCL-90-R scores were trichotomized into categories representing high, medium, and low distress. Basic base-line sociodemographic data (including age, ethnicity, education, and marital status) and medical data (including lymph node status, estrogen receptor status, menopausal status, and performance status) were collected. Subjects with psychosocial data differed from those without psychosocial data solely in their higher percentage of classification in the mild limitation category of the Zubrod (Eastern Cooperative Oncology Group) performance status rating (subjects with psychosocial data : 14% ; subjects without psychosocial data : 8%). Results : In stepwise Cox regression analyses that controlled for sociodemographic and medical variables, there was no significant predictive effect of the level of distress (as measured by the SCL-90-R trichotomized scores) on length of disease-free and overall survival of the study subjects. Risk ratios for low versus high distress were 1.01 (95% confidence interval [CI] = 0.62-1.66) for disease-free survival and 1.03 (95% CI = 0.58-1.82) for overall survival. Conclusions : This study failed to provide evidence that psychological factors contributed to length of disease-free or overall survival of women who received adjuvant chemotherapy (either CMFVP alone or CMFVP followed by VATH) for treatment of stage II breast cancer. Implications : In the context of far more potent medical factors, the contribution of psychological factors to disease-free and overall survival is likely to be relatively small. Future research should focus on specific theory-driven predictors rather than on general psychological symptoms. Moreover, it should be based on clinical studies using a controlled, prospective design, in which the effects of medical factors may be distinguished and psychological predictors are clear antecedents of survival outcomes.

Background. Chemotherapy is most effective when applied during the biologically active stage of tumor cells. According to the authors' previous tumor marker kinetic study, methotrexate plus 5-fluorouracil (MF) was found to yield either a cytolytic effect in an MF-sensitive tumor cell population or a cytostatic effect in an MF-resistant population. In the latter, the suppressive effect was transient and the biologic activity resumed in one week after MF administration. Methods. Based on this marker kinetic study, an alternating chemotherapy program was designed to study its antitumor and side effects. Methotrexate (M) (200 mg/ m 2 ) and 5-fluorouracil (F) (500 mg/m 2 ) were administered intravenously on day 1 followed 24 hours later by leucovorin (L) (10 mg/m 2 orally every 6 hours for 6 doses). Cyclophosphamide (C) 300 (mg/m 2 ), doxorubicin (A) (50 mg/ m 2 ), and vincristine (V) (1 mg/m 2 ) were given on day 8. The MFL/CAV was given every 4 weeks. Results. Forty-nine patients with metastatic breast cancer were enrolled; 41 were eligible. There were 5 complete and 23 partial remissions, producing a total response rate of 68%. In 15 patients with liver metastases, the response rate was 73% and the median survival 13.7 months, results superior to those previously reported for this subgroup of patients. Side effects were manageable. Conclusions. This regimen, which can be given safely in an outpatient setting, yielded encouraging response and survival rates in patients with visceral-dominant disease with poor prognoses

Controversy exists in using carcinoembryonic antigen (CEA) for monitoring the clinical course of breast cancer. In this study, the kinetics of two plasma tumor markers, CEA and CA15-3, immediately after the initiation of chemotherapy were assessed in 30 patients with advanced breast cancer. Four distinct kinetic patterns were seen. Two patterns fitted the expected relationship where the plasma marker increased during tumor progression (nine patients), and declined in tumor regression (five patients). The third pattern was paradoxical in that objective tumor regression in eight patients was associated with an acute surge of these markers followed by a steady decline. The doubling times for both CEA and CA15-3 were immediately shortened four-fold after therapy suggesting tumor cytolysis in treatment responders. Equally paradoxical was the fourth pattern where tumor progression in eight patients was associated with a rapid and transient decline of markers followed by rebounds. Such a rapid decline may be due to a suppression of marker release, as demonstrated in an in vitro study. Adequate knowledge of these putative paradoxical patterns will permit their effective use in monitoring the disease course and perhaps in the early prediction of the therapeutic response.

Systemic treatments with hormones and/or chemotherapy attained outstanding success in producing objective regressions of local and distant metastases of breast cancer. With these demonstrations, similar therapies were employed in the adjuvant setting for stage II patients resulting in improved disease-free and overall survival (1,2). For locally advanced disease, systemic treatments caused substantial shrinkage of unresectable primary tumors (3,4). Because of the poor prognosis of stage III breast cancer, a positive approach to its management has been neglected or at least variable. This has been associated, in part, with the changing of staging systems of breast cancer. Further confusion occurred with clinical trials that incorporated stages IIB and III breast cancer. For clarification in this report, reference will be made to stage IIIB breast cancer (5,6). Stage IIIB breast cancer consists of tumors of any size with direct extension to the chest wall or skin (T4) with axillary node involvement (N1 and ...

Reversal of myelofibrosis and splenomegaly is described in a 41 year old woman with metastatic breast cancer. After intensive chemotherapy and hormonal therapy, the tumor regressed, the splenomegaly receded, the hemogram showed no abnormalities, and the dense collagen and reticulin fibers in the marrow disappeared. The severe thrombocytopenia and leukoerythroblastosis noted before therapy were not obstacles to clinical management. In our report we document that myelofibrosis associated with breast cancer is not an ominous sign. Patients may benefit from an intensive, but well titrated, therapeutic program.

Estrogen receptor contents (ER), determined by a sucrose gradient method in 250 primary or metastatic breast cancers, were analyzed with respect to the influence of the patient's menopausal status, chemotherapy, and tissue sampling. The incidence of the presence of estrogen receptors (ER+) increased in the order of para-, pre- and postmenopausal status of the patient, suggesting that a tumor occurring at the paramenopausal phase tends to be a hormone-independent type. Chemotherapy did not alter the incidence of ER(+), nor the quantity of ER in metastatic lesions. Multiple biopsies done simultaneously or sequentially in the same patient are consistent in their qualities and quantities of ER, provided histological confirmation and examination of the amount of cellularity are included in the process of interpretation.

Tumor estrogen receptor status in women with advanced breast cancer was correlated with clinical response to cytotoxic chemotherapy in a retrospective study. Following an extramural review of the clinical data of 40 patients, 26 responded to chemotherapy (65%). The response rate in 19 receptor-rich tumors was 89% and in 21 receptor-poor tumors, 43% (P < 0.01). The lowest response rate (14%) was observed in seven postmenopausal patients with receptor-poor tumors. Clinical characteristics of patients and variants in chemotherapy programs failed to explain the favorable response of receptor-rich tumors to cytotoxic chemotherapy.

The effectiveness of combination therapy with diethylstilbestrol, cyclophosphamide, and 5-fluorouracil (DES + CTx + FU) was compared with DES alone or CTx + FU in 87 postmenopausal women with advanced breast cancer. Therapy was randomized according to the tumor estrogen-receptor (ER) status. In 30 patients with ER-rich tumors and 35 patients with ER-unknown tumors, combination therapy yielded a higher response rate than DES therapy (87% vs. 64% and 59% vs. 23%, respectively). The pooled data from these two groups of patients suggest that the improved response rate from DES + CTx + FU against DES becomes more apparent in patients with visceral involvement (89% vs. 47%) (P less than 0.025) and that patients treated initially with combination therapy (DES + CTx + FU) appeared to have a longer survival than those treated with sequential therapy (DES leads to CTx + FU) (P = 0.06). The survival data in 22 patients with receptor-poor tumors were significantly inferior to those with receptor-rich tumors (P = 0.001). The ER status and presence of visceral metastases are significant factors in the selection of treatment programs.

The effectiveness of hypophysectomy and tamoxifen in treating advanced breast cancer was compared in a randomized study of 26 patients who had responded to prior oophorectomy or additive hormonal therapy. When patients failed to respond or relapsed from tamoxifen or hypophysectomy, the therapy was crossed over. In this designed sequence, the rate and duration of response observed with tamoxifen or hypophysectomy used as the first regimen were comparable. The results suggest that tamoxifen is effective in the posthypophysectomy phase and the sequence of hypophysectomy followed by tamoxifen in hormone-dependent breast cancer is preferable to achieve a maximal control of the disease.

By the conventional steroid-binding assay method for receptor, 3% of 1,095 primary breast cancers (or 10.6% of 263 premenopausal tumors) were classified as negative for estrogen receptor (ER), but positive for progesterone receptor (PR). The true ER status in this rare group of tumors was further investigated by the enzyme-immunoassay (EIA) or immunocytochemical (ICA) staining method using monoclonal antibodies H222 and D547. Immunoreactive ER was present in nine ER-/PR+ tumors studied, whereas it was not detectable in nine age-matched ER-/PR- tumors. Immunoreactive ER was also present in 24 ER+ breast cancers studied, and was particularly higher in tumors that were PR+. Measurement of immunoreactive ER by monoclonal antibody method provides certain advantages over the conventional dextran-coated charcoal (DCC) method, especially in ER-/PR+ tumors.

Estrogen receptor status, tumor histology, and the interval between the development of tumors were assessed in 99 patients with bilateral breast cancer. Tumors were first grouped into those simultaneously detected in both breasts or within 12 months of each other (synchronous bilateral breast cancer, of which there were 64) and second, those detected within more than 12 months of each other (asynchronous bilateral breast cancer, of which there were 35). Nineteen percent of all tumors were lobular carcinomas. Overall, the rate of receptor discordance between the two tumors was not significantly different from that previously reported between biopsies of primary tumor and metastases in patients with unilateral breast cancer. Synchronous receptor-positive tumors occurred significantly more frequently than expected, suggesting that the development of the two tumors was influenced by a common mechanism. In patients with asynchronous bilateral breast cancer there was a significantly longer interval between tumors if both were receptor-positive compared with concordant receptor-negative tumors and tumors with discordant receptor status. There was a significant discordance in the receptor status of asynchronous tumors when the histology also differed, indicating that the tumors in this group were likely to be separate primary tumors.

A patient with an unresectable well-differentiated bile duct tumor who survived for 15 yr after biopsy diagnosis is presented. Histologic examination of the tumor revealed bland features of bile duct adenoma despite extensive spread within the liver. Over its subsequent course, the tumor progressively replaced the liver, achieving huge size, although there was no evidence of metastases until shortly before the patient's death. This clinical course was very unusual for either bile duct adenoma or cholangiocarcinoma, but would be more characteristic of another tumor of intrahepatic bile duct origin, the biliary cystadenoma. However, this latter diagnosis was excluded with both gross and microscopic pathologic criteria. Evidence is presented to support classification of this tumor as an unusual varient of peripheral cholangiocarcinoma which requires correlation of the clinical and pathologic findings for correct diagnosis.

To determine the correlation between the estrogen-receptor status and responses to chemotherapy or hormonal therapy, we retrospectively analyzed the clinical data of 143 patients with advanced breast cancer. Receptor contents were determined by a sucrose-gradient method and designated arbitrarily as "rich" or "poor." The response rate to chemotherapy was significantly higher in receptor-rich tumors (86 per cent) than in receptor-poor tumors (36 per cent) (P

RAPIDLY growing tumor cells depend on a high rate of pyrimidine synthesis for the generation of RNA and DNA. Fluorouracil is a pyrimidine-base analogue that acts as an antimetabolite to block the s...

Fifty-three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C-V-P). Complete remissions occurred in 68% with CVP and 48% with C-V-P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C-V-P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C-V-P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C-V-P in patients with nodular lymphoma. However, in patients with diffuse lymphocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.

We randomized 81 postmenopausal women with advanced breast cancer, whose tumors were rich in estrogen receptors or of unknown estrogen-receptor status, to receive either estrogen therapy alone or estrogen therapy combined with chemotherapy. An additional 31 patients, whose tumors were poor in estrogen receptors, were randomized to receive either chemotherapy alone or estrogen combined with chemotherapy. The median duration of follow-up was 87 months. In the receptor-rich group, the survival of the 21 patients receiving combined therapy was significantly longer than that of 19 patients receiving estrogen as initial therapy (followed by chemotherapy after failure or relapse). The median survivals were 72 and 29 months, respectively (P = 0.05 by the generalized Wilcoxon method). Among 41 patients with tumors of unknown receptor status, a survival advantage from combined therapy over chemotherapy was seen in the first two years and then disappeared. The survival in 31 patients with receptor-poor tumors was uniformly short regardless of the therapeutic method. We conclude that combined therapy offers a survival advantage in postmenopausal patients with receptor-rich tumors.

Immunoassayable insulin was elevated in the plasma and in the primary and metastatic lesions of a patient with carcinoma of the cervix. The release of insulin from the tumor tissue could have been the important factor in precipitating acute episodes of hypoglycemia in this patient.

Hypophysectomy was performed on two male patients with disseminated breast cancer. One of them went through a sequential treatment program and lived 15 years after the initial mastectomy. An objective remission lasting 13 months was observed following hypophysectomy. The other patient is still in remission 7 months after hypophysectomy. Both of them had a previous response to orchiectomy. The response of six other patients reported in the literature was reviewed. From these preliminary results, hypophysectomy could be considered as an effective procedure in the further control of this disease. A sequential therapy for advanced male breast cancer is proposed. Although estrogen therapy may have antitumor activity in male breast cancer, one patient had an apparent stimulation of skin lesions from administered estrogen.

Cytosols from breast cancers were measured for estrogen receptor (ER) and thymidine kinase (TK) activity. There was no correlation between ER and TK in 137 primary breast cancers studied. The results of TK from 57 metastatic breast cancers were correlated with the response or failure to subsequent hormonal therapy or chemotherapy. TK did not predict the responses to hormonal therapy in 12 patients. Of the 45 patients treated with chemotherapies, 13 of 15 tumors with TK over 80 pmol/mg/min responded (86%), while only 4 of the 30 tumors (13%) with TK below 80 pmol/mg/min responded (p less than 0.001). TK appears to be useful in predicting the responses to chemotherapy.

The effect of a combination of endocrine and chemical therapies has been studied during the past decade in DMBA-induced rat mammary tumors and advanced human breast cancers. Although interferential effects have been observed between endocrine therapy and chemotherapy in highly hormone-dependent tumors or cell lines, beneficial effects can be achieved from a combination of these two treatment modalities in human breast cancer when the steroid receptor status and the presence or absence of visceral metastases are considered in the selection of treatment programs.

Advanced renal cell carcinoma is relatively resistant to most adequately evaluated chemotherapeutic agents. The combination of CCNU and vinblastine, which has antitumor activity in a frog renal carcinoma model system, has demonstrated activity in initial studies in man. The current study investigated this combination of drugs together with a progestational agent, Delalutin. Seventeen patients with metastatic renal cell carcinoma were treated with CCNU, vinblastine and Delalutin. There were no objective responses. Four patients with stable disease had a mean survival of 18 months compared to 13 patients with progressive disease who had a mean survival of 5 months. The survival of the four patients with stable disease was in large part due to the slowly progressive natural history of their disease.

Stimulation of tumor growth and induced hypercalcemia both may occur during the initiation of estrogen therapy in breast cancer. This study was conducted to determine whether cyclophosphamide (CTX) as an adjuvant to estrogen therapy might (1) prevent induced hypercalcemia or (2) achieve a higher tumoricidal effect during the phase of tumor stimulation. Fifty postmenopausal women with inoperable or recurrent disseminated breast carcinoma were divided into two random groups. Results could be evaluated in 44 patients; 21 received diethylstilbestrol (DES), and 23 received DES plus a 4-week course of cyclophosphamide (DES + CTX). The response rate was 5/21 (24%) in the DES group and 8/23 (35%) in the DES + CTX group (p > 0.05). The median duration of response for both groups was 9 months. The survival rate at 24 months was 52% in the DES group and 25% in the DES + CTX group (p = 0.05). Induced hypercalcemia occurred in 3 patients treated with DES + CTX. Short-term cyclophosphamide adjuvant to estrogen therapy did not prevent induced hypercalcemia nor prolong the duration of response or survival.

HYPOGLYCEMIA occurs in 90 per cent of patients with functioning islet-cell tumors and is difficult to manage.1 Although diazoxide and streptozotocin are useful agents for treatment,2 they are not uniformly successful. We report here the initially successful use of mithramycin, an inhibitor of RNA synthesis,3 in a patient with intractable hypoglycemia due to metastatic islet-cell carcinoma. Materials and Methods A 59-year-old woman had symptomatic hypoglycemia with a low plasma glucose (29 mg per 100 ml) and a concomitant increased serum insulin (114 μU per milliliter). Exploratory laparotomy revealed a large tumor in the pancreas and multiple hepatic nodules that on . . .

Estrogen receptor determination by the sucrose gradient method was applied to 295 tumor tissues of various origins. Estrogen receptor of the 8 S type was found only in adenocarcinoma of the breast, uterus, and ovary. Of 19 patients with metastatic carcinoma of unknown origin, four benefited from estrogen receptor study (ie, appropriate therapy could be initiated) and one was helped retrospectively on the clinical diagnosis. Estrogen receptor assays may also be useful in determining whether bilateral breast involvement represents two primary lesions or metastasis. Estrogen receptor studies should be included in evaluating cancers of unknown origin in female patients. ( JAMA 238:32-34, 1977)

Excerpt To the editor: Tumor estrogen receptor activity has been described in a case of Hodgkin's disease that regressed under estrogen therapy (1), and has also been reported in malignancies of "n...

In Reply.— Two crucial points regarding the use and interpretation of estrogen receptor results should be brought up after reading Dr Tashima's letter: (1) one should not accept the receptor results readily without understanding the method of assays, and (2) one should not depend on estrogen receptor assay solely and neglect the importance of clinical information as a whole in the management of patients. In the quoted report of McClendon et al, 1 "estrogen receptor" in five colonic neoplasms were all less than 70 fmole/g of tissue. According to our experience and that of others, 2 a substantial 8 S receptor peak usually could not be identified with confidence by sucrose gradient method when the receptor level was below 3 fmole/mg cytosol protein, or equivalent to about 100 fmole/g of tissue. Any claim for the presence of estrogen receptors below this level should be supported by Scatchard analysis and K

Fifty-nine postmenopausal women with advanced breast cancer were treated with tamoxifen (antiestrogen), 20 mg orally twice a day for at least 2 months. They had been previously treated with other types of hormonal therapy or intensive chemotherapies, or both. Nineteen of the 59 patients (32%) had either a complete response (seven patients) or partial response (12 patients). The median duration of response was 9+ months. Tumors containing estrogen receptors and those that responded to previous hormonal manipulation tended to respond to tamoxifen (60% and 69%, respectively). Patients with receptor-negative tumor or with a history of failure of previous hormonal treatments did not respond to tamoxifen therapy. Tamoxifen is effective against advanced breast cancer. Side effects of the treatment were mild.

In Reply.— It is possible, as stated by Posey et al, that 8S estrogen receptors may exist in human renal cell carcinoma, as its presence had previously been reported in hamster renal adenocarcinoma.1However, more detailed information as to the method of determination of sedimentation coefficients and the exact quantitative level of 8S receptors in the two male patients with renal cell carcinoma should be described. Estrogen receptor studies in human kidney and renal cell carcinoma were previously reported.2,3The report3described the presence of 4S receptors (varying from 3.5S to 5.7S) under lowsalt condition in sucrose gradient analysis of renal cell carcinoma from six male patients. The discrepancy of the results from different institutions may reflect the variation of method employed. We are looking forward to reading the detailed report of the findings of Posey et al. We certainly agree that more studies and reports in