Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.

PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2-overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.

Pregnancy and breast cancer.

Breast cancer and pregnancy are best considered as two discrete events which may occur either simultaneously or sequentially without any discernible biological interaction. There is no epidemiologic, clinical, or prognostic evidence that pregnancy, or its termination, will alter the natural history of breast cancer. Further, the existence of a pregnancy need not compromise effective breast cancer treatment, although the selection of modalities must consider fetal safety. Adjuvant radiotherapy, and thus breast conservation, is contraindicated unless it can be deferred until after completion of the pregnancy. Adjuvant chemotherapy is best delayed until after completion of the first trimester, and then, use of antimetabolites such as methotrexate and flourouracil should be avoided. Although the diagnosis of breast cancer during pregnancy may be only a biological coincidence, the emotional impact of this coincidence can be devastating on both patient and family. Informed medical care and compassionate support are both essential for women who simultaneously must confront the diametrically opposed implications and expectations of a life-giving and a life-threatening process.

DNA flow cytometry and pathologic grading as prognostic guides in axillary lymph node-negative breast cancer.

BACKGROUND: The recurrence or mortality rate of axillary lymph node-negative invasive breast cancer has been associated with the tumor S-phase fraction, which is measured by DNA flow cytometry. Because many of the studies that established this association were performed using frozen, pulverized tumor specimens, this association could not be tested for independence from the established prognostic factors of histologic and nuclear grading. METHODS: Histologic, nuclear, and mitotic grades, DNA ploidy, and S-phase fraction (SPF) were determined from paraffin-embedded tumors obtained from 280 women with node-negative invasive ductal carcinomas using standard grading schemes and flow cytometric techniques. These variables were compared with disease-free and cancer-specific survival (CSS) in univariate and multivariate analyses of these patients. RESULTS: Tumor diameter, SPF, histologic grade, and nuclear grade were significant predictors of disease-free survival (DFS); diameter and SPF had significant associations with CSS. Cox analysis showed histologic grade to be the only independent predictor of relapse, whereas diameter and SPF were independent predictors of mortality. The patients with low nuclear or histologic grade tumors had only a 5% risk of recurrence at 5 years. In contrast, 36% of patients in this series with medium-grade or high-grade high SPF tumors had a 30% risk of recurrence over the same interval. CONCLUSIONS: Histopathologic grading and flow cytometric determination of SPF appear to provide additive prognostic information for patients with early invasive ductal carcinomas of the breast.

Achieving local control for inflammatory carcinoma of the breast.

A single institution, retrospective study of 28 patients with inflammatory carcinoma of the breast treated from 1984 to 1990 was performed. Patients received two to four cycles of cyclophosphamide, doxorubicin and 5-fluorouracil (CDF) and were then evaluated for mastectomy. Mastectomy was accomplished in 26 patients after CDF. In 21 patients, the breast was resectable after the initial doses of chemotherapy and modified radical mastectomy was done. Radiation therapy was given to 16 of the 21 patients after six to nine cycles of postoperative chemotherapy. The remaining five of 26 patients had a marginal response to CDF and underwent preoperative radiation therapy. Local recurrence occurred in four of five patients receiving preoperative radiation, in three of 16 receiving postoperative radiation and in one of five receiving mastectomy without radiation therapy. The overall observed five year survival rate was 18 percent, with a median of 34 months. Neither dermal lymphatic invasion nor estrogen receptor status were statistically significant variables when analyzing patients for local recurrence or survival. Despite poor long term survival results, the combination of induction CDF, mastectomy and postoperative radiation achieved local control in 81 percent of patients.

The importance of DNA flow cytometry in node-negative breast cancer.

DNA flow cytometric analysis and conventional clinical factors were compared with disease outcome in 257 patients with node-negative infiltrating ductal carcinoma who had been treated between 1976 and 1983. Median follow-up was 80 months; none of the patients received adjuvant therapy. The relative prognostic importance of clinical variables, ploidy, and S-phase fraction was analyzed by Cox multivariate analysis. Ploidy was analyzable for 198 tumors and did not predict survival. Nuclear grade predicted disease-free survival for all patients. For 71 patients with diploid tumors, only high S-phase had a statistically significant association with relapse. For 127 patients with aneuploid tumors, tumor diameter predicted both disease-free survival and cancer death; histologic grade was also significant for predicting disease-free survival. In conclusion, flow cytometric determination of ploidy and S-phase fraction can provide valuable predictive information in node-negative breast cancer in addition to conventional variables.

Ploidy, proliferative activity and prognosis. DNA flow cytometry of solid tumors.

Flow cytometric study has been used to measure the cellular DNA content of solid tumors for the last decade, and of paraffin-embedded tumor specimens for the last 5 years. Ploidy and proliferative activity are the two properties commonly measured by DNA content flow cytometric study. The ability to study archival, paraffin-embedded tumors has hastened an appreciation of the prognostic utility of this assay. Either abnormal ploidy or elevated proliferative activity predict a worsened disease-free or overall survival in most common adult malignancies. Both abnormalities are associated with poor outcome in locoregional breast, non-small cell lung, and colorectal cancers, and in all stages of ovarian cancer. Abnormal ploidy is also a dire prognostic indicator for cancers arising from the kidney, bladder, prostate, and endometrium. Clinical management of patients with these diseases may be aided by studying their tumors for these objective markers of biological aggressiveness.

Prognostic factors in breast cancer.

A variety of tumor characteristics can provide prognostic information useful in managing the patient with primary breast cancer. Some of these characteristics are firmly established, whereas others are observer dependent or require prospective validation. No single characteristic, however, is likely to fully define which patient with primary breast cancer is destined to relapse. This clinical dilemma--recognition of the high-risk patient--is particularly important in the management of women with node-negative breast cancer. Because most women with this early stage of disease will be cured by surgery alone, the use of adjuvant chemotherapy must be limited to high-risk subsets. Tumor size and ER status are established prognostic factors. Histologic and nuclear grade may be important, but problems of interobserver variability remain. Some studies have shown that aneuploidy or a high S-phase fraction may be independent, high-risk characteristics. Flow cytometric DNA content analysis must be applied with caution, however, because the calculation of S-phase fraction has not been standardized and because the prognostic utility of this approach has not been prospectively confirmed. For now, a prudent approach might be to gather as much prognostic information about each patient's tumor as possible. Those with several of the high-risk characteristics listed in Table 2 should receive strongest consideration for adjuvant treatment. Some of these same prognostic factors, along with several others, can be used to characterize the high-risk node-positive patient. The number of involved axillary nodes is the most important established predictor. Progesterone-receptor status is associated with both disease-free and overall survival, whereas ER status is independently related only to overall survival. Histologic grade, DNA ploidy, and S-phase fraction can also be used to help define the high-risk patient. Finally, tumors that amplify or overexpress the HER-2 gene may have a higher risk of relapse, although this finding has been questioned. Management of patients with breast cancer requires an individualized approach that is based on a careful weighing of a variety of prognostic considerations. The relative importance of these factors will require further large-scale, prospective, multiparameter studies. Although results from such studies are awaited, an understanding of the clinical heterogeneity of breast cancer must be based on a multiplicity of observations, each of which characterizes, in a limited way, the biology of this disease.

Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression or gene amplification.

Multiple drug resistance (MDR), consisting of acquired cross resistance to anthracyclines, vinca alkyloids, and other antineoplastic antibiotics, has been described in a variety of cell lines. This MDR phenotype is associated with overexpression and sometimes amplification of a gene coding for a 170 kDa glycoprotein, termed P-glycoprotein. To understand the role of this mechanism in clinical breast cancer, 248 breast cancer specimens representing both untreated primary and refractory relapsing disease were probed for evidence of P-glycoprotein gene amplification or overexpression using Southern, Northern, or Western blot techniques. In no case was an increase in P-glycoprotein gene copy number or expression detected. Though these findings do not necessarily rule out a role for P-glycoprotein in mediating drug resistance in breast cancer, electrophoretic analysis of clinical specimens is unlikely to provide useful predictive information. More sensitive assays must be developed to overcome the difficulties inherent in analyzing heterogenous tissue samples.

Adjuvant treatment of node-negative breast cancer.

About half of all breast cancer patients do not have axillary nodal involvement at the time of diagnosis, and this fraction will become even larger as more women participate in screening mammography programs. Recently completed trails of limited surgery have changed the primary management of node-negative disease for many women. Now, early results from a number of carefully controlled clinical trails suggest ways in which the approach to adjuvant treatment of this disease can be improved.

Flow cytometry, cellular DNA content, and prognosis in human malignancy.

The use of flow cytometry to analyze the cellular DNA content of human malignancies has become increasingly commonplace. The relationship between abnormalities in DNA content or proliferative characteristics and prognosis is becoming clear for a variety of malignancies in part through new techniques that permit analysis of archival material. High- and low-risk groups of patients with early breast and bladder carcinomas, non-small-cell lung cancer, and colorectal, ovarian, and cervical carcinoma can be distinguished on the basis of abnormal stemline DNA content. In several hematologic and common pediatric malignancies, the prognostic relevance of DNA content flow cytometry has been similarly established. Though the interpretation of tumor cell cycle analyses is less certain, this characteristic may also be prognostically important. However, generalizations cannot be made when applying flow cytometric DNA analysis to clinical decision making. The prognostic importance of an abnormal DNA histogram for an individual patient must be assessed on the basis of the relevant data base for that particular tumor type. The current extent of this data base for various malignancies is reviewed.

Central nervous system toxicity with fludarabine.

A serious delayed neurotoxicity marked by encephalopathy and cortical blindness has occurred in patients treated with fludarabine. This toxicity had only been reported in patients receiving high doses (ie, aplasia-inducing). We describe a similar subacute neurological deterioration occurring in two patients, including one who received only low doses of this agent. Neurologic vulnerability to low doses of fludarabine may be multifactorial and at present cannot be predicted. Continued caution in the use of this new antineoplastic agent is appropriate.

Prognostic implications of ploidy and proliferative activity in diffuse large cell lymphomas.

Paraffin-embedded surgical biopsies from 50 patients with newly diagnosed diffuse large cell lymphoma (DLCL) were examined for proliferative activity and DNA aneuploidy by flow cytometry. These results were correlated with the clinical characteristics of these patients and the course of their disease. High proliferative activity, defined as less than 80% of cells in G0 or G1, was found to be the single most important pretreatment adverse prognostic factor in these patients. This relationship remained significant after correcting for poor performance status and advanced Ann Arbor stage, the other factors found to be associated with a shortened survival. DLCLs with high proliferative activity were more probable to present with extranodal involvement than those with lower proliferative activity. The mitotic count as determined by light microscopy did not correlate with flow cytometry-defined proliferative activity and may be a less accurate method for assessing this important biological characteristic in DLCL. DNA aneuploidy was detected in 62% of cases but did not appear to have any prognostic significance. Biopsies from patients who presented with lymphomatous bone marrow involvement, however, invariably demonstrated an aneuploid stemline. These results suggest that differences in proliferative activity may be an important biological basis for the variable prognosis seen in DLCL.