Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.

Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers: NCT00513292, NCT00353483.

Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511).

PURPOSE: We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. METHODS: We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. RESULTS: On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65] = 3.13, 95% confidence interval [CI] 1.18-8.33; HR for anthracycline receipt [vs. no anthracycline] = 5.16, 95% CI 1.47-18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. CONCLUSIONS: We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.

Which threshold for ER positivity? a retrospective study based on 9639 patients.

BACKGROUND: Guidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%. METHODS: The study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%-9% positive staining for ER (ER-positive 1%-9%) and <1% positive staining (ER-negative). RESULTS: Of 9639 patients included, 80.5% had tumors that were ER-positive ≥10%, 2.6% had tumors that were ER-positive 1%-9% and 16.9% had tumors that were ER-negative. Patients with ER-positive 1%-9% tumors were younger with more advanced disease compared with patients with ER-positive ≥10% tumors. At a median follow-up of 5.1 years, patients with ER-positive 1%-9% tumors had worse survival rates than did patients with ER-positive ≥10% tumors, with and without adjustment for clinical stage and grade. Survival rates did not differ significantly between patients with ER-positive 1%-9% and ER-negative tumors. CONCLUSIONS: Patients with tumors that are ER-positive 1%-9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%-9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer.

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Randomized phase II non-inferiority study (NO16853) of two different doses of capecitabine in combination with docetaxel for locally advanced/metastatic breast cancer.

BACKGROUND: This phase II study investigated whether a lower-than-approved dose of capecitabine, plus docetaxel (XT), would improve tolerability versus standard-dose XT without compromising efficacy. PATIENTS AND METHODS: Women aged ≥18 years with locally advanced/metastatic breast cancer resistant to anthracycline-based chemotherapy in the (neo)adjuvant, first- or second-line metastatic setting were eligible. Patients were randomly assigned to receive standard-dose XT (capecitabine 1250 mg/m(2) twice daily, days 1-14; docetaxel 75 mg/m(2), day 1 every 3 weeks) or low-dose XT (capecitabine 825 mg/m(2) twice daily, days 1-14; docetaxel as above). The primary objective was to demonstrate non-inferiority of low-dose to standard-dose XT in terms of progression-free survival (PFS). RESULTS: 470 patients were randomly allocated in a 1 : 1 ratio to standard-dose or low-dose XT. Median PFS was 7.9 versus 5.8 months [hazard ratio 1.16, 95% confidence interval (CI) 0.95-1.43] in the standard-dose and low-dose arms, respectively. The upper limit of the 95% CI was above the predefined non-inferiority margin (1.35, P = 0.078). Secondary efficacy end points were consistent with PFS. The frequency and severity of adverse events was similar in both treatment arms. CONCLUSIONS: Non-inferiority of low-dose to standard-dose XT in terms of PFS was not demonstrated; this may be due to regional subgroup effects.

Role of biologic therapy and chemotherapy in hormone receptor- and HER2-positive breast cancer.

BACKGROUND: To review the efficacy of chemotherapy and human epidermal growth factor receptor 2 (HER2)-targeted therapy when used in addition to hormonal therapy for the optimal management of estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer. DESIGN: Literature published from January 2003 to March 2008 was reviewed to assess the use of chemotherapy and biologic therapy in addition to hormonal agents. RESULTS: Aromatase inhibitors (AIs) demonstrated greater effectiveness in the adjuvant setting than tamoxifen for the management of ER+ and HER2+ breast cancer. Evidence of cross talk between HER2- and ER-signaling pathways suggests that combined treatment with HER2 blockade and hormonal therapy may offer clinical advantages beyond those provided by hormonal therapy alone in ER+/HER2+ disease. Combined therapy with trastuzumab plus an aromatase AI significantly improves progression-free survival, response rates, and clinical benefits when compared with AI monotherapy in postmenopausal women. Several large studies demonstrated that trastuzumab significantly improves disease-free and overall survival when given in combination with, or following, chemotherapy, regardless of hormone receptor status. CONCLUSIONS: HER2-targeted therapy maybe combined with AIs for the treatment of ER+/HER2+ metastatic breast cancer in postmenopausal women. HER2-targeted therapy in combination with AIs for treatment of ER+/HER2+ early breast cancer needs to be prospectively evaluated.

Collagen IV levels are elevated in the serum of patients with primary breast cancer compared to healthy volunteers.

Collagen IV is a major component of the vascular basement membrane and may be a marker of angiogenesis. Serum levels of this protein are elevated in some human cancers. Our objectives were to compare collagen IV levels in the serum of breast cancer patients and healthy women and to examine changes during preoperative chemotherapy. Sera from 51 patients with stage II-III breast cancer and 55 healthy controls were analysed. Collagen IV level was measured by a commercially available sandwich enzyme link immunoassay. Baseline serum levels were compared between cancer patients and healthy women and paired pre- and post-chemotherapy measurements were also performed in 39 patients who received preoperative chemotherapy and were correlated with response to therapy. The median serum collagen IV concentration was significantly higher in cancer patients (166 microg l(-1)) than in healthy women (115 microg l(-1)), P<0.001. Chemotherapy induced a significant further increase in serum collagen IV (167 microg l(-1) prechemo vs 206 microg l(-1) postchemo, P=0.001). There were no correlations between baseline collagen IV levels and response to therapy, age, clinical stage or HER2 status. In conclusion, patients with breast cancer have elevated levels of collagen IV compared to healthy women and collagen IV levels increase further during chemotherapy.

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab.

BACKGROUND: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status. PATIENTS AND METHODS: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease. RESULTS: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%). CONCLUSIONS: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.

Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.

Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).

Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.

BACKGROUND: Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS AND METHODS: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests. RESULTS: Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy. CONCLUSIONS: No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial.

Aminoglutethimide after tamoxifen therapy in advanced breast cancer: M. D. Anderson Hospital experience.

Forty-six patients with progressive metastatic disease following initial response to tamoxifen therapy were treated with aminoglutethimide. Three patients (6%) achieved complete remission, 15 patients (33%) had partial response, and eight patients (17%) had stable disease. Twenty patients (44%) had progressive disease. The most common side effects were transient skin rash, lethargy, or dizziness. In four patients (7%), treatment was discontinued because of undesirable side effects within the first 2 weeks of the study. These data show that aminoglutethimide is an effective agent following tamoxifen therapy.

Pathological assessment of response to induction chemotherapy in breast cancer.

Macroscopic and microscopic pathology review was used to assess the degree of tumor reduction after preoperative chemotherapy in 90 patients with inflammatory and locally advanced breast cancer. Fifteen (17%) patients had no evident residual macroscopic tumor on gross pathological examination, and 6 of these 15 had no residual tumor on microscopic review either. There was no significant difference in disease-free and overall survival between the six patients with no microscopic disease and the nine patients with only microscopic residual disease but no residual macroscopic tumor. These 15 patients with major reduction after induction chemotherapy had a longer disease-free survival (DFS) (median not reached at 5 yr) than the other 75 patients with lesser degrees of tumor reduction (DFS = 22 mo; P less than 0.01). Clinical evaluation of response to chemotherapy was a less accurate predictor of outcome than was the pathological assessment of response. Complete clinical responders had a 4-yr DFS of 55%, whereas patients with non macroscopic residual tumor following preoperative chemotherapy, less than one-half of whom had been judged to be a complete clinical responder, had a median DFS of greater than 60 mo and a 4-yr DFS of 75%. Patients whose mastectomy specimen had no macroscopic residual disease had a 93% 5-yr survival compared to patients with a less marked response to therapy who had a 5-yr survival of 30% (P less than 0.01). No pretreatment patient or tumor-related variables correlated with the degree of tumor reduction following preoperative therapy. Achievement of a mastectomy specimen free of residual macroscopic tumor after preoperative chemotherapy is an excellent prognostic factor for a prolonged DFS and survival. This information should be considered in the selection of postoperative systemic therapy.

Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy.

PURPOSE: Tamoxifen is currently the standard hormonal treatment of breast cancer, both for metastatic disease and in the adjuvant setting. A new antiestrogen, toremifene, was approved recently for use in managing metastatic breast cancer in postmenopausal women. METHODS: Toremifene is structurally similar to tamoxifen, differing only by a single chlorine atom, and has a similar pharmacologic profile. The major difference between the two compounds is in the preclinical activity; chronic, high-dose tamoxifen is hepatocarcinogenic in the rat, whereas toremifene is not. Neither agent is hepatocarcinogenic in mice, hamsters, or humans; therefore, clinical relevance of the rat data may not be significant. RESULTS: In a worldwide phase III trial, the two agents demonstrated comparable efficacy and safety against metastatic breast cancer. Both agents have shown a significant hypocholesterolemic effect after long-term administration. CONCLUSION: Due to the paucity of long-term clinical data on toremifene, important unresolved questions remain, which include its effects on bone mineral density, the frequency of cardiac events, and the risk for endometrial cancer. Tamoxifen has been associated with maintenance of bone mineral density, a reduction in cardiac events, and a slightly increased risk of endometrial cancer. Toremifene is not likely to be used as second-line therapy after tamoxifen failure due to cross-resistance, and its ultimate place in therapy of advanced breast cancer remains to be determined.

Inflammatory breast cancer: a review.

PURPOSE: The natural history of inflammatory breast cancer and the recent advances in its management were reviewed. DESIGN: The English medical literature from 1924 to 1990 was reviewed using the Cancerline and Medline retrieval systems, and through a manual review of bibliographies of identified articles. RESULTS: The majority of patients with inflammatory breast cancer treated only with local therapies died 18 to 24 months after diagnosis. A combined modality approach with chemotherapy, surgery, and radiation therapy has improved disease-free and overall survival rates for inflammatory breast cancer. Approximately 35% to 55% of patients treated with combined modality regimens remain disease-free and alive at 5 years. CONCLUSION: Induction combination chemotherapy administered with radiation therapy, mastectomy, both, or with additional chemotherapy favorably alters the natural history of inflammatory breast cancer. New drug combinations and high-dose chemotherapy with autologous bone marrow support are being evaluated to improve further patient survival.

Inflammatory breast cancer and body mass index.

PURPOSE: No studies have investigated the etiology of inflammatory breast cancer (IBC), the most lethal form of breast cancer. Because high body mass index (BMI) is associated with decreased risk of premenopausal breast cancer but increased risk of postmenopausal breast cancer, we evaluated whether high BMI was a risk factor for IBC. PATIENTS AND METHODS: In a case-comparison study, we matched by ethnicity and registration date 68 IBC patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1996 with 143 patients with non-IBC and 134 patients with cancer at sites other than the breast or reproductive tract (non-breast cancer). The non-breast cancer group was used in lieu of a population-based, healthy control group, which was not available. RESULTS: IBC patients were younger at menarche and the time of their first live birth than non-IBC and non-breast cancer patients. The proportion of premenopausal IBC patients was higher than the proportion of premenopausal women in the comparison groups, although differences were not significant. There were no differences in height, but IBC patients were heavier (77.6 kg) than non-IBC (70.0 kg) and non-breast cancer patients (68.0 kg). After adjusting for other factors, women in the highest BMI tertile (BMI > 26.65 kg/m2) relative to the lowest tertile (BMI < 22.27) had significantly increased IBC risk (IBC v non-IBC, odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.05 to 5.73; IBC v non-breast cancer, OR = 4.52, 95% CI = 1.85 to 11.04). This association was not significantly modified by menopausal status and was independent of age at menarche, family history of breast cancer, gravidity, smoking status, and alcohol use. CONCLUSION: Our investigation showed that high BMI was significantly associated with an increased risk of IBC. This association did not vary by menopausal status, although IBC patients were more likely to be premenopausal. Confirming our findings and identifying other IBC risk factors may provide directions for future research on the aggressive nature of IBC.

Use of tamoxifen for breast cancer: twenty-eight years later.

PURPOSE: The mechanisms of antitumor activity, clinical pharmacology, toxicity, and efficacy of tamoxifen in women with early and advanced breast cancer and the drug's potential role in prevention of breast cancer were reviewed. DESIGN: A comprehensive review of the literature from 1966 to 1994 was conducted; reports were identified using the Cancerline and Medline data bases. RESULTS: The cellular actions of tamoxifen are not completely understood, but it appears that the drug's antiproliferative effects are mediated primarily by inhibition of the activities of estrogen through binding to estrogen receptors (ERs). Disease-free and overall survival rates have been increased in postmenopausal women with ER-positive tumors when tamoxifen has been used as adjuvant therapy (irrespective of nodal status). In premenopausal women, adjuvant therapy with tamoxifen has been associated with prolongation of disease-free survival, but its impact on survival remains to be defined. Tamoxifen is the initial hormonal treatment of choice in both premenopausal and postmenopausal women with ER-positive metastatic disease. Retrospective review of adjuvant therapy studies showed an approximately 39% reduction in the incidence of contralateral primary breast carcinoma in tamoxifen-treated women, which indicates that tamoxifen could have a role in breast cancer prevention. CONCLUSION: The use of tamoxifen has resulted in a substantial modification of breast cancer's natural history, particularly in postmenopausal women. Ongoing clinical trials will examine the effects of tamoxifen therapy on lipids, coagulation proteins, bone, and endometrium, and its effectiveness as an agent in the prevention of breast cancer.

Clinical course of breast cancer patients with liver metastases.

Between June 1973 and November 1980, 1,171 patients with metastatic breast cancer were treated with various doxorubicin-containing regimens at our institution (M.D. Anderson Hospital and Tumor Institute, Houston). Retrospective analysis of all 233 cases (20%) with liver metastases was done to correlate various clinical and biochemical characteristics with response to treatment, survival, and causes of death. A similar analysis was performed for 58 consecutive patients with liver metastases treated at this hospital between December 1955 and December 1957 with hormone therapy or single-agent chemotherapy. Objective responses were observed in 132 of 233 patients (57%) treated with combination chemotherapy. The median survival was 14 months in the 1970s and 5 months in the 1950s. Among patients who had liver metastases at the time of initial diagnosis of breast cancer, survival was longer for the group treated with combination chemotherapy. All cases were classified according to the number of organ sites involved by metastases. Patients with only liver metastases, or liver plus bone lesions had the longest survival. Other clinical and biochemical factors that correlated significantly with longer survival were: no prior chemotherapy, performance status of 1 to 2, absence of ascites, normal bilirubin and lactic dehydrogenase (LDH), SGOT less than or equal to 2 times normal and albumin greater than 4.5 g/dL. The main cause of death was multiorgan failure, with only 20% of patients dying of liver failure. The present study shows that the presence of liver metastases in breast cancer is not by itself an ominous factor. Most patients respond to therapy, and significant palliation with extended survival is possible for several prognostic subgroups. Further improvement in length and quality of survival is expected with earlier diagnosis.

Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience.

PURPOSE: Adjuvant chemotherapy for breast cancer has been the routine practice in the past decade. A number of studies have observed an increased incidence of treatment-related leukemias following chemotherapy with alkylating agents and/or topoisomerase II inhibitors. We evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials at The University of Texas M.D. Anderson Cancer Center. PATIENTS AND METHODS: Between 1974 and 1989, 1,474 patients with stage II or III breast cancer were treated in six prospective trials of adjuvant (n = 4) or neoadjuvant (n = 2) chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (CTX) (FAC) with or without other drugs. The median observation time was 97 months. In 1,107 patients, FAC chemotherapy was given postoperatively; 367 patients received induction chemotherapy, as well as postoperative chemotherapy. Eight hundred ten patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy only. Patients in two adjuvant and one neoadjuvant study received higher cumulative doses of CTX compared with those in the other studies. RESULTS: Fourteen cases of leukemia were observed. Twelve of these patients had received radiotherapy and chemotherapy, and two had received chemotherapy only. Six of the reported patients with leukemia were treated with a cumulative CTX dose of greater than 6 g/ m2. Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range, 22 to 113). Six of 10 patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The rest of the patients had nonspecific cytogenetic abnormalities or lacked cytogenetic information. The 10-year estimated leukemia rate was 1.5% (95% confidence interval [CI], 0.7% to 2.9%) for all patients treated, 2.5% (95% CI, 1.0% to 5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI, 0.1% to 2.4%) for the chemotherapy-only group; this difference was statistically significant (P = .01). The 10-year estimated leukemia risk for the higher-dose (> 6 g/m2) CTX group was 2% (95% CI, 0.5% to 5.0%) compared with 1.3% (95% CI, 0.4% to 3.0%) for the lower-dose group, a difference that was not statistically significant (P = .53). CONCLUSION: These data illustrate that patients treated with adjuvant FAC chemotherapy plus radiotherapy have a slightly increased risk of leukemia. This information needs to be considered in the treatment plans for patients with breast cancer. However, for most patients, the benefits of adjuvant therapy exceed the risk of treatment-related leukemia.

Analysis of dose intensity in doxorubicin-containing adjuvant chemotherapy in stage II and III breast carcinoma.

Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.

Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer.

PURPOSE: To determine the efficacy (objective response rate and duration of response and survival) and toxicity of docetaxel in patients with strictly defined anthracycline-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-five patients with bidimensionally measurable MBC who had progressive disease while receiving anthracycline-containing chemotherapy were registered onto the phase II trial. Docetaxel was administered at a dose of 100 mg/m2 over 1 hour every 21 days. RESULTS: Thirty-four patients were assessable for disease response; 18 (53%; 95% confidence interval [CI], 35% to 70%) achieved a partial response. The median times to disease progression and survival duration were 7.5 and 13.5 months, respectively, for responding patients. The median overall survival duration was 9 months. Two hundred eight cycles (median, five) of docetaxel were administered. Neutropenia with less than 500 cells/microL developed in 31 of 35 patients; it was complicated by fever in 30 (14%) of 208 cycles and in 18 (51%) of 35 patients, including one treatment-related death. Fluid retention was seen in 15 (43%) of 35 patients, including pleural effusions in 11 patients (31%). Moderate skin toxicity, asthenia, and myalgia were observed in 16%, 58%, and 37% of cycles, respectively. CONCLUSION: Docetaxel has the highest reported antitumor activity in anthracycline-resistant MBC. High objective response rates were seen in patients with visceral-dominant involvement, multiple metastatic sites, or extensive previous therapy. Docetaxel is associated with severe but reversible neutropenia, asthenia, and cumulative dose-related fluid retention. Dexamethasone decreased the frequency and severity of skin toxicity and appeared to ameliorate fluid retention.