Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

Secretin/vasoactive intestinal peptide-stimulated secretion of bombesin/gastrin releasing peptide from human small cell carcinoma of the lung.

Bombesin/gastrin releasing peptide-like immunoreactivity (BLI) is found in the majority of small cell carcinoma of the lung (SCCL) cell lines examined. Because BLI is present in high concentration in SCCL we studied the mechanism of BLI secretion from several SCCL cell lines and in patients with SCCL. In cell line NCI-H345 the structurally related polypeptide hormones secretin, vasoactive intestinal peptide, and peptide histidine isoleucine as well as theophylline, a phosphodiesterase inhibitor, N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate, a cyclic nucleotide analogue, increased BLI release by 16-120% and cyclic adenosine 3':5'-monophosphate by 36-350%. Similar results were obtained in SCCL cell line NCI-H209. i.v. injection of secretin (2 units/kg) significantly increased plasma BLI in 2 patients with extrapulmonary SCCL. These data suggest that SCCL cells possess receptors for secretin/vasoactive intestinal peptide and that receptor occupation stimulates in vitro and in vivo BLI secretion.

Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain.

PURPOSE: This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediate-release (IR) oxycodone tablets administered four times daily in patients with cancer-related pain. PATIENTS AND METHODS: Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n=81) or IR oxycodone four times daily (n=83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). RESULTS: Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34% to 4% with CR and from 31% to 19% with IR before and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7% with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P=.006). CONCLUSION: CR oxycodone every 12 hours was as effective as IR oxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events.

Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study.

PURPOSE: The Intergroup conducted this breast cancer adjuvant trial to compare an investigational 16-week regimen with cyclophosphamide, doxorubicin, and fluorouracil (5-FU; CAF). The 16-week regimen features greater doxorubicin and 5-FU dose-intensity than CAF and improved scheduling of antimetabolites with sequential methotrexate and 5-FU, as well as infusion 5-FU. PATIENTS AND METHODS: A total of 646 node-positive, receptor-negative patients were randomly assigned to receive either the 1 6-week regimen or six cycles of CAF. Breast cancer outcomes included recurrence as well as disease-free and overall survival. Toxicity was evaluated by the Common Toxicity Criteria (CTC). Treatment-related quality of life was assessed by the Breast Chemotherapy Questionnaire (BCQ) before, during, and 4 months after treatment in 163 patients. The trial was designed to use one-sided tests of significance for power calculations, but is now reported with both one-sided and the traditional two-sided tests of significance. RESULTS: At a median follow-up of 3.9 years, the estimated 4-year recurrence-free survival rate was 67.5% with the 16-week regimen versus 62.7% with CAF (P = .19, two-sided; P = .095, one-sided). The estimated 4-year survival rate was 78.1% with the 16-week regimen versus 71.4% with CAF (P = .10, two-sided; P = .05, one-sided). CAF produced significantly higher grades of leukopenia, granulocytopenia, and thrombocytopenia, as well as liver and cardiac toxicity, whereas the 16-week regimen produced significantly higher grades of anemia, nausea, stomatitis, and weight loss, as well as skin and neurotoxicity. There were three treatment-related deaths with CAF but none with the 16-week regimen. During treatment, quality of life declined significantly more with the 16-week regimen than CAF, but by 4 months posttreatment, there was no difference. CONCLUSION: The 16-week regimen produced marginally better breast cancer outcomes than CAF with similar toxicity but a greater reduction in during-treatment quality of life. The 16-week regimen should not be used instead of a standard-dose regimen without careful consideration of the 16-week regimen's pros and cons, which include its complicated schedule. It should probably not be tested further, but its antimetabolite schedules and frequent drug administration (ie, dose density) should be considered in the development of new regimens.

Combined therapy for stage III-IV head and neck cancer: preliminary results.

As part of a combined modality treatment program using chemotherapy, surgery, and/or radiotherapy, 25 patients with previously untreated stage III or IV head and neck cancer received initial combination chemotherapy. Pathologically confirmed complete remission was noted in nine patients (36%). The overall objective major response rate (with all patients included in analysis) was 68%. The chemotherapy regimen included bleomycin, cisplatin, vinblastine, methotrexate, and 5-fluorouracil. A novel concept of drug scheduling was used, based on chemotherapy-induced improvement in RBC deformability. The underlying concept is that improved RBC deformability results in improved capillary blood flow and thereby, increased drug delivery to tumor cells. Treatment resulted in moderate hematologic and renal toxicity with no treatment-related deaths. This exceptionally high, pathologically confirmed complete response rate will hopefully provide a mechanism by which combined modality therapy can adequately be tested for its ability to prolong survival of patients with advanced head and neck cancer.

Tumor seeding associated with bone marrow aspiration and biopsy.

A 53-year-old man with small-cell lung carcinoma underwent bone marrow aspirations and biopsies for tumor staging and harvest for autologous bone marrow infusion. Fourteen months after bone marrow aspiration and biopsy, a subcutaneous lesion grew over the posterior iliac crest, and a biopsy specimen disclosed small-cell carcinoma. To our knowledge, this is the first case report of tumor seeding associated with bone marrow aspirate and biopsy.

Patient-controlled analgesia for severe cancer pain.

Concern with the suboptimal management of pain in hospitalized patients has led to the development of a patient-controlled analgesia system. In this system, a preset amount of narcotic is delivered intravenously when the patient activates the demand button. We tested the safety and efficacy of this mode of treatment in eight patients with cancer suffering from severe pain. Respiratory rates, mental status, and pain relief were recorded at baseline and during the study period. Morphine sulfate doses ranged from 1 to 5 mg, and lockout intervals from 15 to 90 minutes. Patients had a higher analgesic demand, ie, self-administered more doses, during the first four hours than during the remaining time of treatment. Respiratory rates decreased during the first four hours of treatment, but no cases of significant respiratory depression were encountered during this period or thereafter in the study. Significant pain relief was produced in all patients without causing undue sedation. Patient acceptance of this mode of therapy was excellent, and the majority of patients preferred this type of analgesia to other forms of pain treatment. In conclusion, patient-controlled analgesic is effective and safe therapy for cancer pain.

Breast cancer risk in relation to adipose concentrations of organochlorine pesticides and polychlorinated biphenyls in Long Island, New York.

To assess a possible etiological role of organochlorine compounds in breast cancer development on Long Island, a high-risk region of New York State, concentrations of organochlorine pesticides and polychlorinated biphenyls (PCBs) were measured in the adipose tissue of 232 women with breast cancer and 323 hospital controls admitted to surgery for benign breast disease or non-breast-related conditions. Seven pesticide residues and 14 PCB congeners were assayed via a supercritical fluid extraction method followed by gas chromatography with electron capture detection. After adjustment for age and body mass index, which were strongly correlated with organochlorine levels, adipose concentrations of 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, and total polychlorinated biphenyls (PCBs) did not differ significantly between cases and controls. The relative abundance of individual pesticide species and PCB congeners was similar in cases and controls. Odds ratios adjusted for age, BMI, hospital, and race gave no evidence of a dose-response for 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, or total PCBs, whether stratified by estrogen receptor status or not. Breast cancer risk among Long Island residents was not elevated compared with residents of the adjacent New York City borough of Queens. We did not confirm a previously reported association between breast cancer risk and levels of PCB congener 118 (2,3',4,4',5-pentachlorobiphenyl), nor did we observe an association with the most abundant congener 153 (2,2',4,4',5,5'-hexachlorobiphenyl), a strong inducer of phase I enzymes that was reported recently to have estrogenic properties. Only PCB congener 183 (2,2',3,4,4',5',6-heptachlorobiphenyl), which is also an inducer, was significantly associated with risk, with an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.4) in women with adipose levels >5.67 ng/g; the biological importance of this observation is unclear without confirmation in additional studies. Although neither the present nor other studies have provided convincing evidence of an association between body burden of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane and PCBs with cancer of the breast, these compounds are rated as "possible" and "probable" human carcinogens, respectively, by the International Agency for Research on Cancer. Investigations of associations with cancer at other sites should be carried out.

Relative abundance of organochlorine pesticides and polychlorinated biphenyls in adipose tissue and serum of women in Long Island, New York.

Some organochlorine pesticides (OCPs) and PCBs are under investigation as possible risk factors for breast cancer because of their estrogenic properties and widespread presence in the environment. It is important to know whether adipose tissue used by some investigators and serum assays used by others can provide comparable information on body burden. Concentrations of seven OCPs or their breakdown products as well as 14 PCB congeners were measured in the adipose tissue and serum of 293 women enrolled as controls in a case-control study of environmental factors for breast cancer in Long Island, New York, a high-risk region. Adipose OCP/PCB levels were measured using a supercritical fluid extraction method developed by the authors. 1,1-Dichloro-2,2-di(4-chlorophenyl)ethylene (p,p'-DDE) was detected in all adipose and serum samples; two chlordane derivatives, beta-hexachlorocyclohexane (a lindane isomer) and hexachlorobenzene, were detected in at least 92% of adipose samples. The di-ortho hexachlorinated PCB congeners 2,4,5,2',4',5'-hexachlorobiphenyl and 2,3,4,2',4',5'-hexachlorobiphenyl were detected in all adipose and over 98% of serum samples. 1,1-Dichloro-2,2-di(4-chlorophenyl)ethylene comprised 77% of total pesticide residues in adipose and 71% in serum. 2,4,5,2',4',5'-Hexachlorobiphenyl comprised 24% of adipose and 21% of serum PCBs. The relative concentration patterns of the 14 PCB congeners were similar to those reported in other human studies and were also typical of patterns reported in environmental samples from various biota, including mammals and birds, but differed substantially from patterns reported in occupationally exposed workers. All adipose-serum correlations for pesticides and most PCBs were statistically significant. Either serum or adipose OCP/PCB levels of a variety of environmental organochlorine compounds may serve as useful biomarkers of body burden.

Smoking and lung cancer risk in American and Japanese men: an international case-control study.

Rates of lung cancer in American men have greatly exceeded those in Japanese men for several decades despite the higher smoking prevalence in Japanese men. It is not known whether the relative risk of lung cancer associated with cigarette smoking is lower in Japanese men than American men and whether these risks vary by the amount and duration of smoking. To estimate smoking-specific relative risks for lung cancer in men, a multicentric case-control study was carried out in New York City, Washington, DC, and Nagoya, Japan from 1992 to 1998. A total of 371 cases and 373 age-matched controls were interviewed in United States hospitals and 410 cases and 252 hospital controls in Japanese hospitals; 411 Japanese age-matched healthy controls were also randomly selected from electoral rolls. The odds ratio (OR) for lung cancer in current United States smokers relative to nonsmokers was 40.4 [95% confidence interval (CI) = 21.8-79.6], which was >10 times higher than the OR of 3.5 for current smokers in Japanese relative to hospital controls (95% CI = 1.6-7.5) and six times higher than in Japanese relative to community controls (OR = 6.3; 95% CI = 3.7-10.9). There were no substantial differences in the mean number of years of smoking or average daily number of cigarettes smoked between United States and Japanese cases or between United States and Japanese controls, but American cases began smoking on average 2.5 years earlier than Japanese cases. The risk of lung cancer associated with cigarette smoking was substantially higher in United States than in Japanese males, consistent with population-based statistics on smoking prevalence and lung cancer incidence. Possible explanations for this difference in risk include a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking.

Safety and efficacy of continuous intravenous morphine for severe cancer pain.

To study the efficacy and safety of continuously administered intravenous morphine for cancer pain unrelieved by standard narcotic therapy, bolus intravenous injections of 2 to 5 mg of morphine were given every 10 minutes until pain relief was achieved. Within the next hour, continuous intravenous morphine infusion was begun with the hourly dose equal to the cumulative bolus dose. Respiratory rate, pulse, blood pressure, arterial blood gas values, mental status, and pain relief were recorded at baseline and during the study period. A reduction in arterial oxygen pressure (PaO2) and/or increase in arterial carbon dioxide pressure PaCO2 of more than 20 percent of baseline values occurred, during the first 24 hours of infusion, in a minority of patients. This did not require changes in hourly morphine dose. Despite subsequent increases in morphine dose, blood gas values tended to remain at or return toward baseline values. Severe toxicity occurred during one trial and was heralded by bradypnea and marked somnolence. Major pain relief was achieved in 11 of 15 trials. Therefore, continuous intravenous morphine is effective and safe therapy. Bradypnea associated with marked somnolence is a cause for dose reduction.

Thrombosis: the major Hickman catheter complication in patients with solid tumor.

Major complications of Hickman catheter placement (thrombosis and infection) were determined in 168 patients with solid tumor (lung, 79; head and neck, 56; esophagus, 24; and miscellaneous, 9). Catheter-related thrombosis was clinically detected in 22 individuals and was detected at autopsy in six (total 17 percent). The 17 percent figure underestimates the true incidence of thrombosis since only 25 percent of study patients had autopsies. Patients with adenocarcinoma of the lung constituted a high risk group. Nine of 20 (45 percent) of these patients had thrombosis compared to 25, 9, and 16 percent of patients with squamous cell cancers of lung, head and neck and esophagus, respectively (p less than 0.002). Three patients with thrombosis had pulmonary emboli and two died. Thrombosis occurred despite daily heparin catheter flushing. INfections occurred in 11 patients. One had suspected endocarditis, one had a subcutaneous tunnel infection, and nine had exit site infections. All responded to local or systemic antibiotics. Better methods to prevent thrombosis are needed.

Intracellular Localization and intercellular heterogeneity of the human DNA repair protein O(6)-methylguanine-DNA methyltransferase.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl adducts from DNA and may be important in tumor resistance to alkylation chemotherapy. MGMT was visualized in human cells and tumor tissues with monoclonal antibodies against MGMT and immunofluorescence microscopy, and fluorescent signals were quantified by digital image analysis. MGMT was found both in the cytoplasm and the nucleus, and in either locale the protein reacts with alkylated DNA bases and becomes inactivated and lost from the cell. Cell lines in culture and xenografts showed a broad normal distribution of nuclear MGMT levels, but human brain tumors often showed a skewed distribution, with a significant fraction of cells with high levels of MGMT. O(6)-Benzylguanine, a suicide substrate inactivator for MGMT activity, reduced MGMT in human cells and in a mouse xenograft to levels undetectable by antibody assay 1 h post-treatment. In melanoma specimens taken from a patient 3 h post-treatment with temozolomide, MGMT levels were reduced by 70%. This quantitative immunofluorescence assay can be used to monitor MGMT and it depletion in human tumors to improve the use of alkylating agents in cancer chemotherapy.

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p

Analysis of O6-methylguanine-DNA methyltransferase in individual human cells by quantitative immunofluorescence microscopy.

A quantitative assay of immunofluorescence is described that can be performed on individual cells from standard pathologic specimens using fluorescence microscopy. The technique has been applied to measurement of O6-methylguanine-DNA methyltransferase, a DNA repair protein that is a molecular marker for resistance to chloroethylnitrosources used in cancer chemotherapy. The immunofluorescence assay makes use of monoclonal antibodies with specificity for human transferase, fluorescence microscopy with digital imaging, fluorescent bead internal standards, and computerized image analysis. This method is specific for the transferase, produces results correlated with activity measurements, and yields new data about tissue heterogeneity and subcellular localization previously unavailable with standard assay methods.

5-Fluorouracil pharmacokinetics in patients with metastatic colorectal carcinoma after high-dose leucovorin.

The effect of high-dose leucovorin on 5-fluorouracil (5-FU) pharmacokinetics was studied in 5 patients with metastatic colorectal carcinoma. Patients received leucovorin, 500 mg/m2, and 5-FU, 600 mg/m2, on 1 day and 5-FU alone 1 week later. Plasma concentrations of 5-FU and 5-FU anabolites were determined over 2 hr. Levels of 5-FU were highest initially and then fell rapidly. Plasma concentration-time curves suggested a two-compartment kinetic model. Anabolite levels exceeded 5-FU levels after 15 min. When leucovorin was administered, the time of distribution (t1/2 alpha for 5-FU increased from 8.9 +/- 2.4 to 12.8 +/- 2.5 min (p < 0.0005) and the volume of distribution (Vd) increased from 0.129 +/- 0.039 to 0.237 +/- 0.033 L/kg (p < 0.03). Elimination and plasma clearance of 5-FU were unchanged. Anabolite levels were initially lower (p < 0.05) with leucovorin, suggesting increased tissue extraction of 5-FU.

Phase II trial of high-dose 24-hour continuous intravenous 5-fluorouracil for advanced non-small cell lung cancer: a Cancer and Leukemia Group B study.

Eighty-six eligible patients with non-small cell lung cancer were treated on a Phase II, CALGB study with high-dose, 24-h continuous intravenous 5-fluorouracil every 2 weeks. Objective responses were seen in 7 (8%) patients with 1 (1%) complete response and 6 (7%) partial responses. The median survival for these patients without prior chemotherapy was 3.8 months. Gastrointestinal and hematologic toxicity were acceptable for most patients. However, two patients experienced acute clinical deterioration characterized by worsening central nervous system and hemodynamic function beginning near the completion of chemotherapy treatment and resulting in death. Because of its potential for severe, unpredictable neurologic and cardiac toxicity, we do not recommend this dose and schedule of 5-FU for future trials.

Modulation of human tumor colony growth in soft agar by serum.

The factors controlling the growth of human tumor cells in soft agar are poorly understood. However, it has been demonstrated that serum provides factors which promote anchorage-independent growth. We tested 58 tumor specimens, which were obtained from patients with adenocarcinoma of the lung, colon, ovary or squamous cell carcinoma, for their ability to form colonies in soft agar in serum-free or serum-supplemented media. The cells were unable to replicate, and none of the hormones or growth factors tested: insulin (I), transferrin (T), selenium (S), estradiol (E), hydrocortisone (H) or epidermal growth factor (EGF) could substitute for serum. Examination of the serum dose-response curves indicated that growth factors reduced the serum concentrations needed to support anchorage-independent growth. The addition of the supplements and the lowering of serum concentrations increased cloning efficiencies (C.E.) in 38/51 trials, when cells were able to grow initially. The addition of ITS increased C.E. in 18/21 cases, HITES in 15/17 cases and EGF in 12/18 cases as compared to controls. ITS and HITES increased the number of colonies only when serum was the limiting factor. EGF, however, increased the number of colonies even when serum was not the limiting factor. The ability of the supplements to enhance growth could not be correlated to tumor type or initial cloning efficiencies. However, in only 1/25 cases were cells that were unable to form colonies under standard conditions induced to form colonies in the presence of the growth factors. Normal and tumor-derived human fibroblasts did not form colonies in soft agar in the presence of these growth factors. The results suggest that human tumor cells may require the presence of serum-derived factors for growth in soft agar.

Hickman catheter tip displacement.

In a series of 60 consecutive patients in whom Hickman catheters were placed for treatment of malignancy, four properly positioned catheter tips migrated secondarily from the superior vena cava to the ipsilateral jugular vein 2, 4, 21, and 25 days after placement. Three of the four patients had begun to have catheter dysfunction when the displacement was diagnosed. No satisfactory explanation for this rarely reported complication was evident in three of the cases. Maneuvers such as coughing, Valsalva's maneuver, and forceful heparin flushing produced no motion in three normally directed catheter tips in other patients observed under fluoroscopy. The phenomenon may be more common than previously reported. Evaluation of any new Hickman catheter dysfunction should include a chest x-ray film to ascertain the position of the catheter.