Gail L. Shaw

Lung cancer risk associated with cancer in relatives

Family history data from an incident case-control study of lung cancer conducted in the Texas Gulf Coast region between 1976 and 1980 were analyzed to evaluate the contribution of cancer in first-degree relatives to lung cancer risk. Odds ratios (OR) increased slightly as the number of relatives with any cancer increased (reaching 1.5 with 4 or more relatives with cancer). Risks were higher for tobacco-related cancers (OR = 1.5 for 2 or more relatives with these tumors) and greatest for first-degree relatives with lung cancer (OR = 2.8 for lung cancer in 2 or more relatives). For cases of squamous cell carcinoma and adenocarcinoma of the lung, risks with 3 or more relatives with any cancer were increased 2-fold (OR = 1.8 and 1.9 respectively), and a significantly elevated risk was found for having a first-degree relative with lung cancer for each histologic type (ORs from 1.7-2.1). Having a spouse with lung cancer increased lung cancer risk (OR = 2.5), and cases with lung cancer reported in a first-degree relative were diagnosed at an earlier age, as were case siblings with lung cancer.

Scientific basis for cancer prevention. Intermediate cancer markers.

Promising cancer clinical trials results involving the disruption of early stages of cancer with intervention agents such as tamoxifen or retinoids have led to significant new research interest in developing preventative strategy for the control of epithelial cancers. Key to the efficient progress in this field is a clear understanding of the complex biology of the early stages of cancerization that proceed on the epithelial surface. Systematic analysis of the biology of strategic targets such as growth factors is one approach to this problem. Gastrin‐releasing peptide is an autocrine growth factor for certain types of lung cancer cells. Mechanisms involved in the production and activation of this peptide are discussed as an example of how rational approaches to neutralization of cancer promotion biology can be achieved. The tools to monitor the success of this type of intervention also emerge from the understanding of the biology of growth factors, and intermediate end point markers that determine the presence or effects of a growth factor are attractive candidates for evaluation. Additional biologic tools reflecting the early stages of the cancer process need to be validated for use in serially evaluating the status of the relevant epithelium so that the ongoing success of a cancer intervention procedure can be established. Through this type of translational research, important applications of molecular biology may greatly improve the success of preventative strategies for cancer control.

Peptide amidating activity in human bronchoalveolar lavage fluid.

Monitoring respiratory epithelial biology may reveal individuals with incipient lung cancer. The expression of neuroendocrine (NE) markers in pulmonary epithelium is thought to be central to lung development, repair of injury and may contribute to carcinogenesis. In this study, we evaluate several candidate NE markers to determine the feasibility of prospective analysis of clinical specimens. The potential NE markers include the enzyme L-DOPA decarboxylase (DDC), the neuropeptide gastrin releasing peptide (GRP), and peptidyl-glycine alpha-amidating monooxygenase (PAM), the bifunctional enzyme responsible for the final bioactivation step of many neuropeptides. A comparison of PAM activity and DDC levels in 30 lung cancer cell lines indicated that peptide amidating activity may be an indicator of NE status. Bronchoalveolar lavage (BAL) fluid from subjects at risk of developing second primary lung cancer and from volunteers was obtained. The activity of the first PAM enzyme, peptidylglycine alpha-hydroxylating monooxygenase (PHM), ranged from not detectable to 507 pmol/h/mg protein in 57 specimens. The second PAM enzyme, peptidylamidoglycolate lyase (PAL), ranged from not detectable to 414 pmol/h/mg protein in 56 specimens. Using cluster analysis by the average linkage method, a group of enzyme values with PHM greater than 230 pmol/h/mg protein was determined. Long-term follow-up of these patients for new second primary lung cancers may help to determine the potential predictive value of PAM detected in the BAL fluid.

Intermediate Markers and Molecular Genetics of Lung Carcinogenesis.

BACKGROUND: Various options are available for the local control of cancer in the breast - mastectomy, conservation therapy, and mastectomy with reconstruction. METHODS: To evaluate the benefits and drawbacks of the available management options, the authors combine their extensive experience with a review of the literature on outcomes from these approaches. RESULTS: Conservation therapy provides survival outcomes similar to those from mastectomy. Differences in local recurrence rates can be minimized by close adherence to guidelines for patient selection, operative approach, and radiation technique. CONCLUSIONS: The role of the physician in selecting a local therapy for breast cancer has changed from one of informing the patient of the treatment to assessing the presence of medical contraindications to any of the treatments, educating the patients on each treatment approach, providing access to multidisciplinary consultation, and allowing the patient to choose an appropriate treatment approach.

Primary and Secondary Prevention of Lung Cancer: an International Association for the Study of Lung Cancer workshop

aMolecular Structure Section, Division of Developmental Therapeutics Program, Bethesda, MD 20892, USA bBiomarkers and Prevention Research Branch, Division of Cancer Prevention and Control, National Cancer Institute, Rockville, MD 20852, USA ‘Department of Behavioral Science, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA ‘Department of Thoracic. Head and Neck Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA eNational Cancer Institute, Navy Medical Oncology Branch, Division of Cancer Treatment, National Cancer Institute, Be&es&, MD 20897, USA tDepartment of Medical Oncology and Hematology, Tufts University Medical School, Boston, MA 02111-1526, USA K?ntcer Control Science Program, Division of Cancer Prevention and Control, National Cancer Institute. Rockville, IUD 20852, USA hDepartment of Pathology, Harvard Medical School, Boston, MA 0211.5, USA

Frequency of the variant allele CYP2D6(C) among North American Caucasian lung cancer patients and controls

Previous reports of the association between the debrisoquine polymorphism and lung cancer risk are conflicting. Following the report of an association between lung cancer risk and the variant allele CYP2D6(C), we examined the presence of this allele in 98 incident Caucasian lung cancer patients and 110 age, race, and sex matched hospital controls from a case-control study conducted at the National Naval Medical Center in Bethesda, MD. Debrisoquine metabolic phenotype was determined by debrisoquine administration and analysis of debrisoquine and 4-hydroxydebrisoquine in the subsequent 8 h urine collected. Genomic DNA was genotyped by a specific polymerase chain reaction amplification and subsequent restriction enzyme digestion, and Southern analysis. Twenty subjects were heterozygous for the CYP2D6(C) allele but none were homozygous for this allele. There was no significant difference in frequency of CYP2D6(C) between lung cancer patients and controls (5.61% and 4.09%, respectively), and there was no significant heterogeneity among cases by histologic type of lung cancer (P = 0.08). However, 7 of 11 cases (64%) with the CYP2D6(C) allele had small cell lung cancer, and none had squamous cell carcinoma. Carrying the CYP2D6(C) allele did not impair debrisoquine metabolism to the same degree as the known inactivating mutations, CYP2D6(A) and CYP2D6(B), or deletion of CYP2D6. Thus, the CYP2D6(C) allele does not encode a completely inactivating mutation, and the suggestion of a role for this variant allele in the risk for specific histologic types of lung cancer justifies further investigation.

Integrated clinical and basic studies related to circumventing non-small cell lung cancer drug resistance

Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancers chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium.