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Tuberous sclerosis complex (TSC) is an autosomaldominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSCassociated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.

Amplification or increased expression of the c-erbB-2 gene has previously been reported to be a prognostic marker for breast cancer. Gene amplification is usually measured by Southern blotting, whereas increased protein expression is usually detected by immunocytochemistry. We measured c-erbB-2 protein with an enzyme-linked immunosorbent assay (ELISA). High concentrations of oncoprotein were found in 25 of 161 (16%) primary breast cancers and in 3 of 6 (50%) breast cancer metastases. High concentrations were not found in normal breast tissue or benign breast tumors. In the primary cancers, high concentrations of c-erbB-2 protein were found more frequently (a) in estrogen receptor-negative tumors than in estrogen receptor-positive tumors, (b) in progesterone receptor-negative tumors than in progesterone-positive tumors, and (c) in axillary node-positive cancers than in node-negative cancers. Patients with tumors containing high amounts of the c-erbB-2 protein had a significantly shorter (P less than 0.001) disease-free interval and overall survival rate than did patients with low amounts. We conclude that assay of c-erbB-2 protein by ELISA is simple, rapid, and quantitative and offers important prognostic information in breast cancer.

No abstract

Background: The addition of trastuzumab (H) to pre-operative chemotherapy in H+BC increases the rate of pathological complete remission (pCR). H causes cardiac toxicity, especially when given with anthracyclines (Anth). TCH is a widely used adjuvant regimen with decreased cardiac toxiciy. We reported that TCH produces pCR in 40% of non-randomised pts with H+BC. Lapatinib is an alternative HER2 antagonist, which produces responses following trastuzumab failure, and which has been reported to augment H activity in combination. We studied the non-Anth regimens TCH v TCL v TCHL in pts with H+BC. The primary objective of this study was pCR. Secondary endpoints were toxicity and translational. Methods: Eligibility criteria included: primary BC, HER-2 +, node + disease (histologically or cytologically confirmed) or node-negative with >T1, normal left ventricle ejection fraction, no active/uncontrolled cardiovascular disease, normal organ and marrow function. Treatment consisted of 6 cycles of D (75mg/m2) + C (AUC 6) q3 weekly and H (8 mg/kg on cycle 1 day 1 and 6 mg/kg q3weekly thereafter for one year) ± L (1000mg OD) for up to 1 week before surgery. A sample size of 36 evaluable pts is required to detect an absolute 25% difference in the pCR rate between the hypothesised 65% pCR rate vs the historical-control pCR rate of 40%. Results: Following presentation of NCIC MA31 we decided to suspend accrual on our TCL arm.78 female pts were accrued to TCH/TCHL in 11 ICORG sites between 12/2010- 06/2013. Of 40 patients accrued to TCHL, only 18 pts completed 6 cycles. 17pts came off study early due to toxicity, 3 pts after cycle 3, 2 pts after cycle 2, 12pts after cycle 1. (1 patient was also registered but never started). Of 38 pts accrued to the TCH arm,33 pts completed 6 cycles,2 pts completed 5 cycles and 2 pts w/d after cycle 1. 3 TCHL & 1 TCH pt still remain on Rx. 2 pts have not yet had surgery. 52 SAEs occurred on study, 49 involving hospital admission, & 3 of medical significance. The most frequent SAEs were diarrhoea (10), febrile neutropenia (4), nausea (4), neutropenic sepsis (3), dehydration (2), wound infection (2), vomiting (2) neutropenia (2) decreased haemoglobin (2), GI perforation (1). There was 1 fatality on the TCH arm due to Neutropenic sepsis and typhlitis. One TCHL pt suffered GI perforation at cycle 1. pCR rates were 48% (16/33) for the TCH arm and 44% (7/16) for the TCHL arm. Translational studies are underway. Conclusions: TCH containing treatment produces a high rate of pCR. TCHL will not produce a statistically higher rate of pCR in this sample. The addition of lapatinib to TCH results in substantial GI toxicity. TCHL appears to be less tolerable than other active chemotherapy +H+L regimens such as that used in Neo-ALLTO. ICORG is currently leading an international study of paclitaxel+H +/- L in metastatic BC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-25.