No abstract

Summary Secretory breast carcinoma (SBC) is a rare type of invasive breast cancer. Since little is known about the biology of this rare tumour, it is useful to report every such case, in order to make as much information as possible available in the medical literature. We present the case of an 18-year-old woman with a SBC treated by mastectomy (Madden) and axillary node dissection (stage pT3N1M0) 1 followed by chemotherapy (FEC 2 regimen) and radiotherapy. The patient has meanwhile completed 4 years of follow-up with no evidence of recurrence. The authors review the literature and summarize relevant findings concerning definition, pathology, clinical picture, treatment, and follow-up.

487 Background: The phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer overall survival (OS) with avelumab + best supportive care (BSC) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy. Avelumab 1L maintenance is now considered standard of care in treatment guidelines. We report trial data with ≥2-years follow-up in all pts (additional 19 months from the initial analysis). Methods: Pts with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS, assessed from randomization in all pts and in pts with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) and safety. Results: 700 pts were randomized (350 per arm); 358 (51.1%) had PD-L1+ tumors. With extended follow-up (median, ≥38 months in both arms for all pts; data cutoff, June 4, 2021), OS remained significantly longer in the avelumab + BSC vs BSC alone arm in all randomized pts and in pts with PD-L1+ tumors (Table). An OS benefit was observed across prespecified subgroups. PFS (by investigator) was longer with avelumab + BSC vs BSC alone in all randomized pts and in pts with PD-L1+ tumors (Table). In the avelumab + BSC and BSC alone arms, respectively, 185 (52.9%) vs 252 (72.0%) pts received a subsequent anticancer drug therapy, including a PD-(L)1 inhibitor in 40 (11.4%) vs 186 (53.1%) pts. Long-term safety was consistent with previous avelumab monotherapy studies, with no new safety signals. Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial continues to show prolonged OS with avelumab + BSC vs BSC alone. These results further support the standard-of-care role for avelumab as 1L maintenance in pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]

Purpose: Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14ϩ1G3 A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency. Methods: We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute. Results: Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14ϩ1G3 A, whereas the second patient was heterozygous for a novel missense mutation 1845G3 T (E615D) in exon 14 of DPYD gene. Conclusion: We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients. Genet Med 2004:6(2):102-107. Key Words: DPYD mutations, dihydropyrimidine dehydrogenase, 5-FU toxicity, 5-FU catabolism, chemotherapy5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic drugs for the treatment of malignant neoplasms, namely colorectal cancer. 5-FU is a pyrimidine analogue, giving rise to cytotoxic metabolites after metabolization by the pyrimidine pathways. One of them, the 5-fluorodUMP, inhibits thymidylate synthase, thus impairing DNA synthesis. Additional cytotoxic effects arise from 5-FU metabolites being incorporated into RNA and DNA. 1 Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. It has been reported that more than 80% of the administered 5-FU is catabolized by DPD, 2-4 so the activity of this enzyme may be of paramount importance to predict the efficacy and toxicity of this drug. Deficiency in DPD enzyme activity has been correlated with considerable delay in 5-FU clearance from plasma. 4,5 The important role of DPD in 5-FU-based chemotherapy has been demonstrated in cancer patients with major deficiency of this enzyme's activity. These patients may present severe toxicity after the administration of 5-FU, including diarrhea, neutropenia, and neurotoxicity, and death may occasionally occur. 6 -9 Population studies suggested that, although total deficiency is rare, as many as 3% to 5% of the population may have low enzyme levels and thus be at increased risk of severe toxicity if treated with 5-FU. 10 Several of these patients are genotypically heterozygous for a mutant DPYD allele. [11][12][13][14][15][16] To date, more than 30 variant DPYD alleles have been identi...