Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Positive peritoneal cytology is highly predictive of prognosis and relapse patterns in stage III (FIGO 2009) endometrial cancer.

OBJECTIVES: According to the updated FIGO system, positive peritoneal cytology does not affect endometrial cancer stage. This revision may reduce rates of obtaining cytology, with unclear implications in advanced disease. This study evaluates the significance of positive cytology in stage III (FIGO 2009) endometrial cancer. METHODS: Eligible patients received treatment for stage III endometrial cancer at a single institution and had peritoneal cytology performed. RESULTS: Of 196 patients, 58% were ≥ 60 years old, 48% had deep myometrial invasion, 71% lymphovascular invasion, 25% cervical invasion, 37% adnexal involvement, 79% nodal involvement, and 46% aggressive histology. Positive cytology was present in 23% (45/196) and significantly associated with cervical stromal invasion, adnexal involvement, and aggressive histology (P ≤ 0.03). There was no significant difference in rates of lymphadenectomy, chemotherapy, or radiation between negative and positive cytology groups. At a median follow-up of 47 months, the 5-year freedom from relapse was 39% for positive cytology vs. 69% for negative, disease-specific survival 42% vs. 77%, and overall survival 34% vs. 72% (P < 0.001). Positive cytology correlated with higher recurrence rates in the para-aortic nodes and peritoneum (30% vs. 9%, 23% vs. 4%; P ≤ 0.008). When controlling for adverse features including aggressive histology, positive cytology was associated with an increased hazard for relapse (HR 2.3; P = 0.002) and death (HR 2.9; P < 0.001). CONCLUSIONS: In stage III endometrial cancer, positive cytology independently predicts outcome and is associated with distinct relapse patterns. Obtaining peritoneal cytology in stage III endometrial cancer is critical.

The relation between vertebral endplate shape and lumbar disc herniations.

STUDY DESIGN: Blinded review of selected and un-selected computed tomographic myelograms. OBJECTIVE: To determine whether shape of the vertebral body endplate margins is a risk factor for the development of symptomatic lumbar disc herniations. The law of LaPlace for a fluid-filled tube suggests that anular tension could be related to endplate shape and a propensity for disc herniation. SUMMARY OF BACKGROUND DATA: It was hypothesized that the law of Laplace could apply to the lumbar spine because of to the cylindrical shape of the lumbar disc and its high water content in nonelderly individuals. It was further hypothesized that differences in the radius of the curvature could place stresses on the anulus that would make posterior disc herniations more likely with "rounder" endplates. METHODS: Ninety-seven contrast computed tomography scans were reviewed at transitional L4-L5 and L5-S1 in patients under 60 years of age, without previous spine surgery and without spondylolisthesis. Determinations of disc herniations and measurements of endplates were performed by blinded observers. A ratio of these measurements was used to determine the relative circularity of the endplate. Height, weight, body mass index, and disc endplate size and shape were related to the presence of disc herniation. RESULTS: By multiple logistic regression, only endplate shape was strongly related to disc herniations. Endplate area was a less significant factor in men. CONCLUSIONS: The shape of the vertebral body margin at the endplate is an important factor contributing to the development of disc herniations at L4-L5 and L5-S1.