Blanco, Ellen W.

239 Background: After trastuzumab (T) approval for advanced HER2-positive E/GEJ-AC, HER2 testing has increased in patients (pts) with resectable disease. Neoadjuvant carboplatin/paclitaxel chemoradiation (nCP-CRT) is a common therapy approach. We performed the largest evaluation, to our knowledge, of the prognostic impact of HER2 in E/GEJ-AC pts treated with nCP-CRT. Methods: We retrospectively reviewed medical records of all trimodality-eligible (T2+ or N+) pts with E/GEJ-AC who started nCP-CRT (usually 50.4 Gy) with planned surgery at Mayo Clinic (2014-2019). HER2 was tested using standard criteria for HER2 positivity (ie, immunohistochemistry 3+ or amplification by in situ hybridization). Clinicopathologic data and time to recurrence (TTR), disease free survival (DFS), overall survival (OS), survival after recurrence (SAR), and pathologic complete response (pCR – ie, no residual tumor in primary or nodes) were collected. Kaplan Meier and multivariate Cox analysis were used. Results: Of 161 consecutive eligible pts, HER2 status was available in 107 pts (HER2-positive n=26, HER2-negative n=81) of whom n=82 had surgery and n=19 had pCR. Most tumors were clinical T3 (80%) or N+ (81%), histologic grade 3 of 3 (62%). HER2 positivity was significantly associated with lower grade, but not with age, clinical T or N, or ECOG performance status (PS). A similar proportion of HER2-positive ( vs negative) pts had surgery. Among pts who had surgery, pCR rates were lower in HER2-positive ( vs negative) pts (11% [2/19] vs 27% [17/63]). After a median follow up of 23 mo, DFS and TTR were significantly shorter in HER2 positive ( vs negative) pts, independent of other pretreatment covariables (Table). Yet OS was comparable. Lung recurrence was enriched in HER2 positive ( vs negative) pts. Among pts with recurrence, SAR was longer in HER2-positive vs -negative pts. A total of 53% (10/19) of previously HER2-positive pts received T-based therapy after recurrence, and these pts were the drivers of favorable SAR (median 22 mo in n=10 HER2-positive pts who received T vs 11 mo in n=9 HER2-positive pts who did not receive T vs 11 mo in n=40 HER2-negative pts; P log-rank=.01). Conclusions: HER2 positivity ( vs negativity) is independently associated with shorter TTR and DFS, but more comparable OS. The adverse association of HER2 on tumor response and TTR may have been largely overcome through enhanced survival after recurrence, although OS data are maturing. These data may have implications for the design of endpoints in future curative-intent anti-HER2 trials. [Table: see text]

Abstract The kidney is the most common organ involved in systemic light-chain amyloidosis (AL), seen in up to 40% of patients. Renal involvement can result in proteinuria and/or renal insufficiency. The mechanism of renal injury in amyloidosis remains unclear. We present data supporting a central role for oxidative stress in amyloid-induced renal damage. Soluble free light chains(LCs) were isolated from plasma of AL and myeloma patients obtained at the time of stem cell collection. LCs were purified by liquid-phase iso-electric fractionation of pooled plasma samples from each patient. Purified LC were incubated with cultured rat renal epithelial cells, both wild-type and heme oxygenase-1 (HO-1) over-expressing, for 16 hours. Macrophage chemoattractant protein-1 (MCP-1) induction was measured in the media by ELISA. LC from myeloma patients were used as negative controls. Significant induction of MCP-1, a sensitive indicator of oxidative stress, was seen in 4/5 patients with lambda light-chain amyloidosis and 0/4 kappa light-chain amyloidosis patients. Induction of MCP-1 was seen in only 1/8 myeloma patients tested (4 lambda and 4 kappa). Induction of MCP-1 was reduced in the presence of HO-1 overexpression, implicating oxidative stress as a critical pathway of toxicity of amyloidogenic lambda light chains in this system. These results suggest that lambda and kappa light chains may cause renal injury through distinct pathways in the kidney.