Personalized analysis of minimal residual cancer cells in peritoneal lavage fluid predicts peritoneal dissemination of gastric cancer

Peritoneal dissemination (PD) is a major type of gastric cancer (GC) recurrence and leads to rapid death. Current approaches cannot precisely determine which patients are at high risk of PD to provide early intervention. In this study, we developed a technology to detect minimal residual cancer cells in peritoneal lavage fluid (PLF) samples with a personalized assay profiling tumor-specific mutations. In a prospective cohort of 104 GC patients, the technology detected all the cases that developed PD with 100% sensitivity and 85% specificity. The minimal residual cancer cells in PLF were associated with a significantly increased risk of PD (HR = 145.13; 95% CI 20.20–18,435.79; p < 0.001), which was the strongest independent predictor over pathologic diagnosis and cytological diagnosis. In pathologically high-risk (pT4) patients, the PLF mutation profiling model exhibited a greater specificity of 91% and a positive predictive value of 88% while retaining a sensitivity of 100%. This approach may help in the postsurgical management of GC patients by detecting PD far before metastatic lesions grow to a significant size detectable by conventional methods such as MRI and CT scanning.

Personalized analysis of minimal residual cancer cells in peritoneal lavage fluid predicts peritoneal dissemination of gastric cancer

Peritoneal dissemination (PD) is the major type of gastric cancer (GC) recurrence and leads to rapid death. Current approach cannot precisely determine which patients are at high risk of PD. In this study, we developed a technology to detect minimal residual cancer cells in peritoneal lavage fluid (PLF) samples by parallel profiling tumor-specific mutations. We applied the technology to a prospective cohort of 110 GC patients. The technology showed ultra-high sensitivity by successfully detecting all the 27 cases that developed PD. The minimal residual cancer cells in PLF was associated with an increased risk of PD (HR = 145.13; 95%CI = 20.20-18435.79; p < 0.001) and significantly shorter overall survival. In pathologically high-risk (T4) patients, the PLF mutation profiling model exhibited even greater specificity of 91% and positive predictive value of 88%, while retaining sensitivity of 100%. PLF cancer cell fraction remained the strongest independent predictor of PD and recurrence-free survival over pathologic diagnosis and cytological diagnosis in GC patients. This approach may help in the postsurgical management of GC patients by detecting PD far before the metastatic lesions grow to significant size detectable by conventional methods such as MRI and CT scanning.

Perioperative Period is a Critical Gap for Minimal Residual Cancer Cells Progression and Therapy: Biological and Molecular Based Evidences

Although surgery is the main treatment for solid tumors, it could enhance the growth and metastasis of minimal residual cancer. In this review article we have discussed the perioperative changes in cancer cells and surrounding environment as well as the alterations in the immune system. Several trials are ongoing to develop new diagnostic and therapeutic options for minimal residual cancer after surgery.

A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC).

1043 Background: Notch receptors are overexpressed in TNBC. Notch activation involves the cleavage of Notch ligand/receptor complex by GS. RO4929097 (RO) is an oral inhibitor of GS. We are conducting a phase I NCT trial of intermittent RO in combination with P and C in TNBC to determine the dose limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of RO. Because RO induces CYP3A4/5, plasma P and RO are quantified in real time to ensure P AUC exposure is not decreased. Methods: Women ≥ 18 years with clinical stage II/III TNBC received C AUC=6 on day 1 and weekly P 80 mg/m2 in combination with RO on days 1-3, 8-10 and 15-17 for six 21-day cycles. The starting dose of RO was 10 mg and escalated according to the 3+3 rule. DLT was defined as grade ≥3 (G3) non-hematologic toxicity (n-HT), grade 4 (G4) thrombocytopenia (TCP) or G4 neutropenia (NP) during cycle#1 (c1). Plasma specimens were analyzed for PK by a validated LC-MS/MS assay. Results: 13 pts were enrolled. Two pts enrolled at 10 mg RO with C AUC 6 developed G3,4 TCP during c1. The study was amended; the dose of C was decreased to AUC 5. No DLTs were observed with 10 mg RO and C AUC 5. Only 1 DLT ( G3 HTN) occured with 20 mg RO, but all 4 pts enrolled on this cohort required dose reductions of RO during subsequent cycles. The RO dose was de-escalated to 10 mg, additional 3 pts were treated with 10 mg RO. G≥3 HT included: G4 NP in 2 pts, G4 TCP in 1 pt, G3 NP in 6 pts, G3 anemia in 4 pts and G3 TCP in 5 pts. G≥3 n-HT included: G3 sensory neuropathy in 3 pts. G3 HTN, G3 fatigue and G3 depression occured in 1 pt each. There were no hospitalizations for treatment-related toxicities. PK studies indicate that P AUC ranged from 80% to 134% on week 3 compared to week 1. Ten pts completed 6 cycles of NCT, 3 are still receiving NCT. Five of 10 (50%) pts had complete pathologic response (pCR) in breast and axilla and 3 (30%) pts had minimal residual cancer in breast. Conclusions: The MTD of intermittent RO administered in combination with P and C is 10 mg. This MTD does not result in decreased P exposures. The pCR (50%) and minimal residual disease (30%) suggests this regimen is active in TNBC. Supported by the NCI/NIH Award Number U01CA076576. Clinical trial information: NCT01238133.

Molecular Detection of Minimal Residual Cancer in Surgical Margins of Head and Neck Cancer Patients

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins.Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters.A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p < 0.001), and the group of patients with histopathological tumor-free surgical margins (p = 0.001).This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising.