James Laird

Unravelling the biology of SCLC: implications for therapy

Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

Impact of an In Situ Component on Outcome After In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy

BackgroundAmong all in-breast tumor recurrences (IBTR) following breast-conserving therapy (BCT), some comprise metachronous new primaries (NPs) while others are true recurrences (TRs). Establishing this distinction remains a challenge.MethodsWe studied 3932 women who underwent BCT for stage I–III breast cancer from 1998 to 2008. Of these, 115 (2.9%) had an IBTR. Excluding patients with inoperable/unresectable recurrences or simultaneous distant metastases, 81 patients with isolated IBTR comprised the study population. An IBTR was categorized as an NP rather than a TR if it included an in situ component. The log-rank test and Kaplan–Meier method were used to evaluate disease-free survival (DFS) and overall survival (OS), and univariate and multivariate analyses were performed using Cox proportional hazards regression models.ResultsAt a median of 64.5xa0months from IBTR diagnosis, 28 of 81 patients had DFS events. Five-year DFS was 43.1% in the TR group (pxa0=xa00.0001) versus 80.3% in the NP group, while 5-year OS was 59.7% in the TR group versus 91.7% among those with NPs (pxa0=xa00.0011). On univariate analysis, increasing tumor size, high grade, positive margins, lymphovascular invasion, node involvement, lack of axillary surgery, chemotherapy, radiation therapy, and IBTR type (TR vs. NP) were significantly associated with worse DFS. Controlling for tumor size and margin status, TRs remained significantly associated with lower DFS (hazard ratio 3.717, 95% confidence interval 1.607–8.595, pxa0=xa00.002).ConclusionThe presence of an in situ component is associated with prognosis among patients with IBTR following BCT and may be useful in differentiating TRs and NPs.

Talazoparib is a Potent Radiosensitizer in Small Cell Lung Cancer Cell Lines and Xenografts

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization. Experimental Design: Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models. Results: Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models. Conclusions: PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. Clin Cancer Res; 24(20); 5143–52. ©2018 AACR.

ASO Author Reflections: Breast Cancer Local Recurrence Versus New Primary—Clinical Predictors and Prognostic Implications

It has long been observed that controlling a locally recurrent tumor that persisted despite definitive therapy is more challenging than the management of a de novo unselected primary cancer. Indeed, 10-year overall survival rates can approximate 40% following local recurrence, whereas overall breast cancer outcomes are significantly more favorable. An in-breast tumor recurrence (IBTR) may represent a true recurrence (TR) arising from the original tumor, or a new primary (NP). However, there is no standard approach for differentiating TRs from NPs. Some have used in-quadrant recurrence as an indicator of a TR, whereas others have used concordance of histology and subtype, all with variable reliability. Our study sought to establish the presence of an in situ component within an IBTR as a marker of a NP that, thereby, portends favorable disease-free survival (DFS). To date, the majority of breast cancer studies have focused on overall IBTR, likely overestimating treatment failures given the occasional presence of de novo carcinogenesis. PRESENT

Reply to "Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy"

Dr. Altundag raises an interesting question regarding the influence of breast cancer biologic subtype on survival after a local recurrence. Although we previously reported that subtype approximations do maintain prognostic significance after a first recurrence, in the context of the current study, this raises another issue about the propensity for a breast cancer recurrence to harbor ductal carcinoma in situ (DCIS) as a function of the primary disease subtype. This was addressed in Table 2, demonstrating no significant differences in the rates between true recurrence (TR) and new primaries (NP) by biologic subtype. In addition, with regard to the overall cohort from which these recurrences derive, the nearly 4000 patients treated with breast-conserving therapy (BCT) were representative of previously reported American population distributions of breast cancer biologic subtypes, including approximately 80% estrogen receptor-positive (ER?) lesions, the majority of which retained their luminal (ER?) subtype at the time of local recurrence. We currently are performing additional analyses to identify whether variations in subtype and location between primary and recurrent lesions are as informative as our DCIS definition of true recurrence versus new primary disease. Sincerely, James Laird, BA and Lior Z. Braunstein, MD

Outcome after Radiotherapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement

PURPOSEnTo characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence.nnnPATIENTS AND METHODSnBetween 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion.nnnRESULTSnMedian age at radiation therapy was 35xa0years (range, 1.5-67xa0years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4xa0Gy (range, 7.5-50.4xa0Gy). At a median follow-up of 45xa0months (range, 6-199xa0months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease.nnnCONCLUSIONnRadiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities.