Interleukin-10 in cancer immunotherapy: from bench to bedside.

Interleukin (IL)-10 was one of the first cytokines to be recognized. However, its functionality in promoting antitumor immunity was described more recently. Context- and concentration-dependent biological effects are the hallmarks of the pleiotropic role of IL-10. Despite reducing tumor-promoting inflammation, IL-10 may have a role in rejuvenating exhausted tumor-resident T cells. Contrary to the assumption that IL-10 produces an immunosuppressive tumor microenvironment (TME), it promotes activation of tumor-resident CD8+ T cells, which aids tumor rejection. Emerging data from published early-Phase trials have shown mixed results in different tumor types. In this review, we summarize the biological effects of IL-10 and highlight the clinical experience using pegilodecakin.

Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer.

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10.

PURPOSE: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab. PATIENTS AND METHODS: In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally. RESULTS: Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue. CONCLUSION: We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.

Prognostic factors in breast cancer patients evaluated by positron-emission tomography/computed tomography before neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is a significant modality in breast cancer therapy. We sought to characterize prognostic factors in patients scheduled for NAC who had a pretreatment positron-emission tomography paired with diagnostic quality contrast-enhanced computed tomography (CT) (positron-emission tomography/CT [PET/CT]). A total of 118 breast cancer patients were analyzed through chart review who underwent pretreatment PET/CT imaging and received NAC from 2008 to 2014. We collected information on molecular markers, PET/CT, pathologic complete response (pCR), survival, and disease status. Pretreatment standard uptake value (SUV) max of the primary breast tumor showed no relationship to pCR; however, there was a statistically significant relationship with relapse-free survival (RFS) using univariate cox regression (P = 0.03, odds ratio (OR) = 1.06 [1.01-1.12]) with comparable findings observed with overall survival (OS). Multivariate analysis revealed SUV max to be significantly correlated with shortened OS (P = 0.022, OR = 1.08 [1.01-1.16]), with a similar trend reported for RFS. By pathological subtype, this correlation was the strongest within hormone receptor (HR+)/human epidermal growth factor receptor 2 (HER2-) tumors. In addition, Kaplan-Meier estimates demonstrated a significant difference between the RFS of triple-negative tumors and HER2 positive tumors (P = 0.001). Interestingly, within this cohort, multivariate Cox regression analysis showed HER2 positivity to be associated with favorable outcome (P = 0.04, HR = 0.22 [0.05-0.94]). These findings demonstrate a significant association between SUV max of HR+/HER2-- tumors and relapse-free and OS. Furthermore, highlighted here is the favorable survival in the once classically aggressive HER2+ breast cancer subgroup.

Metastatic breast cancer: Endocrine therapy landscape reshaped.

Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus. Although still considered incurable by currently available treatment modalities, many patients with MBC nowadays enjoy several years of good quality life coupled with decent tumor control. The diversity of therapies and unusual pattern of side effects can be quite perplexing to the treating physician. The sequence of variable agents and management of side effects, in addition to the timing of initiation of cytotoxic chemotherapy, is among the challenges faced by oncologists. In this review, we shed a spotlight on mechanisms of resistance to ET, and provide a review of landmark studies that have recently reshaped the landscape of treatment options for patients with metastatic HR-positive, HER2-negative MBC. A suggested treatment strategy for newly diagnosed patients is also discussed herein.