Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint ...inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a 'pro-inflammatory' tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers.
There has been substantial interest in HER2 intratumoral heterogeneity as an explanation for the development of resistance to anti-HER2 therapies in breast cancer, particularly to trastuzumab ...emtansine (T-DM1).
Through a literature-based approach, we discuss mechanisms of resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer.
We describe results from clinical studies reporting the effect of anti-HER2 strategies particularly ADCs and their mechanistic effect. We review biological findings underlying HER2 heterogeneity and its implication in the development of novel anti-HER2 drugs including new ADCs in clinical development like trastuzumab deruxtecan (DS-8201).
We suggest potential mechanisms to optimize these compounds and their future clinical implementation.
The presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with ...breast cancer, and examine the effect of clinicopathologic factors on its prognostic value.
A systematic search of electronic databases was conducted to identify publications exploring the association of blood NLR (measured pre treatment) and overall survival (OS) and disease-free survival (DFS) among patients with breast cancer. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance. Meta-regression was performed to evaluate the influence of clinicopathologic factors such as age, disease stage, tumor grade, nodal involvement, receptor status, and NLR cutoff on the HR for OS and DFS. All statistical tests were two-sided.
Fifteen studies comprising a total of 8563 patients were included. The studies used different cutoff values to classify high NLR (range 1.9-5.0). The median cutoff value for high NLR used in these studies was 3.0 amongst 13 studies reporting a HR for OS, and 2.5 in 10 studies reporting DFS outcomes. NLR greater than the cutoff value was associated with worse OS (HR 2.56, 95% CI = 1.96-3.35; P < 0.001) and DFS (HR 1.74, 95% CI = 1.47-2.07; P < 0.001). This association was similar in studies including only early-stage disease and those comprising patients with both early-stage and metastatic disease. Estrogen receptor (ER) and HER-2 appeared to modify the effect of NLR on DFS, because NLR had greater prognostic value for DFS in ER-negative and HER2-negative breast cancer. No subgroup showed an influence on the association between NLR and OS.
High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease. NLR is an easily accessible prognostic marker, and its addition to established risk prediction models warrants further investigation.
Background
Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to ...examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.
Methods
We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.
Results
Seven trials enrolling 30 023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).
Conclusions
The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.
The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the ...impact of AT on survival.
Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling.
Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no difference between gallbladder and bile duct tumors (P = .68). The association was significant when the two registry analyses were excluded. Those receiving CT or CRT derived statistically greater benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; P = .02). The greatest benefit for AT was in those with LN-positive disease (OR, 0.49; P = .004) and R1 disease (OR, 0.36; P = .002).
This analysis supports AT for BTC. Prospective randomized trials are needed to provide better rationale for this commonly used strategy. On the basis of our data, such trials could involve two active comparators rather than a no-treatment arm among patients with LN-positive or R1 disease.
Highlights • Meta-analysis of RCTs to quantify cardiovascular risk of angiogenesis inhibitors. • High risk of hypertension, with odds ratio (OR) of 5–6 relative to routine care. • Increased risk of ...cardiac ischemia (OR 2.83, number needed to harm NNH 85). • Increased risk of cardiac dysfunction and arterial thromboembolism but NNH was >100. • No significant difference between VEGF ligand inhibitors and small molecule agents.
Purpose
There is uncertainty about outcomes differences between partial breast irradiation (PBI) and whole breast irradiation (WBI) for early-stage breast cancer.
Methods
Prospective randomized ...trials comparing adjuvant PBI to WBI in early-stage invasive breast cancer were identified using PubMed. Odds ratios (OR), 95% confidence intervals and absolute risks were computed for pre-specified efficacy and toxicity outcomes including cosmesis. Subgroup analysis evaluated the effect of PBI modality (external beam radiation treatment EBRT, intraoperative radiation treatment IORT or brachytherapy) on efficacy. Meta-regression analysis explored the influence of median follow-up, patient and tumor characteristics on results.
Results
Nine trials comprising 14514 patients were included. While PBI was associated with increased odds of local recurrence compared to WBI (OR 1.69,
P
< 0.001), it was associated with reduced odds of death without breast cancer recurrence (OR 0.55,
P
< 0.001) and with improvement in overall survival (OS) that approached, but did not meet statistical significance (OR 0.84,
P
= 0.06). Subgroup analysis for PBI modality showed significant differences in the odds of local recurrence, based on method of PBI with EBRT showing the lowest magnitude of inferiority. Nodal involvement was associated with higher local recurrence risk, while larger tumors were associated with lesser improvement in death without breast cancer recurrence and OS. PBI was associated with higher odds of fat necrosis (OR 1.72,
P
= 0.002). Worse cosmetic outcome with PBI approached statistical significance (OR 1.23,
P
= 0.06).
Conclusions
Compared to WBI, PBI is associated with higher odds for local recurrence and toxicity, but less death without breast cancer recurrence. The balance between benefit and risk of PBI appears optimal for women with smaller hormone receptor positive tumors, without nodal involvement and treated with EBRT.
Inflammation may play an important role in cancer progression, and a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies. Here we ...quantify the prognostic impact of this biomarker and assess its consistency in solid tumors.
A systematic review of electronic databases was conducted to identify publications exploring the association of blood NLR and clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided.
One hundred studies comprising 40559 patients were included in the analysis, 57 of them published in 2012 or later. Median cutoff for NLR was 4. Overall, NLR greater than the cutoff was associated with a hazard ratio for OS of 1.81 (95% CI = 1.67 to 1.97; P < .001), an effect observed in all disease subgroups, sites, and stages. Hazard ratios for NLR greater than the cutoff for CSS, PFS, and DFS were 1.61, 1.63, and 2.27, respectively (all P < .001).
A high NLR is associated with an adverse OS in many solid tumors. The NLR is a readily available and inexpensive biomarker, and its addition to established prognostic scores for clinical decision making warrants further investigation.
Opinion statement
Bisphosphonates are utilized routinely in breast cancer. In metastatic disease with bone involvement, bisphosphonates prevent or delay skeletal-related events and can improve pain ...control. Different agents have shown benefit compared with placebo or no treatment. While in unselected patients, comparison between zoledronic acid and pamidronate did not show a significant difference, exploratory analyses showed that in patients with osteolytic lesions or hypercalcemia, zoledronic acid is superior to pamidronate. De-escalating treatment with zoledronic acid from every 4 to every 12 weeks has been shown to provide similar control of skeletal morbidity and may result in less toxicity and reduced cost. While available data support bisphosphonate treatment for 2 years in metastatic disease, typical treatment duration is influenced by performance status with treatment discontinued only once patients are not well enough to continue receiving systemic therapy or developed treatment-related adverse events. In early-stage breast cancer, individual trials of adjuvant bisphosphonates have reported inconsistent results. However, the Early Breast Cancer Trialists’ Collaborative Group showed that bisphosphonates significantly reduce distant recurrence, bone recurrence, and breast cancer mortality, an effect observed in postmenopausal women only. The relative benefit of bisphosphonates was not influenced by receptor status, tumor grade, nodal involvement, or administration of adjuvant chemotherapy. Current guidelines support consideration of adjuvant zoledronic acid or oral clodronate for 3–5 years in postmenopausal women with early-stage disease. Although bisphosphonates are tolerated well, serious adverse events, including osteonecrosis of the jaw and renal impairment, can occur, especially for higher dose density schedules utilized in metastatic disease. Decision to include bisphosphonates in the treatment plan should be based on the anticipated absolute benefit and potential for adverse effects. In some patients with both early-stage and metastatic disease, omission of bisphosphonates is reasonable as the potential benefit from this treatment is not likely to outweigh its risks.
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