Effect of multifocality and multicentricity on outcome in early stage breast cancer: a systematic review and meta-analysis.

Women with multifocal or multicentric breast tumors (multifocality henceforth) have been reported to have greater probability of nodal metastasis and relapse and worse survival than women with unifocal tumors. However, these associations have been inconsistent and multifocality is not taken into account by staging guidelines and prognostic models. A systematic review of electronic databases identified publications exploring the association between multifocality and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and loco-regional relapse (LRR). The hazard ratios (HRs) for OS and DFS for multifocal compared to unifocal tumors were extracted from multivariable analyses and included in a meta-analysis. For studies not reporting multivariable analyses, odds ratios (OR) were estimated from Kaplan-Meier curves for all endpoints at 5 and 10 years. Twenty-two studies comprising 67,557 women were included. Multifocality was reported in 9.5 % of patients. Classical prognostic factors were well balanced between unifocal and multifocal populations. In multivariable analyses, multifocality was associated with significantly worse OS (HR 1.65; P = 0.02), and a non-significant association with worse DFS (HR 1.96; P = 0.07). In univariable analyses, multifocality was associated with worse OS, DFS, DSS, and LRR at 5 years (OR 1.39, P = 0.02; OR 1.52, P = 0.02; OR 1.56, P = 0.03; and OR 3.23, P = 0.02, respectively). Similar estimates were observed at 10 years, but statistical significance was only reached for DSS and LRR. Mutifocality appears to be associated with a worse prognosis, however, substantial inter-study heterogeneity limits the precise determination of increased risk. Further validation of the independent prognostic impact of multifocality is warranted.

Benefit and harms of new anti-cancer drugs.

Phase III randomized controlled trials (RCTs) assess clinically important differences in endpoints that reflect benefit to and harm of patients. Defining benefit of cancer drugs can be difficult. Overall survival and quality of life are the most relevant primary endpoints, but difficulty in measuring these mean that other endpoints are often used, although their surrogacy or clinical relevance has not always been established. In general, advances in drug development have led to numerous new drugs to enter the market. Pivotal RCT of several new drugs have shown that benefit appeared greater for targeted anticancer agents than for chemotherapeutic agents. This effect seems particularly evident with targeted agents evaluated in biomarker-driven studies. Unfortunately, new therapies have also shown an increase in toxicity. Such toxicity is not always evident in the initial reports of RCTs. This may be a result of a statistical inability to detect differences between arms of RCTs, or occasionally due to biased reporting. There are several examples where reports of new toxicities could only be found in drug labels. In some cases, the small improvement in survival has come at a cost of substantial excess toxicity, leading some to consider such therapy as having equipoise.

Hodgkin lymphoma involving extranodal sites in head and neck: report of twenty-nine cases and review of three-hundred and fifty-seven cases.

INTRODUCTION: Hodgkin lymphoma (HL) involving the Waldeyer's ring (WR) and other extranodal head and neck sites are rare. We report our experience and PubMed literature review. METHODS: Retrospective single institution cohort study using lymphoma data base and PubMed literature search using twenty-six various search terms. RESULTS: Twenty-nine patients were treated in our institution (1975-2018). Male:Female 22:7, median age at diagnosis 33 years (15-64), stages I-II:III-IV 25:4. Sites were nasopharynx (10), tonsil (9), parotid (5), mandible (2) and others (3). 20/29 patients received radiation therapy, 22/29 received chemotherapy. Ten years overall-survival and progression-free survival are 92% and 66% respectively. PubMed search showed 8766 citations and identified 357 patients including our patients. Male:Female 199:131, median age 45 years (5-89). Stages I-II in 286 (80%). Involvement was nasopharynx 109 (30.5%), tonsil 67 (18.8%), parotid 58 (16.2%), thyroid 45 (12.6%), adenoid 10 (2.8%), mandible 10 (2.8%) and others in 58 (16.2%). Pathology: mixed cellularity 99 (27.7%), nodular sclerosis 88 (24.6%), nodular lymphocyte-predominant 56 (15.7%), lymphocyte rich 25 (7%), classical-HL-not otherwise specified 16 (4.5%) and lymphocyte depleted 7 (2%) patients. Treatment details are available for 233 patients; 165 (46%) received radiation therapy, 137 (38%) chemotherapy. Complete remission in 208 (58%), progressive disease 14 (4%), no information 135 (38%). Overall, treatment failure in 54 (15%). Thirty (8.4%) have died; 21 disease related. KM overall-survival at 5 and 10 years was 88.5% and 77.6% respectively. CONCLUSION: This largest report showed that HL involving extranodal head and neck sites is not very uncommon and has excellent prognosis.

Extended adjuvant tamoxifen for early breast cancer: a meta-analysis.

BACKGROUND: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. METHODS: We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried. RESULTS: Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76-1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84-1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65-2.58, p<0.001, number needed to harm:89). CONCLUSION: In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.

Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis.

BACKGROUND: The androgen receptor (AR) is expressed frequently in breast cancer, but its prognostic significance is unclear. Preclinical data suggest that expression of AR may modify clinical outcomes in early breast cancer with improved prognosis in estrogen receptor (ER)-positive disease and poorer prognosis in ER-negative disease. METHODS: A systematic review of electronic databases was conducted to identify studies published between 1946 and July 2012 and to explore the association between AR expression and overall survival (OS) and disease-free survival (DFS) in women diagnosed with early breast cancer. The odds ratios (OR) for OS and DFS at 3 and 5 years were calculated and then weighted and pooled in a meta-analysis with Mantel-Haenszel random-effect modeling. All statistical tests were two-sided. RESULTS: Nineteen studies with a total of 7693 women were included. AR expression was documented in 60.5% of patients. ER-positive tumors were more likely to express AR- than ER-negative tumors (74.8% vs 31.8%, χ(2) P < .001). Compared with tumors without AR expression, those expressing AR were associated with improved OS at both 3 and 5 years (OR = 0.47, 95% confidence interval [CI] = 0.39 to 0.58, P < .001; and OR = 0.40, 95% CI = 0.29 to 0.56, P < .001). The absolute differences in the probability of OS at 3 and 5 years were 6.7% (95% CI = 3.5% to 9.8%) and 13.5% (95% CI = 7.5% to 19.6%), respectively. Results for 3- and 5-year DFS were similar. Coexpression of the ER did not influence OS at 3 or at 5 years. CONCLUSIONS: Expression of AR in women with breast cancer is associated with better OS and DFS irrespective of coexpression of ER.

Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis.

BACKGROUND: Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear. METHODS: PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model. RESULTS: Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13). CONCLUSION: Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.

Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis.

BACKGROUND: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker. METHODS: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling. RESULTS: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups (<150/150-300/>300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49-2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97-1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6-2.7; HR[group 2] = 1.6; 95% CI, 1.1-2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0-2.2; HR[group 2] = 1.0; 95% CI, 0.8-1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2. CONCLUSION: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted. IMPACT: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors.

Fulvestrant for advanced breast cancer: a meta-analysis.

BACKGROUND: Fulvestrant is an endocrine agent which degrades the estrogen receptor, thereby downregulating its signaling. Trials of fulvestrant are limited by inconsistent study populations and drug dosing. The optimal use of fulvestrant in advanced breast cancer is therefore unclear. METHODS: A systematic review of electronic databases was conducted to identify randomized trials of fulvestrant versus other endocrine therapy. The hazard ratios (HR) for time to progression (TTP) and the odds ratios (OR) for serious adverse events (SAEs), discontinuation of treatment due to toxicity and commonly reported toxicities (hot flashes, venous thrombosis, gastrointestinal disturbance, arthralgia, and asthenia) were pooled in a meta-analysis. Meta-regression explored heterogeneity in study population and fulvestrant dosing. RESULTS: Eight studies were included in the analysis. Overall, there was no difference in TTP between fulvestrant and control groups (HR: 0.94, p=0.18). On meta-regression, fulvestrant showed reduced hazards for TTP compared to aromatase inhibitors (AI) if used in first line, in studies where fewer patients received adjuvant endocrine therapy and at higher doses. Rates of SAEs and treatment discontinuation were similar for fulvestrant and control groups, but fulvestrant monotherapy was associated with significantly less arthralgia (OR: 0.73, p=0.02). The addition of fulvestrant to AI was not associated with improved TTP, but led to increased toxicity. CONCLUSION: In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia compared with other endocrine therapy options. Use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with AI.