Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study

Purpose

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or >1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation.

Patients and methods

A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade.

Results

A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10–0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07–0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07–0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors.

Conclusions

Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

     

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

Background

Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as “gastroesophageal adenocarcinoma”; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA.

Methods

Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy.

Results

PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G₁ cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5).

Conclusions

PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

     

Monosomy 17 in potentially curable <Emphasis Type="Italic">HER2</Emphasis>-amplified breast cancer: prognostic and predictive impact

Purpose

HER2 copy number by fluorescence in situ hybridization (FISH) is typically reported relative to the centromere enumeration probe 17 (CEP17). HER2/CEP17 ratio could be impacted by alterations in the number of chromosome 17 copies. Monosomy of chromosome 17 (m17) is found in ~ 1900 cases of early-stage HER2-positive breast cancer annually in the United States; however, the efficacy of HER2-directed trastuzumab therapy in these patients is not well characterized. Here, we retrospectively identified HER2-amplified, stage I–III breast cancers with m17 and characterized the impact of trastuzumab treatment.

Methods

From January 1, 2000 to June 1, 2011, we identified 99 women with HER2-amplified m17 breast cancers, as defined by a CEP17 signal of < 1.5 per nucleus and a HER2/CEP17 ratio of ≥ 2.0.

Results

Most HER2-amplified m17 patients were treated with trastuzumab plus chemotherapy (51%, n = 50), whereas 31% (n = 31) received chemotherapy alone and 18% (n = 18) received no chemotherapy. The 4-year overall survival (OS) was superior with trastuzumab compared to chemotherapy alone or no chemotherapy (100 vs. 93 vs. 81%, respectively; p = 0.005). OS was not influenced by estrogen/progesterone-receptor (ER/PR) status, tumor stage, or degree of FISH positivity. A proportion of patients who would be considered HER2-negative by standard immunohistochemistry staging criteria (0–1+) were HER2 amplified by FISH.

Conclusions

In the largest series reported to date, patients with HER2-amplified m17 cancers treated with trastuzumab have outcomes comparable to patients from the large phase III adjuvant trastuzumab trials who were HER2-positive, supporting the critical role of HER2-directed therapy in this patient population.

     

Malignant and borderline phyllodes tumors of the breast: a multicenter study of 362 patients (KROG 16-08)

Purpose

To identify risk factors for local recurrence (LR) and investigate roles of adjuvant local therapy for malignant and borderline phyllodes tumors of the breast.

Methods

From 1981 to 2014, 362 patients with malignant (n?=?235) and borderline (n?=?127) phyllodes tumors were treated by breast-conserving surgery (BCS) or total mastectomy (TM) at 10 centers. Thirty-one patients received adjuvant radiation therapy (RT), and those who received adjuvant chemotherapy were excluded from the study.

Results

Median follow-up was 5 years. LR developed in 60 (16.6%) patients. Regional recurrence occurred in 2 (0.6%) patients and distant metastasis (DM) developed in 19 (5.2%) patients. Patients receiving BCS (p?=?0.025) and those not undergoing adjuvant RT (p?=?0.041) showed higher LR rates. For malignant subtypes, local control (LC) rates at 5 years for BCS alone, BCS with adjuvant RT, TM alone, and TM with adjuvant RT were 80.7, 93.3, 92.4, and 100%, respectively (p?=?0.033). Multivariate analyses revealed BCS alone, tumor?size ≥?5 cm, and positive margins as independent risk factors for LR. Margin-positive BCS alone showed poorest LC regardless of tumor size (62.5%, p?=?0.007). For margin-negative BCS alone, 5-year LC rates for tumors?≥?5 cm versus those?<?5 cm were 71.8% versus 89.5% (p?=?0.012). For borderline subtypes, only positive margins (p?=?0.044) independently increased the risk of LR. DM developed exclusively in malignant subtypes and a prior LR event increased the risk of DM by sixfold (HR 6.2, 95% CI 1.6–16.1, p?=?0.001).

Conclusions

Malignant and borderline phyllodes tumors with positive margins after surgery have high LR rates. After treatment by margin-negative BCS alone, patients with large malignant phyllodes tumors?≥?5 cm also have heightened risk of LR. Thus, such patients should be considered for additional local therapy.

     

Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy

Purpose

Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer.

Patients and methods

This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis.

Results

The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08–1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥?1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p?=?0.038) and in patients with one to three lymph node metastases (HR 1.32, p?=?0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p?=?0.085 and HR 1.53, p?=?0.067). No significant interaction was observed between the treatment arm and dNLR.

Conclusion

Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer.

Trial registration

EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7–11, 2016, Copenhagen, Denmark (oral presentation).

     

Intratumoral heterogeneity on dedicated breast positron emission tomography predicts malignancy grade of breast cancer

Purpose

Dedicated breast positron emission tomography (DbPET) provides detailed high-resolution images and can detect intratumoral heterogeneity using ¹⁸F-fluorodeoxyglucose (FDG). We aimed to evaluate the correlation between FDG uptake on DbPET and the clinicopathological features of breast cancer, particularly those with an intratumoral heterogeneous distribution of FDG on DbPET.

Methods

We evaluated 195 consecutive patients with invasive breast cancer who underwent preoperative whole-body PET (WBPET) and DbPET concurrently between January 2016 and March 2017. The relationships between clinicopathological factors and the maximum standard uptake values (SUVmax) of DbPET and WBPET, including clinical stage, nuclear grade, Ki67 proliferation index, estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2) statuses, and the intratumoral heterogeneous distribution of FDG on DbPET, were evaluated.

Results

The SUVmax of DbPET was significantly correlated with clinical T stage, N stage, nuclear grade, and Ki67 proliferation index (all p?<?0.001) as well as the ER (p?=?0.006) and HER2 (p?=?0.040) statuses. Intratumoral heterogeneous distribution of FDG on DbPET was significantly related with high nuclear grade (p?=?0.016) and high Ki67 proliferation index (p?=?0.015) but not with clinical T stage, N stage, and ER and HER2 statuses.

Conclusions

The SUVmax of DbPET correlates with clinicopathological factors and also WBPET does. In addition, intratumoral heterogeneity on DbPET provides predictive value for malignancy grade and could inform therapeutic decisions.

     

Randomized controlled pilot trial of mindfulness-based stress reduction for breast and colorectal cancer survivors: effects on cancer-related cognitive impairment

Purpose

Cancer-related cognitive impairment (CRCI) is a common, fatigue-related symptom that disrupts cancer survivors’ quality of life. Few interventions for CRCI exist. As part of a randomized pilot study targeting cancer-related fatigue, the effects of mindfulness-based stress reduction (MBSR) on survivors’ cognitive outcomes were investigated.

Methods

Breast and colorectal cancer survivors (n?=?71) with moderate-to-severe fatigue were randomized to MBSR (n?=?35) or a fatigue education and support (ES; n?=?36) condition. The Attentional Function Index (AFI) and the Stroop test were used to assess survivors’ cognitive function at baseline (T1), after the 8-week intervention period (T2), and 6 months later (T3) using intent-to-treat analysis. Mediation analyses were performed to explore mechanisms of intervention effects on cognitive functioning.

Results

MBSR participants reported significantly greater improvement on the AFI total score compared to ES participants at T2 (d?=?0.83, p?=?0.001) and T3 (d?=?0.55, p?=?0.021). MBSR also significantly outperformed ES on most AFI subscales, although both groups improved over time. MBSR produced greater Stroop accuracy rates relative to ES at T2 (r?=?0.340, p?=?0.005) and T3 (r?=?0.280, p?=?0.030), with improved accuracy over time only for the MBSR group. There were no significant differences in Stroop reaction time between groups. Improvements in mindfulness mediated the effect of group (e.g., MBSR vs. ES) on AFI total score at T2 and T3.

Conclusions

Additional randomized trials with more comprehensive cognitive measures are warranted to definitively assess the efficacy of MBSR for CRCI.

Implications for Cancer Survivors

This pilot study has important implications for all cancer survivors as it is the first published trial to show that MBSR offers robust and durable improvements in CRCI.

     

New pre-treatment eosinophil-related ratios as prognostic biomarkers for survival outcomes in endometrial cancer

Background

Systemic inflammation has long been related with adverse survival outcomes in cancer patients, and its biomarkers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), are recognized as poor prognostic indicators. However, the role of eosinophils in this field has been largely overlooked. Here, we describe two new pre-treatment biomarkers, expressed as Eosinophil-to-Lymphocytes Ratio (ELR) and Eosinophil*Neutrophil-to-Lymphocytes ratio (ENLR), and we analyse their impact on prognosis of endometrial cancer (EC) patients.

Methods

A total of 163 consecutive patients diagnosed with EC and treated with postoperative radiotherapy +/? chemotherapy in our institution from January 2011 to December 2015 were evaluated. The cohort was divided in two groups applying the cut-off value of 0.1 and 0.5 according to ROC curve for pre-treatment ELR and ENLR, respectively. After patients’ stratification according to the ESMO-ESGO-ESTRO modified risk assessment, subgroup analyses were conducted.

Results

Higher values of ELR and ENLR were associated with worse OS (p?=?0.004 and p?=?0.010, respectively). On univariate analysis, the factors associated with shorter OS were ELR?≥?0.1 (HR?=?2.9, p?=?0.017), ENLR ≥ 0.5 (HR?=?3.0, p?=?0.015), advanced FIGO stage (HR?=?3.4, p?=?0.007), endometrioid histology (HR?=?0.26, p?=?0.003) and ESMO-ESGO-ESTRO high-risk (HR?=?10.2, p?=?0.023). On multivariate Cox regression, higher ELR and ENLR were independently associated with a worse outcome adjusted for the standardly applied prognostic factors.

Conclusions

Increased values of ELR and ENLR portend worse OS in EC, especially in patients classified by the ESMO-ESGO-ESTRO guidelines as a high-risk group. To our best knowledge, this is the first report describing eosinophils-related ratios as prognostic biomarkers in malignant tumours.

     

Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma

Background

The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation.

Methods

This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66?Gy (66?Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60?Gy or twice daily to a total dose of 59.2?Gy (60?Gy RT).

Results

A total of 133 patients received standard 60?Gy RT, while 23 received 66?Gy RT. Patients in the 66?Gy RT group were younger (p?<? 0.001), whereas concomitant temozolomide use was more frequent in the 60?Gy RT group (p?<? 0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66?Gy RT arm versus the 60?Gy RT arm (12.2 versus 7.6?months, p?=?0.011), and this translated to an improved OS (18.8 versus 15.3?months, p?=?0.012). A multivariate analysis revealed a strong association of 66?Gy RT with a prolonged time to ICR (hazard ratio?=?0.498, p?=?0.01) and OS (hazard ratio?=?0.451, p?=?0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p?=?0.008, OS p?=?0.007) and propensity-scored matched pairing (ICR p?=?0.099, OS p?=?0.023).

Conclusion

Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted.

     

Inflammatory Indexes as Prognostic and Predictive Factors in Ovarian Cancer Treated with Chemotherapy Alone or Together with Bevacizumab. A Multicenter,Retrospective Analysis by the MITO Group (MITO 24)

Background

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking.

Objective

The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab.

Patients and Methods

Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms.

Results

In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p?<?0.0001). In multivariate analyses, the NLR was significantly associated with OS (p?=?0.016), and the PLR was significantly associated with PFS (p?=?0.024). Inflammatory indexes were significantly correlated with patient prognosis in the chemotherapy-alone group (p?<?0.0001). Patients in the chemotherapy with bevacizumab group with a high NLR had a higher PFS and OS (p?=?0.026 and p?=?0.029, respectively) than those in the chemotherapy-alone group. Conversely, PFS and OS were significantly poorer in patients with a high SII (p?=?0.024 and p?=?0.017, respectively).

Conclusion

Our results suggest that bevacizumab improves clinical outcome in patients with a high NLR but may be detrimental in those with a high SII.

     

Tai Chi and Qigong for cancer-related symptoms and quality of life: a systematic review and meta-analysis

Purpose

This study aims to summarize and critically evaluate the effects of Tai Chi and Qigong (TCQ) mind–body exercises on symptoms and quality of life (QOL) in cancer survivors.

Methods

A systematic search in four electronic databases targeted randomized and non-randomized clinical studies evaluating TCQ for fatigue, sleep difficulty, depression, pain, and QOL in cancer patients, published through August 2016. Meta-analysis was used to estimate effect sizes (ES, Hedges’ g) and publication bias for randomized controlled trials (RCTs). Methodological bias in RCTs was assessed.

Results

Our search identified 22 studies, including 15 RCTs that evaluated 1283 participants in total, 75% women. RCTs evaluated breast (n?=?7), prostate (n?=?2), lymphoma (n?=?1), lung (n?=?1), or combined (n?=?4) cancers. RCT comparison groups included active intervention (n?=?7), usual care (n?=?5), or both (n?=?3). Duration of TCQ training ranged from 3 to 12 weeks. Methodological bias was low in 12 studies and high in 3 studies. TCQ was associated with significant improvement in fatigue (ES?=???0.53, p?<?0.001), sleep difficulty (ES?=???0.49, p?=?0.018), depression (ES?=???0.27, p?=?0.001), and overall QOL (ES?=?0.33, p?=?0.004); a statistically non-significant trend was observed for pain (ES?=???0.38, p?=?0.136). Random effects models were used for meta-analysis based on Q test and I ² criteria. Funnel plots suggest some degree of publication bias. Findings in non-randomized studies largely paralleled meta-analysis results.

Conclusions

Larger and methodologically sound trials with longer follow-up periods and appropriate comparison groups are needed before definitive conclusions can be drawn, and cancer- and symptom-specific recommendations can be made.

Implications for Cancer Survivors

TCQ shows promise in addressing cancer-related symptoms and QOL in cancer survivors.

     

Synchronous endometrial and ovarian carcinomas: predictors of risk and associations with survival and tumor expression profiles

Purpose

Synchronous endometrial and ovarian tumors (SEOs) are diagnosed in 10% of ovarian cancer patients. We examined predictors of SEOs, evaluated associations of SEOs with survival and characterized ovarian tumor profiles using immunohistochemistry.

Methods

We included patients with endometrioid (n?=?180) and clear cell (n?=?165) ovarian carcinoma identified from the Alberta Cancer Registry between 1979 and 2010 for whom we abstracted medical records and constructed tumor tissue microarrays (TMAs). A concurrent diagnosis of endometrial cancer was obtained from the medical chart. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs. Protein expression in ovarian tumors of patients with and without SEOs was evaluated using Fisher’s exact test.

Results

Comparing 52 patients with SEO tumors to 293 patients with endometrioid or clear cell ovarian carcinomas, endometriosis at the ovary (OR?=?0.45, 95% CI?=?0.23–0.87, p?=?0.02) was the strongest predictor of decreased risk in multivariable models. Premenopausal status (OR?=?2.17, 95% CI?=?0.92–5.13, p?=?0.08) and lower pre-treatment CA125 levels (OR?=?0.17, 95% CI?=?0.02–1.32, p?=?0.09) showed weaker associations. There were no significant differences in survival between patients with or without SEO tumors. More patients with SEO tumors compared to endometrioid ovarian carcinoma were deficient in MLH1, PMS2 and PTEN (p?≤?0.03).

Conclusions

Endometriosis may not be the mechanism by which SEO cancers arise. Altered tumor oncoprotein expression between women with and without SEOs indicates important biological differences although this did not translate into prognostic differences.

     

Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy

Background

Stromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined.

Objective

The predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice.

Patients and Methods

A total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed.

Results

First, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p?=?0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00–1.07, p?=?0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12–0.52, p?<?0.001) and multivariate analyses (OR 0.35, 95% CI 0.14–0.87, p?=?0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88–0.95, p?<?0.001; OS: HR 0.88, 95% CI 0.83–0.94, p?<?0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90–0.97, p?<?0.001; OS: HR 0.92, 95% CI 0.86–0.98, p?=?0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91–14.95, p?<?0.001; OS: HR 10.29, 95% CI 2.37–44.66, p?=?0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65–9.12, p?=?0.002; OS: HR 4.74, 95% CI 1.02–22.01, p?=?0.047) indicated that patients with ≥ 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs.

Conclusions

Our study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle biopsy specimens are significantly correlated with pCR and prognosis in HER2-positive breast cancers. A 20% threshold for sTILs may be a feasible diagnostic marker to predict pCR to NAC and prognosis in patients with HER2-positive breast cancers.

     

Fingernail and toenail clippings as a non-invasive measure of chronic cortisol levels in adult cancer survivors

Purpose

Cancer survivors are at greater risk of comorbidities and functional decline due to physiological and psychological stress which can be measured by salivary cortisol. If saliva is used, multiple samples must be collected to accurately quantify long-term stress; however, fingernail (FN) and toenail (TN) clippings offer an opportunity to measure retrospective cortisol levels in a non-invasive manner.

Methods

Three sets of FN and TN clippings were collected at 12-month intervals in conjunction with saliva samples from cancer survivors (n?=?109) participating in two clinical trials. FN and TN samples were stored at room temperature (RT); a subset underwent additional processing and freezing before analysis. Cortisol levels were determined via enzyme immunoassay, and correlation coefficients were generated to determine overall correspondence of the individual measures.

Results

Matched RT and frozen samples were highly correlated for TN (r?=?0.950, p?=?5.44?×?10^?37) and FN (r?=?0.784, p?=?1.05?×?10^?10). Correlations between RT FN and TN were statistically significant (r?=?0.621, p?=?3.61?×?10^??17), as were frozen FN and TN (r?=?0.310, p?=?0.0283). RT, but not frozen TN and FN correlated with salivary cortisol (r?=?0.580, p?=?1.65?×?10^??16 and r?=?0.287, p?=?0.00042 for TN and FN, respectively).

Conclusions

FN and TN cortisol levels correlate with salivary cortisol in adult cancer survivors and may offer a less invasive and convenient means for measuring chronic cortisol levels.

     

The effect of dose escalation for large squamous cell carcinomas of the anal canal

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (>?5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors?>?5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p?=?0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR?=?0.998, CI 0.805–1.239, p?=?0.9887). On multivariate analysis, high-dose RT (HR?=?0.948, CI 0.757–1.187, p?=?0.6420) was not associated with improved OS but older age (HR?=?1.535, CI 1.233–1.911, p?=?0.0001), male sex (HR?=?1.695, CI 1.382–2.080, p?<?0.0001), comorbidities (HR?=?1.389, CI 1.097–1.759, p?=?0.0064), and long RT (HR?=?1.299, CI 1.047–1.611, p?=?0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers?>?5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

     

Feasibility and preliminary efficacy of an exercise telephone counseling intervention for hematologic cancer survivors: a phase II randomized controlled trial

Background

Supervised exercise interventions produce the largest improvements in patient-reported outcomes in cancer survivors but their scalability has been questioned. Telephone counseling has been proposed as a more feasible alternative but its impact on exercise behavior and health outcomes have been modest. Basing telephone counseling exercise (TCE) interventions on the theoretical advances described in the multi-process action control framework (M-PAC) may improve these outcomes.

Purpose

To assess the feasibility and preliminary efficacy of a M-PAC-based TCE intervention for increasing aerobic exercise behavior in hematologic cancer survivors (HCS).

Methods

We recruited 51 HCS who were randomized to either a weekly TCE group (n?=?26) or a self-directed exercise (SDE) group (n?=?25). Participants completed online measures of self-reported aerobic exercise behavior, quality of life (QoL), fatigue, and program satisfaction at baseline and post-intervention (12 weeks).

Results

Adherence to the TCE intervention was 93% and retention was 100%. Participants receiving TCE increased their weekly aerobic exercise by 218 min compared to 93 min in the SDE group [mean-adjusted between-group difference (MBGD_adj)?=?139, 95%CI?=?65 to 213, p?<?.001, effect size (d)?=?2.19]. Clinically meaningful QoL improvements favored the TCE group for mental health (MBGD_adj?=?3.7, 95%CI?=???0.4 to 7.9, p?=?.08, d?=?0.42) and mental health component (MBGD_adj?=?3.6, 95%CI?=???0.8 to 8.1, p?=?.10, d?=?0.35) subscales.

Conclusions

The 12-week TCE intervention substantially increased exercise behavior and may have meaningfully improved QoL in HCS.

Implications for Cancer Survivors

Though more definitive trials are needed, remote TCE interventions based on the M-PAC may improve exercise behavior and QoL in HCS and perhaps other cancer survivor groups.

Trial registration number

Clinical Trials ID: NCT03052777

     

Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy

Purpose

Capecitabine has been studied as a radiosensitizer, and our study seeks to examine the association of concurrent capecitabine/radiation therapy (RT) on event-free- (EFS) and overall survival (OS) in women with breast cancer (BC) with residual disease after neoadjuvant chemotherapy (NAC).

Methods/patients

In a retrospective study of women with BC who received adriamycin/taxane-based NAC from 2004–2016, we identified 21 women administered concurrent capecitabine/RT. To assess differences in survival, we selected a clinical control cohort (n?=?57) based on criteria used to select patients for capecitabine/RT. We also created a matched cohort (2:1), matching on tumor subtype, pathological stage and age (<?50 or 50+ years). Differences in EFS, using STEEP criteria, and OS, using all-cause mortality, between those who received capecitabine/RT and controls were assessed.

Results

Of the 21 women who received capecitabine/RT, median age was 52 years. The majority were pathologic stage III (n?=?15) and hormone receptor-positive/HER2-negative BC (n?=?20). In those receiving capecitabine/RT, there were 9 events, compared with 14 events in clinical and 10 events in matched controls. Capecitabine/RT was associated with worse OS in clinical (HR 3.83 95% CI 1.12–13.11, p?=?0.03) and matched controls (HR 3.71 95% CI 1.04–13.18, p?=?0.04), after adjusting for clinical size, pathological stage and lymphovascular invasion. Capecitabine/RT was also associated with a trend towards worse EFS in clinical (HR 2.41 95% CI 0.86–6.74, p?=?0.09) and matched controls (HR 2.68 95% CI 0.91–7.90, p?=?0.07) after adjustment.

Conclusion

Concurrent capecitabine/RT after NAC is associated with worse survival and should be carefully considered in BC.

     

Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Background

The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

Methods

The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy.

Results

Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p?<?0.001) and extracapsular spread (p?=?0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p?=?0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p?=?0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p?=?0.048), lymphovascular invasion (p?=?0.041), extracapsular spread (p?=?0.015), and esophageal invasion (p?=?0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p?=?0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p?=?0.005) remained significant factors associated with 5-year DSS.

Conclusion

Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

     

Barriers to physical activity: a study of academic and community cancer survivors with pain

Purpose

Despite the numerous benefits of physical activity (PA) for patients with cancer, many cancer survivors report challenges to participating in PA. The objectives of this study were (1) to assess barriers to PA and (2) to examine participant characteristics associated with modifiable barriers to PA among cancer survivors with pain.

Methods

We conducted a cross-sectional survey study at one academic medical center and 11 community hospitals. Participants completed the 12-item Physical Activity Barriers After Cancer (PABAC) instrument (Cronbach’s alpha?=?0.75). Multivariable regression models examined participant characteristics associated with PABAC scores with a higher score indicating more barriers to PA.

Results

Among 662 survivors, 67% had moderate or severe pain (rating 4 or greater on a scale of 0 to 10). Seventy-five percent of survivors did not meet the American Cancer Society PA recommendations on average, and these individuals had higher mean PABAC scores (beta coefficient (β)?=?2.02, 95% confidence interval (CI) 0.96–3.09, p?<?0.001). In adjusted analyses, cancer survivors who were non-white (β?=?1.55, 0.28–2.82, p?=?0.02), treated at a community hospital (β?=?1.07, 0.09–2.05, p?=?0.03), had surgery (β?=?1.69, 0.69–2.69, p?=?0.001), or within 12 months of diagnosis (β?=?1.15, 0.20–2.10, p?=?0.02) reported greater barriers to PA.

Conclusions

The majority of cancer survivors with pain are not adequately participating in PA. Key demographic and clinical characteristics are associated with survivors’ barriers.

Implications for Cancer Survivors

Efforts to overcome specific barriers are needed to promote PA after a cancer diagnosis.

     

Magnetic resonance examination to predict pathological complete response following neoadjuvant chemotherapy: when is it appropriate for HER2-positive and triple-negative breast cancers?

Background

To clarify appropriate timing for magnetic resonance examination to predict pathological complete response to neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers in terms of tumor volume change.

Methods

Between September 2009 and December 2014, 113 women with HER2-positive (n = 51) and triple-negative (n = 62) invasive breast cancers undergoing neoadjuvant chemotherapy were enrolled. Patients with HER2-positive tumors underwent neoadjuvant chemotherapy with an anthracycline-based regimen followed by docetaxel with trastuzumab. Patients with triple-negative tumors underwent neoadjuvant chemotherapy with anthracycline-based (first in most cases) and taxane-based regimens. Magnetic resonance imaging was performed before neoadjuvant chemotherapy, between the regimens (midpoint examination), and after neoadjuvant chemotherapy (final examination). Response ratio of tumor volume was calculated and receiver-operating characteristic analyses for them for both subtypes were performed at the midpoint and final examinations.

Results

Twenty-eight women with HER2-positive tumors (54.9 %) and 29 women with triple-negative tumors (46.8 %) had pathological complete response. The response ratios were better in cases with pathological complete response than in those without (p = 0.0341, p < 0.0001). The area under the curve at the final examination was higher than that at the midpoint examination for HER2-positive tumors (p = 0.039); whereas for the triple-negative tumors, no significant difference between the two examinations was shown (p = 0.5218).

Conclusions

Magnetic resonance examination to predict pathological complete response would be feasible after completion of a regimen including trastuzumab for HER2-positive tumors and at the midpoint of neoadjuvant chemotherapy for triple-negative tumors.