Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. METHODS: Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. RESULTS: A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. CONCLUSIONS: A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

Outcomes of young patients diagnosed with locally advanced rectal cancer.

BACKGROUND: The incidence of rectal cancer is higher in the older population. In developed nations, there has been a rise in incidence in young onset colorectal cancer (CRC). We examined the outcomes of locally advanced rectal cancer (LARC) in younger patients (yRC) compared with older patients, using a retrospective audit. METHODS: All cases of LARC referred to two tertiary referral cancer centres in Western Sydney were examined. Patient demographics, presenting symptoms, treatment, relapse free survival (RFS), overall survival (OS) and progression free survival (PFS) were obtained. Under 50 years old was used as the cut-off age for defining yRC. RESULTS: All 145 consecutive patients were treated for LARC, including 28 in the yRC and 117 in the older patient group. Median follow-up was 54 months. yRC were more likely to complete neoadjuvant therapy (100% vs. 86%; P=0.032) and to undergo more extensive surgical procedures (24% vs. 2%, P<0.0001). yRC were more likely to have microsatellite high (MSI) tumours (30% vs. 4.7%; P=0.003). yRC demonstrated significantly poorer RFS compared with the standard group (HR 2.79; median RFS 4.67 vs. 16.02 months; P=0.023). In the relapsed setting, yRC had poorer PFS compared with the standard group (median PFS 2.66 vs. 9.70, P=0.006, HR 3.04). A difference in OS was also seen between the two groups, with yRC demonstrating poorer OS (median OS 40.46 vs. 58.26 months, HR 3.48, P=0.036). CONCLUSIONS: Patients under 50 years with LARC are more likely to have MSI tumours with a more aggressive disease course and poorer RFS, PFS and OS. Initiatives to improve early detection of these patients may improve outcomes. Further research is necessary to understand this disease and optimise its treatment.

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.

PURPOSE: APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease-free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)-negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up. METHODS: After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab. RESULTS: This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance (P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen. CONCLUSION: This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

Simplified phenotyping of CYP2D6 for tamoxifen treatment using the N-desmethyl-tamoxifen/ endoxifen ratio.

INTRODUCTION: CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. MATERIALS AND METHODS: A target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into 'Normal' (NM) and 'Slow' (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA. RESULTS: A target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. CONCLUSIONS: The simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered.

Platinum-containing regimens for triple-negative metastatic breast cancer.

BACKGROUND: In a previous Cochrane Review, we found that for women with metastatic breast cancer unselected for triple-negative disease, there is little or no survival benefit and excess toxicity from platinum-based regimens. In subgroup analyses, however, we found preliminary low-quality evidence of a survival benefit from platinum-based regimens for women with metastatic triple-negative breast cancer (mTNBC). This review updates the evidence from the mTNBC subgroup analyses in the previous Cochrane Review. OBJECTIVES: To assess the effects of platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with mTNBC. SEARCH METHODS: We obtained relevant studies published prior to 2015 and their extracted results from the mTNBC subgroup analysis in the previous Cochrane Review. We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov between 2015 and 27 September 2019. We identified further potentially relevant studies from previous trial reports, systematic reviews, and meta-analyses. SELECTION CRITERIA: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with mTNBC. Individual trials could compare one or more platinum-based regimens to one or more non-platinum regimens; hence there could be more 'treatment-comparisons' (i.e. platinum regimen versus non-platinum regimen comparison) than trials. Trial participants may have been purposely selected for mTNBC or inadvertently selected as a subgroup. DATA COLLECTION AND ANALYSIS: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. We derived hazard ratios (HRs) for time-to-event outcomes, where possible, and used fixed-effect models for meta-analyses. We analysed objective tumour response rates (OTRRs) and toxicities as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. We extracted quality of life data, if available. We used GRADE to rate the quality of evidence for time-to-event and tumour response outcomes. MAIN RESULTS: This review includes 13 treatment-comparisons involving 1349 women from 10 studies. Twelve of the 13 treatment-comparisons were included in one or more meta-analyses. Of the 13 treatment-comparisons, six and eight had published or provided time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively, that could be included in meta-analyses. Ten treatment-comparisons published or provided OTRR data that could be included in meta-analyses. Eight of the 13 treatment-comparisons were from studies that selected participants on the basis of mTNBC status, while the other five treatment-comparisons were from studies that reported mTNBC results as part of subgroup analyses. Analysis of six treatment-comparisons indicated that platinum-containing regimens may have provided a small survival benefit to mTNBC patients (HR 0.85, 95% CI 0.73 to 1.00; 958 women; moderate-quality evidence) with no evidence of heterogeneity (P = 0.41; I2 = 1%). Data from eight treatment-comparisons showed that platinum regimens may improve PFS/TTP (HR 0.77, 95% CI 0.68 to 0.88; 1077 women; very low-quality evidence). There was marked evidence of heterogeneity (P < 0.0001; I2 = 80%). There was also low-quality evidence of better tumour response for platinum recipients (RR 1.40, 95% CI 1.22 to 1.59; 1205 women) with some evidence of heterogeneity (P = 0.01; I2 = 58%). The observed heterogeneity for the PFS/TTP and OTRR outcomes may reflect between-study differences and general difficulties in assessing tumour response, as well as the varying potencies of the comparators. Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were higher for platinum recipients (RR 4.77, 95% CI 1.93 to 11.81; 655 women; low-quality evidence) and rates of grade 3 and 4 anaemia were higher for platinum recipients (RR 3.80, 95% CI 2.25 to 6.42; 843 women; low-quality evidence). In general, however, relatively few intervention-comparisons could be included in meta-analyses for adverse events. None of the studies reported quality of life. AUTHORS' CONCLUSIONS: For women with mTNBC, there was moderate-quality evidence of a small survival benefit from platinum-based regimens compared to non-platinum regimens. This finding is consistent with findings of a PFS/TTP benefit and improved tumour response from platinum-based regimens. These potential benefits, however, should be weighed against previously identified excess toxicities from platinum-based regimens, particularly regimens containing cisplatin. Further randomised trials of platinum-based regimens among women with mTNBC are required.

Survival and cardiac toxicity in patients with HER2-positive, metastatic breast cancer treated with trastuzumab in routine clinical practice.

AIMS: We sought to describe survival outcomes and toxicities of trastuzumab in real-world patients with HER2-positive, metastatic breast cancer (MBC) and compare these to a recent systematic review of clinical trials. METHODS: We searched the medical records of three Sydney cancer centers for patients with HER2-positive, MBC starting trastuzumab from January 2001 to March 2017. We recorded patient, tumor, and treatment characteristics; survival times from start of palliative trastuzumab; and rates of cardiac toxicity. Survival distribution was summarized using the following percentiles (represented scenario): 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). Survival times were compared to recent review of HER2-positive MBC randomized trials. Factors associated with survival were assessed with Cox models. RESULTS: Characteristics of the 126 patients were: median age 53 years, ER positive cancer (50%), de-novo metastatic disease (23%), prior adjuvant trastuzumab (15%), liver metastases (37%), and brain metastases (23%). The median duration of first-line trastuzumab was 11 months (interquartile range, (IQR) 5-27). Survival times in months (vs the systematic review) were: 90th percentile 8 (9); 75th percentile 16 (19); and median 34 (33). Follow-up duration was insufficient to estimate the 25th and 10th percentiles, similar to the systematic review. Liver metastases were associated with shorter survival (HR = 1.74, 95% CI, 1.1-2.76, P = .02). Seventy percent of patients had a baseline cardiac assessment. Five patients (3.9%) developed symptomatic cardiac toxicity, similar to clinical trials. CONCLUSION: Survival and cardiac toxicity rates for women starting trastuzumab in routine practice were comparable to clinical trials. Oncologists can use clinical trial data as a reference point when explaining survival outcomes to women with HER2-positive MBC.

Taxanes for adjuvant treatment of early breast cancer.

BACKGROUND: Adjuvant chemotherapy improves survival in premenopausal and postmenopausal women with early breast cancer. Taxanes are highly active chemotherapy agents used in metastatic breast cancer. Review authors examined their role in early breast cancer. This review is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effects of taxane-containing adjuvant chemotherapy regimens for treatment of women with operable early breast cancer. SEARCH METHODS: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, CENTRAL (2018, Issue 6), the WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 16 July 2018, using key words such as 'early breast cancer' and 'taxanes'. We screened reference lists of other related literature reviews and articles, contacted trial authors, and applied no language restrictions. SELECTION CRITERIA: Randomised trials comparing taxane-containing regimens versus non-taxane-containing regimens in women with operable breast cancer were included. Studies of women receiving neoadjuvant chemotherapy were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and quality of the evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity was represented as odds ratios (ORs), and quality of life (QoL) data were extracted when present. MAIN RESULTS: This review included 29 studies (27 full-text publications and 2 abstracts or online theses). The updated analysis included 41,911 randomised women; the original review included 21,191 women. Taxane-containing regimens improved OS (HR 0.87, 95% confidence interval (CI) 0.83 to 0.92; high-certainty evidence; 27 studies; 39,180 women; 6501 deaths) and DFS (HR, 0.88, 95% CI 0.85 to 0.92; high-certainty evidence; 29 studies; 41,909 women; 10,271 reported events) compared to chemotherapy without a taxane. There was moderate to substantial heterogeneity across studies for OS and DFS (respectively).When a taxane-containing regimen was compared with the same regimen without a taxane, the beneficial effects of taxanes persisted for OS (HR 0.84, 95% CI 0.77 to 0.92; P < 0.001; 7 studies; 10,842 women) and for DFS (HR 0.84, 95% CI 0.78 to 0.90; P < 0.001; 7 studies; 10,842 women). When a taxane-containing regimen was compared with the same regimen with another drug or drugs that were substituted for the taxane, a beneficial effect was observed for OS and DFS with the taxane-containing regimen (OS: HR 0.80, 95% CI 0.74 to 0.86; P < 0.001; 13 studies; 16,196 women; DFS: HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 14 studies; 16,823 women). Preliminary subgroup analysis by lymph node status showed a survival benefit with taxane-containing regimens in studies of women with lymph node-positive disease only (HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 17 studies; 22,055 women) but less benefit in studies of women both with and without lymph node metastases or with no lymph node metastases. Taxane-containing regimens also improved DFS in women with lymph node-positive disease (HR 0.84, 95% CI 0.80 to 0.88; P < 0.001; 17 studies; 22,055 women), although the benefit was marginal in studies of women both with and without lymph node-positive disease (HR 0.95, 95% CI 0.88 to 1.02; 9 studies; 12,998 women) and was not apparent in studies of women with lymph node-negative disease (HR 0.99, 95% CI 0.86 to 1.14; 3 studies; 6856 women).Taxanes probably result in a small increase in risk of febrile neutropenia (odds ratio (OR) 1.55, 95% CI 0.96 to 2.49; moderate-certainty evidence; 24 studies; 33,763 women) and likely lead to a large increase in grade 3/4 neuropathy (OR 6.89, 95% CI 3.23 to 14.71; P < 0.001; moderate-certainty evidence; 22 studies; 31,033 women). Taxanes probably cause little or no difference in cardiotoxicity compared to regimens without a taxane (OR 0.87, 95% CI 0.56 to 1.33; moderate-certainty evidence; 23 studies; 32,894 women). Seven studies reported low-quality evidence for QoL; overall, taxanes may make little or no difference in QoL compared to chemotherapy without a taxane during the follow-up period; however, the duration of follow-up differed across studies. Only one study, which was conducted in Europe, provided cost-effectiveness data. AUTHORS' CONCLUSIONS: This review of studies supports the use of taxane-containing adjuvant chemotherapy regimens, with improvement in overall survival and disease-free survival for women with operable early breast cancer. This benefit persisted when analyses strictly compared a taxane-containing regimen versus the same regimen without a taxane or the same regimen with another drug that was substituted for the taxane. Preliminary evidence suggests that taxanes are more effective for women with lymph node-positive disease than for those with lymph node-negative disease. Considerable heterogeneity across studies probably reflects the varying efficacy of the chemotherapy backbones of the comparator regimens used in these studies. This review update reports results that are remarkably consistent with those of the original review, and it is highly unlikely that this review will be updated, as new trials are assessing treatments based on more detailed breast cancer biology.

Physical Activity for Symptom Management in Women With Metastatic Breast Cancer: A Randomized Feasibility Trial on Physical Activity and Breast Metastases.

CONTEXT: Physical activity for women with early-stage breast cancer is well recognized for managing cancer-related symptoms and improving quality of life. While typically excluded from interventions, women with metastatic breast cancer may also benefit from physical activity. OBJECTIVE: To 1) determine the safety and feasibility of a physical activity program for women with metastatic breast cancer and 2) explore the efficacy of the program. METHODS: Fourteen women with metastatic breast cancer were randomized to either a control group or an 8-week home-based physical activity intervention comprising twice weekly supervised resistance training and an unsupervized walking program. RESULTS: The recruitment rate was 93%. Adherence to the resistance and walking components of the program was 100% and 25%, respectively. No adverse events were reported. When mean change scores from baseline to postintervention were compared, trends in favor of the exercise group over the control group were observed for the Functional Assessment of Chronic Illness Therapy-Fatigue score (+5.6 ± 3.2 vs. -1.8 ± 3.9, respectively), VO2max (+1.6 ml/kg/minute ±1.8 mL/kg/minute vs. -0.2 mL/kg/minute ±0.1 mL/kg/minute, respectively) and six-minute walk test (+40 m ± 23 m vs. -46 m ± 56 m, respectively). CONCLUSION: A partially supervised home-based physical activity program for women with metastatic breast cancer is feasible and safe. The dose of the resistance training component was well tolerated and achievable in this population. In contrast, adherence and compliance to the walking program were poor. Preliminary data suggest a physical activity program, comprising predominantly resistance training, may lead to improvements in physical capacity and may help women to live well with their disease.

Tamoxifen-induced severe hot flashes and endoxifen levels: is dose reduction a safe and effective strategy?

OBJECTIVES: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. MATERIALS AND METHODS: Twenty patients with severe HFs on 20 mg TAM had CYP2D6genotype, trough level tamoxifen and metabolites measured with Loprinzi HF scores (HFS) derived before and after DR of tamoxifen to 10 mg. Other data collected included demographics, smoking, alcohol, menstrual and breast cancer history, previous chemotherapies, concurrent medications, BMI and other tamoxifen toxicities. RESULTS: At the 20 mg tamoxifen dose, endoxifen levels were 25.6, 0-91.9 nM (median, range) with HFS 131, 22-1482 (median, range). Upon DR to 10 mg, median endoxifen level fell to 14.1, 0.6-71.9 nM (difference in means p = 0.11, two-tailed T test) with HFS 47, 5-864 (difference in means p = 0.24, two-tailed T test). Despite lacking statistical significance, 85% of patients reported subjective improvement of HFs with DR. After DR, the proportion of patients with endoxifen level <15 nM increased from 20% to 50%. HFS did not correlate with any other parameter. CONCLUSION: DR of tamoxifen from 20 mg to 10 mg daily resulted in halving of endoxifen levels and subjective improvement of HF. While half the dose-reduced patients were below a potential therapeutic level of endoxifen, other recent studies suggest that low endoxifen levels may not indicate reduced effectiveness of tamoxifen.

Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer.

BACKGROUND: Anthracyclines and taxanes are chemotherapeutic agents widely used in a sequential regimen in the adjuvant and neoadjuvant treatment of early breast cancer to reduce the risk of cancer recurrence. Standard practice is to administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines tend to be administered first as they were established before taxanes for treatment of early breast cancer. OBJECTIVES: To assess whether the sequence in which anthracyclines and taxanes are administered affects outcomes for people with early breast cancer receiving adjuvant or neoadjuvant therapy. SEARCH METHODS: We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018. SELECTION CRITERIA: Randomised controlled trials comparing administering a taxane prior to an anthracycline with taxane following anthracycline to people with early breast cancer receiving chemotherapy. The studies needed to have reported on at least one of our outcomes of interest, which included overall survival, disease-free survival, pathological response, treatment adherence, toxicity and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed risk of bias and quality of the evidence. The primary outcome measure was overall survival. Secondary outcomes included disease-free survival, pathological response (in the neoadjuvant setting only), adverse events, treatment adherence and quality of life. For time-to-event outcomes of overall survival and disease-free survival, we derived hazard ratios (HRs) with 95% confidence intervals (CI) where possible. For dichotomous outcomes of pathological complete response, treatment adherence and adverse events, we reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We used GRADE to assess the certainty of the evidence separately for the neoadjuvant and adjuvant settings. MAIN RESULTS: There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data.The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life.Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data. AUTHORS' CONCLUSIONS: In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

Platinum-containing regimens for metastatic breast cancer.

BACKGROUND: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were conducted prior to the 'intrinsic subtype' era, and did not specifically focus on metastatic triple-negative breast cancers (mTNBCs). OBJECTIVES: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer. SEARCH METHODS: For this review update, we searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov on 28 May 2015. We identified further potentially relevant studies from handsearching references of previous trials, systematic reviews, and meta-analyses. Prior to this review update, the most recent search for studies was conducted in May 2003 for the original 2004 review. SELECTION CRITERIA: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. Hazard ratios (HRs) were derived for time-to-event outcomes, where possible, and fixed-effect models were used for meta-analyses. Objective tumour response rates (OTRRs) and toxicities were analysed as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. Quality of life data were extracted where available. GRADE was used to rate the quality of evidence for survival and tumour response outcomes at the level of subgroups selected and unselected for mTNBC, and for toxicity outcomes based on combining data from selected and unselected populations. MAIN RESULTS: This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status.In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I2 =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05).Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I2 = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001).There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I2 = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators.Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate-quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent). AUTHORS' CONCLUSIONS: In women with metastatic breast cancer who do not have triple-negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low-quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required.

Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy.

The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis.

Fulvestrant for hormone-sensitive metastatic breast cancer.

BACKGROUND: Fulvestrant is a selective oestrogen receptor down-regulator (SERD), which by blocking proliferation of breast cancer cells, is an effective endocrine treatment for women with hormone-sensitive advanced breast cancer. The goal of such systemic therapy in this setting is to reduce symptoms, improve quality of life, and increase survival time. OBJECTIVES: To assess the efficacy and safety of fulvestrant for hormone-sensitive locally advanced or metastatic breast cancer in postmenopausal women, as compared to other standard endocrine agents. SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 7 July 2015. We also searched major conference proceedings (American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium) and practice guidelines from major oncology groups (ASCO, European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network, and Cancer Care Ontario). We handsearched reference lists from relevant studies. SELECTION CRITERIA: We included for analyses randomised controlled trials that enrolled postmenopausal women with hormone-sensitive advanced breast cancer (TNM classifications: stages IIIA, IIIB, and IIIC) or metastatic breast cancer (TNM classification: stage IV) with an intervention group treated with fulvestrant with or without other standard anticancer therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from trials identified in the searches, conducted 'Risk of bias' assessments of the included studies, and assessed the overall quality of the evidence using the GRADE approach. Outcome data extracted from these trials for our analyses and review included progression-free survival (PFS) or time to progression (TTP) or time to treatment failure, overall survival, clinical benefit rate, toxicity, and quality of life. We used the fixed-effect model for meta-analysis where possible. MAIN RESULTS: We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I2= 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting.Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented. AUTHORS' CONCLUSIONS: For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.

PURPOSE: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. EXPERIMENTAL DESIGN: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. RESULTS: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). CONCLUSIONS: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121.