Histomorphometric and microarchitectural analysis of bone in metastatic breast cancer patients.

BACKGROUND: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm "Bordier" core needle. We examined the feasibility of using a 2 mm "Jamshidi™" core needle as a more practical and less invasive technique. METHODS: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry. RESULTS: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (<3 lesions) and 7 had extensive bone metastases (ESM) (>3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size. DISCUSSION: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses.

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Economic evaluation of adjuvant trastuzumab emtansine in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in Canada.

Background: In the katherine trial, adjuvant trastuzumab emtansine [T-DM1, Kadcyla (Genentech, South San Francisco, CA, U.S.A.)], compared with trastuzumab, significantly reduced the risk of recurrence or death by 50% (unstratified hazard ratio: 0.50; 95% confidence interval: 0.39 to 0.64; p < 0.0001) in patients with her2-positive early breast cancer (ebc) and residual invasive disease after neoadjuvant systemic treatment. A cost-utility evaluation, with probabilistic analyses, was conducted to examine the incremental cost per quality-adjusted life-year (qaly) gained associated with T-DM1 relative to trastuzumab, given the higher per-cycle cost of T-DM1. Methods: A Markov model comprising a number of health states was used to examine clinical and economic outcomes over a lifetime horizon from the Canadian public payer perspective. Patients entered the model in the invasive disease-free survival (idfs) state, where they received either T-DM1 or trastuzumab. Transition probabilities between the health states were derived from the katherine trial, Canadian life tables, and published literature from other relevant clinical trials (emilia, cleopatra, and M77001). Resource use, costs, and utilities were derived from katherine, other clinical trials, published literature, provincial fee schedules, and clinical expert opinion. Sensitivity analyses were conducted for key assumptions and model parameters. Results: Compared with trastuzumab, adjuvant T-DM1 was associated with a cost savings of $8,300 per patient and a 2.16 incremental qaly gain; thus T-DM1 dominated trastuzumab. Scenario analyses yielded similar results, with T-DM1 dominating trastuzumab or producing highly favourable incremental cost-utility ratios of less than $10,000 per qaly. Conclusions: Adjuvant T-DM1 monotherapy is a cost-effective strategy compared with trastuzumab alone in the treatment of patients with her2-positive ebc and residual invasive disease after neoadjuvant systemic treatment.

Incretin-based drugs and risk of lung cancer among individuals with type 2 diabetes.

AIM: To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. METHODS: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. RESULTS: A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. CONCLUSIONS: In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

A survey of health care professionals and oncology patients at the McGill University Health Centre reveals enthusiasm for establishing a postmortem rapid tissue donation program.

Background: In the early developmental phase of a postmortem rapid tissue donation (rtd) program for patients with metastatic cancer, we surveyed health care professionals (hcps) and oncology patients at the McGill University Health Centre (muhc) to assess their knowledge and attitudes pertaining to rtd from metastatic cancer patients for research purposes. Methods: A 23-item survey was developed and distributed to hcps at tumour board meetings, and a related 26-item survey was developed and distributed to oncology patients at the muhc Cedars Cancer Centre. Results: The survey attracted participation from 73 hcps, including 37 attending physicians, and 102 oncology patients. Despite the fact that 88% of hcps rated their knowledge of rtd as none or limited, 42% indicated that they would feel comfortable discussing rtd with their cancer patients. Of the responding hcps, 67% indicated that their current knowledge of rtd would affect their decision to discuss such a program with patients, which implies the importance of education for hcps to facilitate enrolment of patients into a rtd program. Of responding patients, 78% indicated that they would not be uncomfortable if their doctor discussed rtd with them, and 61% indicated that they would like it if their doctor were to discuss rtd with them. The hcps and patients felt that the best time for patients to be approached about consenting to a rtd program would be at the transition to palliative care when no treatment options remain. Conclusions: At the muhc, hcps and patients are generally enthusiastic about adopting a rtd program for patients with metastatic cancer. Education of hcps and patients will be an important determinant of the program's success.

Aromatase inhibitors and the risk of colorectal cancer in postmenopausal women with breast cancer.

Background: A large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer. Patients and methods: Using the UK Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations. Results: A total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100 000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53-1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity = 0.54), and time since initiation (P-heterogeneity = 0.66). Conclusions: In this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.

Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. Patients and methods: We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. Results: A total of 19 RCTs were included in the meta-analysis (n = 62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07-1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85-1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45-0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77-1.07). Conclusions: The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Can the referring surgeon enhance accrual of breast cancer patients to medical and radiation oncology trials? The ENHANCE study.

INTRODUCTION: The accrual rate to clinical trials in oncology remains low. In this exploratory pilot study, we prospectively assessed the role that engaging a referring surgeon plays in enhancing nonsurgical oncologic clinical trial accrual. METHODS: Newly diagnosed breast cancer patients were seen by a surgeon who actively introduced specific patient-and physician-centred strategies to increase clinical trial accrual. Patient-centred strategies included providing patients, before their oncology appointment, with information about specific clinical trials for which they might be eligible, as evaluated by the surgeon. The attitudes of the patients about clinical trials and the interventions used to improve accrual were assessed at the end of the study. The primary outcome was the clinical trial accrual rate during the study period. RESULTS: Overall clinical trial enrolment during the study period among the 34 participating patients was 15% (5 of 34), which is greater than the institution's historical average of 7%. All patients found the information delivered by the surgeon before the oncology appointment to be very helpful. Almost three quarters of the patients (73%) were informed about clinical trials by their oncologist. The top reasons for nonparticipation reported by the patients who did not participate in clinical trials included lack of interest (35%), failure of the oncologist to mention clinical trials (33%), and inconvenience (19%). CONCLUSIONS: Accrual of patients to clinical trials is a complex multistep process with multiple potential barriers. The findings of this exploratory pilot study demonstrate a potential role for the referring surgeon in enhancing nonsurgical clinical trial accrual.

A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer.

Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec.

BACKGROUND: Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. METHODS: Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. RESULTS: The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. CONCLUSIONS: Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.

Concurrent chemoradiotherapy for locally advanced breast cancer-time for a new paradigm?

BACKGROUND: In cases of locally advanced breast cancer (labc), preoperative ("neoadjuvant") therapy was traditionally reserved to render the patient operable. More recently, neoadjuvant therapy, particularly chemotherapy, is being used in patients with operable disease to increase the opportunity for breast conservation. Despite the increasing use of preoperative chemotherapy, rates of pathologic complete response, a surrogate marker for disease-free survival, remain modest in patients with locally advanced disease and particularly so when the tumour is estrogen or progesterone receptor-positive and her2-negative. A new paradigm for labc patients is needed. In other solid tumours (for example, rectal, esophageal, and lung cancers), concurrent chemoradiotherapy (ccrt) is routinely used in neoadjuvant and adjuvant treatment protocols alike. RESULTS: The literature suggests that ccrt in labc patients with inoperable disease is associated with response rates higher than would be anticipated with systemic therapy alone. CONCLUSIONS: Ongoing trials in this field are eagerly awaited to determine if ccrt should become the new paradigm.

Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again?

In recent years, considerable attention has been paid to the role of neoadjuvant chemotherapy as a pluripotential test bed for the treatment of breast cancer. Although traditionally reserved to render inoperable disease operable, neoadjuvant chemotherapy is increasingly being used to improve the chance for breast-conserving surgery, to gain information on pathologic response rates for a more rapid assessment of new chemotherapy-biologic regimens, and also to study in vivo tumour sensitivity or resistance to the agent being used. Similarly, use of neoadjuvant endocrine treatment was also traditionally restricted to elderly or frail patients who were felt to be unsuitable for chemotherapy. It is therefore not surprising that, given the increasing realization of the pivotal role of endocrine therapy in patient care, there is enhanced interest in neoadjuvant endocrine therapy not only as a less-toxic alternative to chemotherapy, but also to assess tumour sensitivity or resistance to endocrine agents. The availability of newer endocrine manipulations and increasing evidence that the benefits of chemotherapy are frequently marginal in many hormone-positive patients is making endocrine therapy increasingly important in the clinical setting. The hope is that, one day, instead of preoperative endocrine therapy being restricted to the infirm and the elderly, it will be used in the time between biopsy diagnosis and surgery to predict which patients will or will not benefit from chemotherapy in the adjuvant setting.

Preference weights for chemotherapy side effects from the perspective of women with breast cancer.

Perceptions among women with breast cancer about the relative importance of different potential chemotherapy side effects is not well understood. A survey was performed by women receiving chemotherapy for breast cancer. Grade I/II (mild to moderate) and III/IV (moderate to severe) descriptions of nine common chemotherapy side effects were assigned preference weights using the standard gamble technique. For each hypothetical side effect, patients could choose to stay in the respective side effect state or take a gamble between full health (probability p) or being dead (1 - p). For each side effect, p was varied until the patient was indifferent between these options. The survey also included questions about the importance of survival, slowing cancer growth, and quality of life. This analysis included 69 patients; mean age 54 years (range 35-84), representing all cancer stages. Standard gamble preferences were lowest (i.e., least preferred) for grade III/IV nausea/vomiting (0.621), indicating that patients would, on average, risk a 38 % chance of being dead to avoid having grade III/IV nausea/vomiting for the rest of their lives. The next least preferred side effects were grade III/IV diarrhea (0.677) and grade III/IV sensory neuropathy (0.694). Survival appeared more important than slowing cancer growth and maintaining quality of life across cancer stages. Nevertheless, patients with advanced disease placed less importance on survival (p = 0.09) and higher importance on quality of life (p = 0.05). These standard gamble utilities provide unique insights into chemotherapy toxicities from the patient perspective. Differences in the relative importance of overall survival and quality of life with treatment existed between patients with different stages of disease. These studies should be expanded as the data may also be used to calculate quality-adjusted life expectancy in cost-effectiveness evaluations of breast cancer chemotherapies.

Bevacizumab-based therapy for colorectal cancer: experience from a large Canadian cohort at the Jewish General Hospital between 2004 and 2009.

BACKGROUND: Before its regulatory approval in Canada, bevacizumab to treat patients with colorectal cancer (crc) was accessed through the Bevacizumab Expanded Access Trial and a special-access program at the Jewish General Hospital. We retrospectively evaluated patient outcomes in that large cohort. METHODS: All patients (n = 196) had metastatic crc, were bevacizumab-naïve, and received bevacizumab in combination with chemotherapy at the Jewish General Hospital between 2004 and 2009. We collected patient demographics and clinical characteristics; relevant medical history, disease stage and tumour pathology at diagnosis; type, duration, and line of therapy; grades 3 and 4 adverse events (aes), time to disease progression (ttp), and overall survival (os) from diagnosis. RESULTS: Median follow-up was 36.0 months. Median ttp was 8.0 months [95% confidence interval (ci): 7.0 to 9.0 months). Median os was 41.0 months (95% ci: 36.0 to 47.0 months). Of the 40 grades 3 and 4 bevacizumab-related aes experienced by 38 patients (19.4%), the most common were thrombocytopenia (n = 17), deep-vein thrombosis (n = 6), pulmonary embolism (n = 4), and hypertension (n = 3). CONCLUSIONS: In an expanded access setting, our data reflect the efficacy and safety of bevacizumab-based therapy in the controlled post-registration clinical trial setting.

Do alternative methods of measuring tumor size, including consideration of multicentric/multifocal disease, enhance prognostic information beyond TNM staging in women with early stage breast cancer: an analysis of the NCIC CTG MA.5 and MA.12 clinical trials.

The AJCC staging criteria consider tumor size to be the largest dimension of largest tumor. Some case series suggest using summation of all tumor dimensions in patients with multicentric/multifocal (MC/MF) disease. We used data from NCIC CTG MA.5 and MA.12 clinical trials to examine alternative methods of assessing tumor size on breast-cancer-free-interval (BCFI). The 710 MA.5 pre-/peri-menopausal node positive and 672 MA.12 pre-menopausal node-negative/-positive patients have 10-year median follow-up. All patients received adjuvant chemotherapy. Tumors were centrally reviewed for grade, hormone receptor, and HER2 status. Continuous pathologic tumor size was: (1) largest dimension of largest tumor (cm); (2) tumor area (cm(2)); (3) volume of tumor (cm(3)); (4) with MC/MF disease, summation of (1)-(3) for up to 3 foci. We examined univariate and multivariate effects of tumor size on BCFI utilizing (un)stratified Cox regression and the Wald test statistic. In univariate analysis, larger tumor dimension was significantly associated with worse BFCI in node positive patients: p < 0.0001 for MA.5; p = 0.01 for MA.12. In MA.5 multivariate analysis, larger summation of largest tumor dimensions was associated with worse BCFI (p = 0.0003), while larger single dimension was associated with worse BCFI (p = 0.02) for MA.12. Presence of MC/MF and other tumor size measurements were not associated (p > 0.05) with BFCI. While physicians could consider the largest diameter of the largest focus of disease or the sum of the largest diameters of all foci in their T-stage determination, it appears that the current method of T-staging offers equivalent determinations of prognosis.

Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research.

Improvements in adjuvant therapy have led to a sustained fall in recurrences after early breast cancer. The differential reduction in local and systemic recurrences is poorly understood. This study aimed to explore changes in the distribution of loco-regional and distant recurrences in clinical trials reported over the last 20 years. We also aimed to determine the relative impact of adjuvant chemotherapy and endocrine therapy. MEDLINE search for adjuvant, phase III randomized breast cancer clinical studies between January 1990 and March 2011 was performed. Neoadjuvant, single agent biologics and studies that did not report the proportion of loco-regional and distant recurrences were excluded. The change in the frequency of recurrences was assessed as the nonparametric correlation between the number of loco-regional recurrences as a proportion of all recurrences and time. Studies were weighted by sample size. The differential effect of chemotherapy and endocrine therapy was also assessed. Fifty-three randomized clinical trials with a total of 86,598 patients were included in the analysis. Between 1990 and 2011, the proportion of loco-regional recurrences has decreased from approximately 30 to 15 % (Spearman's ρ = -0.40, p < 0.001). There was no interaction between type of surgery (mastectomy vs. lumpectomy), administration of adjuvant radiation therapy and menopausal status and the correlation of loco-regional recurrences and time. Chemotherapy regimen showed a larger negative correlation compared with endocrine therapy ( ρ = 0.49 vs. ρ = 0.24). Advances in treatment of early breast cancer have differentially reduced the proportion of loco-regional recurrences compared with distant recurrences. In recent trials, loco-regional recurrences account for less than 10-15 % of all recurrences. These falling event rates may affect patient care, especially when deciding on treatments influencing loco-regional control. This change may also impact on the design of clinical trials assessing loco-regional therapy such as surgery and/or local radiation therapy.

Use and delivery of granulocyte colony-stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy-single-centre experience.

BACKGROUND: Use of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration. METHODS: Patients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration. RESULTS: The study analyzed 36 patients. Median age was 58 years (range: 31-78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7-10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1-3 visits). Most patients were satisfied with the home care and g-csf teaching they received. CONCLUSIONS: Most of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.

Excision of the primary tumour in patients with metastatic breast cancer: a clinical dilemma.

BACKGROUND: Approximately 10% of new breast cancer patients will present with overt synchronous metastatic disease. The optimal local management of those patients is controversial. Several series suggest that removal of the primary tumour is associated with a survival benefit, but the retrospective nature of those studies raises considerable methodologic challenges. We evaluated our clinical experience with the management of such patients and, more specifically, the impact of surgery in patients with synchronous metastasis. METHODS: We reviewed patients with primary breast cancer and concurrent distant metastases seen at our centre between 2005 and 2007. Demographic and treatment data were collected. Study endpoints included overall survival and symptomatic local progression rates. RESULTS: The 111 patients identified had a median follow-up of 40 months (range: 0.6-71 months). We allocated the patients to one ot two groups: a nonsurgical group (those who did not have breast surgery, n = 63) and a surgical group (those who did have surgery, n = 48, 29 of whom had surgery before the metastatic diagnosis). When compared with patients in the nonsurgical group, patients in the surgical group were less likely to present with T4 tumours (23% vs. 35%), N3 nodal disease (8% vs. 19%), and visceral metastasis (67% vs. 73%). Patients in the surgical group experienced longer overall survival (49 months vs. 33 months, p = 0.01) and lower rates of symptomatic local progression (14% vs. 44%, p < 0.001). CONCLUSIONS: In our study, improved overall survival and symptomatic local control were demonstrated in the surgically treated patients; however, this group had less aggressive disease at presentation. The optimal local management of patients with metastatic breast cancer remains unknown. An ongoing phase iii trial, E2108, has been designed to assess the effect of breast surgery in metastatic patients responding to first-line systemic therapy. If excision of the primary tumour is associated with a survival benefit, then the preselected subgroup of patients who have responded to initial systemic therapy is the desired population in which to put this hypothesis to the test.

Dual blockade of HER2 - twice as good or twice as toxic?

With about 20% of breast cancers overexpressing HER2, the implementation of trastuzumab and, more recently, lapatinib has revolutionised the care of these patients. Despite these successes, de novo and acquired resistance to these agents represent significant barriers that need to be overcome if further progress is to be achieved. Given that resistance can involve interplay between different members of the HER family multi-targeted inhibition of HER receptors represents an interesting therapeutic strategy. To date, clinical trials have shown that a number of targeted drugs can be combined with trastuzumab and lead to improved overall response rates and potentially also survival. However, such progress leads to an increased burden of toxicity. This review will discuss the mechanisms behind HER2 resistance, the preclinical basis for combining different agents with trastuzumab and the available results from clinical studies evaluating these combinations.

Prospective validation of risk prediction indexes for acute and delayed chemotherapy-induced nausea and vomiting.

BACKGROUND: Despite the use of standardized anti-emetic guidelines, up to 20% of cancer patients suffer from moderate-to-severe chemotherapy-induced nausea and vomiting (cinv)-that is, grade 2 or greater according to the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. We previously developed cycle-based prediction models and associated scoring systems for acute and delayed cinv. As part of the validation process, we prospectively evaluated the ability of the scoring systems to accurately identify patients deemed to be high risk for grade 2 or greater cinv. METHODS: Patients who were receiving any chemotherapy for solid tumours and who consented to participate were provided with symptom diaries. Compliance to the diaries was enhanced by 24-hour and 5-day telephone callbacks after chemotherapy in every cycle. All patients received anti-emetic prophylaxis as prescribed by the treating physician. Before each cycle of chemotherapy, the acute and delayed cinv scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression modelling was then applied to compare the risk for grade 2 or greater cinv between patients considered to be at high and at low risk. The external validity of each system was also assessed using an area under the receiver operating characteristic curve (auroc) analysis. RESULTS: We collected cinv outcomes data from 95 patients during 181 cycles of chemotherapy. The incidence of grade 2 or greater acute and delayed cinv was 17.7% and 18.2% respectively. As previously identified, major predictors for grade 2 or greater cinv included younger patient age, platinum- or anthracycline-based chemotherapy, low alcohol consumption, earlier cycles of chemotherapy, previous history of morning sickness, and prior emetic episodes after chemotherapy. The acute and delayed scoring systems both had good predictive accuracy when applied to the external validation sample (acute-auroc: 0.69; 95% confidence interval: 0.59 to 0.79; delayed-auroc: 0.70; 95% confidence interval: 0.60 to 0.80). Patients identified by the scoring systems to be at high risk were 2.8 (p = 0.025) and 3.1 (p = 0.001) times more likely to develop grade 2 or greater acute and delayed cinv. CONCLUSIONS: The present study demonstrates that our scoring systems are able to accurately identify patients at high risk for acute and delayed cinv. Application and planned continued refinement of the scoring systems will be an important means of patient-specific risk assessment that will allow for optimization of anti-emetic therapy.