Tumor levels of the mediators of ErbB2-driven anoikis resistance correlate with breast cancer relapse in patients receiving trastuzumab-based therapies.

PURPOSE: Patients with ErbB2/Her2 oncoprotein-positive breast cancers often receive neoadjuvant therapies (NATs) containing the anti-ErbB2 antibody trastuzumab. Tumors that are still present after NATs are resected, and patients continue receiving trastuzumab. These cancers are associated with high relapse risk. Whether relapse will occur cannot be presently reliably predicted. The ability to make such predictions could improve disease management. We found previously that ErbB2 blocks breast tumor cell anoikis, apoptosis induced by cell detachment from the extracellular matrix, by downregulating the pro-apoptotic protein Irf6 and upregulating the anti-apoptotic protein Epidermal Growth Factor Receptor (EGFR) in the cells and, thus, promotes their three-dimensional growth. We now tested whether tumor levels of these proteins before and after NATs correlate with patients' relapse-free survival (RFS) and overall survival (OS). METHODS: We selected archival breast tumor samples collected from 37 women with ErbB2-positive stages II and III breast cancer before and after NATs. We used immunohistochemistry to test whether levels of the indicated proteins in respective tumors correlate with RFS and OS. RESULTS: We observed that the presence of high Irf6 levels in the tumors following NATs correlated with reduced RFS and OS. Perhaps not by coincidence, we noticed that trastuzumab-sensitive ErbB2-positive breast cancer cells selected for the ability to overproduce exogenous Irf6 in culture acquired trastuzumab resistance. Finally, EGFR presence in patients' tumors before or after NATs was associated with decreased RFS and OS. CONCLUSIONS: This study could help identify patients with ErbB2-positive tumors that are at increased risk of disease relapse following NATs.

Correction to: Trastuzumab-induced upregulation of a protein set in extracellular vesicles emitted by ErbB2-positive breast cancer cells correlates with their trastuzumab sensitivity.

An amendment to this paper has been published and can be accessed via the original article.

Trastuzumab-induced upregulation of a protein set in extracellular vesicles emitted by ErbB2-positive breast cancer cells correlates with their trastuzumab sensitivity.

BACKGROUND: ErbB2/HER2 oncoprotein often drives breast cancers (BCs) which are treated with the anti-ErbB2 antibody trastuzumab. The efficacy of trastuzumab-based metastatic BC therapies is routinely assessed by imaging studies. Trastuzumab typically becomes ineffective in the case of this disease and is then replaced by other drugs. Biomarkers of BC trastuzumab response could allow imaging studies and the switch to other drugs to occur earlier than is now possible. Moreover, bone-only BC metastases can be hard to measure, and biomarkers of their trastuzumab response could facilitate further treatment decisions. Such biomarkers are presently unavailable. In this study, we searched for proteins whose levels in BC cell-emitted extracellular vesicles (EVs) potentially correlate with BC trastuzumab sensitivity. METHODS: We isolated EVs from cultured trastuzumab-sensitive and trastuzumab-resistant human BC cells before and after trastuzumab treatment and characterized these EVs by nanoparticle tracking analysis and electron microscopy. We found previously that ErbB2 drives BC by downregulating a pro-apoptotic protein PERP. We now tested whether trastuzumab-induced PERP upregulation in EVs emitted by cultured human BC cells correlates with their trastuzumab sensitivity. We also used mass spectrometry to search for additional proteins whose levels in such EVs reflect BC cell trastuzumab sensitivity. Once we identified proteins whose EV levels correlate with this sensitivity in culture, we explored the feasibility of testing whether their levels in the blood EVs of trastuzumab-treated metastatic BC patients correlate with patients' response to trastuzumab-based treatments. RESULTS: We found that neither trastuzumab nor acquisition of trastuzumab resistance by BC cells affects the size or morphology of EVs emitted by cultured BC cells. We established that EV levels of proteins PERP, GNAS2, GNA13, ITB1, and RAB10 correlate with BC cell trastuzumab response. Moreover, these proteins were upregulated during trastuzumab-based therapies in the blood EVs of a pilot cohort of metastatic BC patients that benefited from these therapies but not in those derived from patients that failed such treatments. CONCLUSIONS: Upregulation of a protein set in EVs derived from cultured breast tumor cells correlates with tumor cell trastuzumab sensitivity. It is feasible to further evaluate these proteins as biomarkers of metastatic BC trastuzumab response.

The clinical utility of baseline cardiac assessments prior to adjuvant anthracycline chemotherapy in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Cardiac assessment with multi-gated acquisition scan (MUGA) or echocardiography (ECHO) is commonly employed prior to adjuvant anthracycline-based chemotherapy (AA). However, the clinical utility of routine baseline cardiac assessments prior to AA for early-stage breast cancer (EBC) is unknown. OBJECTIVES: To determine: (i) the clinical utility of routine baseline cardiac assessments prior to AA for EBC and (ii) identify patients in whom baseline cardiac assessments may not be warranted. METHODS: A systematic review of the literature was conducted to identify all relevant studies that met predefined criteria. The clinical utility was defined by: (i) the rates of abnormal baseline left ventricular ejection fraction (LVEF) and (ii) the rates of change in chemotherapy decisions prompted by baseline LVEF results. RESULTS: Eight studies met our criteria, of whom six (n = 2545) reported rates of abnormal LVEF and six (n = 1713) reported rates of change in chemotherapy decision. Overall, 2.5% (95% CI 2.0-4.0%) of patients had abnormal baseline LVEF and 1.6% (95% CI 1.0-3.0%) had a change in chemotherapy decision. In subset analyses, the underlying imaging modality (ECHO vs. MUGA) or inclusion of patients with metastatic disease (YES vs. NO) did not significantly affect these rates. There were no consistently identified underlying predictors of abnormal baseline LVEF across studies. CONCLUSIONS: Routine baseline cardiac assessments prior to AA in all EBC patients have low yield and infrequently affect clinical management. Future studies should further examine potential predictors of abnormal cardiac functions in an attempt to identify low risk patients in whom routine baseline LVEF assessment may not be warranted and prevent delay in chemotherapy administration.

ErbB2-driven downregulation of the transcription factor Irf6 in breast epithelial cells is required for their 3D growth.

BACKGROUND: The ability of solid tumor cells to resist anoikis, apoptosis triggered by cell detachment from the extracellular matrix (ECM), is thought to be critical for 3D tumor growth. ErbB2/Her2 oncoprotein is often overproduced by breast tumor cells and blocks their anoikis by partially understood mechanisms. In our effort to understand them better, we observed that detachment of nonmalignant human breast epithelial cells from the ECM upregulates the transcription factor Irf6. Irf6 is thought to play an important role in mammary gland homeostasis and causes apoptosis by unknown mechanisms. We noticed that ErbB2, when overproduced by detached breast epithelial cells, downregulates Irf6. METHODS: To test whether ErbB2 downregulates Irf6 in human ErbB2-positive breast cancer cells, we examined the effect of ErbB2 inhibitors, such as the anti-ErbB2 antibody trastuzumab or the ErbB2/epidermal growth factor receptor small-molecule inhibitor lapatinib, on Irf6 in these cells. Moreover, we performed Irf6 IHC analysis of tumor samples derived from the locally advanced ErbB2-positive breast cancers before and after neoadjuvant trastuzumab-based therapies. To examine the role of Irf6 in anoikis of nonmalignant and ErbB2-overproducing breast epithelial cells, we studied anoikis after knocking down Irf6 in the former cells by RNA interference and after overproducing Irf6 in the latter cells. To examine the mechanisms by which cell detachment and ErbB2 control Irf6 expression in breast epithelial cells, we tested the effects of genetic and pharmacological inhibitors of the known ErbB2-dependent signaling pathways on Irf6 in these cells. RESULTS: We observed that trastuzumab and lapatinib upregulate Irf6 in ErbB2-positive human breast tumor cells and that neoadjuvant trastuzumab-based therapies tend to upregulate Irf6 in human breast tumors. We found that detachment-induced Irf6 upregulation in nonmalignant breast epithelial cells requires the presence of the transcription factor ∆Np63α and that Irf6 mediates their anoikis. We showed that ErbB2 blocks Irf6 upregulation in ErbB2-overproducing cells by activating the mitogen-activated protein kinases that inhibit ∆Np63α-dependent signals required for Irf6 upregulation. Finally, we demonstrated that ErbB2-driven Irf6 downregulation in ErbB2-overproducing breast epithelial cells blocks their anoikis and promotes their anchorage-independent growth. CONCLUSIONS: We have demonstrated that ErbB2 blocks anoikis of breast epithelial cells by downregulating Irf6.

Is febrile neutropenia prophylaxis with granulocyte-colony stimulating factors economically justified for adjuvant TC chemotherapy in breast cancer?

PURPOSE: Febrile neutropenia (FN) during adjuvant chemotherapy is associated with morbidity, mortality risk, and substantial cost, and subsequent chemotherapy dose reductions may result in poorer outcomes. Patients at high risk of, or who develop FN, often receive prophylaxis with granulocyte colony-stimulating factors (G-CSF). We investigated whether different prophylaxis strategies with G-CSF offered favorable value-for-money. METHODS: We developed a decision model to estimate the short- and long-term costs and outcomes of a hypothetical cohort of women with breast cancer receiving adjuvant taxotere + cyclophosphamide (TC) chemotherapy. The short-term phase estimated upfront costs and FN risks with adjuvant TC chemotherapy without G-CSF prophylaxis (i.e., chemotherapy dose reductions) as well as with secondary and primary G-CSF prophylaxis strategies. The long-term phase estimated the expected costs and quality-adjusted life years (QALYs) for patients who completed adjuvant TC chemotherapy with or without one or more episodes of FN. RESULTS: Secondary G-CSF was associated with lower costs and greater QALY gains than a no G-CSF strategy. Primary G-CSF appears likely to be cost-effective relative to secondary G-CSF at FN rates greater than 28%, assuming some loss of chemotherapy efficacy at lower dose intensities. The cost-effectiveness of primary vs. secondary G-CSF was sensitive to FN risk and mortality, and loss of chemotherapy efficacy following FN. CONCLUSIONS: Secondary G-CSF is more effective and less costly than a no G-CSF strategy. Primary G-CSF may be justified at higher willingness-to-pay thresholds and/or higher FN risks, but this threshold FN risk appears to be higher than the 20% rate recommended by current clinical guidelines.

Impact of the 2013 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing of invasive breast carcinoma: a focus on tumours assessed as 'equivocal' for HER2 gene amplification by fluorescence in-situ hybridization.

AIMS: The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 in-situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours. METHODS AND RESULTS: A total of 904 dual-probe HER2/chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty-five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2-negative to -equivocal, 15 cases (1.7%) were reclassified as HER2-positive and four cases from HER2-equivocal to -negative. A subset of primary breast cancers, reported initially as HER2-negative but -equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2-negative and -positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement. CONCLUSIONS: The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting.

Trastuzumab beyond progression for HER2 positive metastatic breast cancer: progression-free survival on first-line therapy predicts overall survival impact.

Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second-line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999-June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab-based therapy (1 versus 2 versus 3 + ), first-line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first-line trastuzumab-based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab-based therapy (range 1-8). Median overall survival was 21.8 months (95% CI = 14.5-27.1 m), by era was 15.6 m (95% CI = 9.7-24.8 m) versus 26.1 m (95% CI = 20.0-39.3 m; p = 0.11) and by lines of trastuzumab-based therapy received was 10.6 m (95% CI = 5.3-17.4 m) versus 13.9 m (95% CI = 9.5-27.6 m) versus 32.5 m (95% CI = 25-49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8-31.4 m versus 14.5 m, 95% CI = 9.4-21.9 m, p = 0.02). Median overall survival with duration of first-line trastuzumab-based therapy =/> cohort median was 31.9 m (95% CI = 26.2-52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9-15.6 m; p < 0.0001). Our observations support progression-free survival on first-line trastuzumab-based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy.

Cost-utility of the 21-gene recurrence score assay in node-negative and node-positive breast cancer.

The 21-gene recurrence score (Oncotype DX: RS) appears to augment clinico-pathologic prognostication and is predictive of adjuvant chemotherapy benefit in node-negative (N-) and node-positive (N+), endocrine-sensitive breast cancer. RS is a costly assay that is associated with good 'value for money' in N- disease, while economic evaluations in N+ disease based on most recent data have not been conducted. We examined the cost-utility (CU) of a RS-guided adjuvant strategy, compared to current practice without RS in N- and N+, endocrine-sensitive, breast cancer from a Canadian health care system perspective. A generic state-transition model was developed to compute cumulative costs and quality-adjusted life years (QALYs) over a 25-year horizon. Patient outcomes with and without chemotherapy in RS-untested cohorts and in those with low, intermediate and high RS were examined based on the reported prognostic and predictive impact of RS in N- and N+ disease. Chemotherapy utilization (current vs. RS-guided), unit costs and utilities were derived from a Nova Scotia Canadian population-based cohort, local unit costs and the literature. Costs and outcomes were discounted at 3% annually, and costs were reported in 2011 Canadian dollars ($). Probabilistic and one-way sensitivity analyses were conducted for key model parameters. Compared to a non-RS-guided strategy, RS-guided adjuvant therapy was associated with $2,585 and $864 incremental costs, 0.27 and 0.06 QALY gains, and resultant CUs of $9,591 and $14,844 per QALY gained for N- and N+ disease, respectively. CU estimates were robust to key model parameters, and were most sensitive to chemo utilization proportions. RS-guided adjuvant therapy appears to be a cost-effective strategy in both N- and N+, endocrine-sensitive breast cancer with resultant CU ratios well below commonly quoted thresholds.

Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis.

BACKGROUND: Variable febrile neutropenia (FN) rates reported with adjuvant TC (taxotere®, cyclophosphamide) and FEC-D (5-flurouracil, epirubicin, cyclophosphamide, docetaxel) outside of clinical trials have precluded definitive recommendations for primary G-CSF (granulocyte colony-stimulating factor) prophylaxis in most jurisdictions. A systematic review and meta-analysis was conducted to assess: (a) FN rates associated with TC and FEC-D without primary G-CSF prophylaxis outside of clinical trial settings, and (b) the potential impact of G-CSF prophylaxis on FN prevention. METHODS: A MEDLINE search was conducted and major conference abstracts were reviewed up to June 15th 2011 to identify all relevant English-language studies. Random- and fixed-effects meta-analysis models were performed. RESULTS: Nine hundred two patients treated with TC and 1342 with FEC-D from 13 to 9 studies, respectively, were included. The pooled random-effects meta-analysis estimates of FN rates for TC and FEC-D without G-CSF were 29% (95% CI 24-35%) and 31% (95% CI 27-35%), with a 76% (RR = 0.24, 95% CI 0.14-0.41) and 63% (RR = 0.37, 95% CI 0.11-1.24) relative risk reduction with G-CSF, respectively. CONCLUSION: In routine clinical practice, TC and FEC-D without G-CSF are associated with FN rates exceeding the 20% threshold for which primary G-CSF prophylaxis is commonly recommended, and are considerably higher than those reported in pivotal clinical trials.

Nurse Navigators' Views on Patient and System Factors Associated with Navigation Needs among Women with Breast Cancer.

Coordinating breast cancer treatment is a complex task that can overwhelm patients and their support networks. Though the Cancer Patient Navigator (CPN) program in Nova Scotia (NS) provides professional assistance to patients, certain groups of patients may still face barriers to accessing its services. Employing interviews and a modified Delphi approach with CPN participants, this study sought to identify factors associated with the need for navigation to help better target CPN program referrals among breast cancer patients. Six CPNs were recruited directly through the CPN program manager for interviews and surveys. The CPNs identified 27 different factors, which were divided into 4 categories: sociodemographic, psychological, clinical and health systems. While these patient factors (particularly sociodemographic) are not directly modifiable, awareness of their association with the need for navigation could be used to better target patients with a high need for navigation for referral to CPN services.

Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects.

PURPOSE: BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality-adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. METHODS: We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-years (QALY) gained for TAC versus FAC was calculated. RESULTS: For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. CONCLUSION: For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy.

The cost-utility of sequential adjuvant trastuzumab in women with Her2/Neu-positive breast cancer: an analysis based on updated results from the HERA Trial.

BACKGROUND: The efficacy of sequential adjuvant trastuzumab (aTZ) after chemotherapy in women with early-stage human epidermal growth factor-2 (HER2/neu)-positive breast cancer reported by the updated Herceptin Adjuvant (HERA) trial appears less favorable than originally reported. Based on these updated results, we estimated the cost-utility (CU) of sequential aTZ relative to chemotherapy alone in terms of incremental cost per quality-adjusted life-year (QALY) gained. METHODS: A Markov model estimated incremental costs and outcomes of 12 months of aTZ after adjuvant chemotherapy in women with HER2/neu-positive breast cancer over a 25-year horizon. The model incorporated four broad health states (disease-free, local recurrence [LCR], distant recurrence [DCR], death), stratified with or without symptomatic cardiotoxicity. Baseline event rates and 3-year relative risk (RR = 0.75) were derived from the HERA trial. As the duration of the benefit remains uncertain, the analysis considered 5-year and 3-year duration of benefit in two scenarios. Costs and utility weights were from the literature. The analysis took a direct payer perspective, with costs reported in 2007 Canadian dollars. Costs and QALYs were discounted by 3% annually. RESULTS: The mean CU of sequential aTZ at a 25-year horizon was $72,292 per QALY gained in the 5-year scenario and $127,862 per QALY gained in the 3-year scenario. Results were particularly sensitive to the magnitude and duration of carryover benefit. CONCLUSIONS: The CU of sequential aTZ is primarily dependent on the magnitude and duration of benefit. Further clinical research is required to establish the optimum sequence and duration of aTZ therapy and clarify the magnitude and duration of treatment benefit.

Comparison of elapsed times from breast cancer detection to first adjuvant therapy in Nova Scotia in 1999/2000 and 2003/04.

BACKGROUND: Waiting times for cancer care continue to be an important issue for Canadians. We evaluated 2 cohorts of breast cancer patients to compare changes in elapsed times to care, to determine the proportion of patients who received their postoperative oncology consultation within the recommended time and to examine elapsed times between date of surgery and start of first adjuvant therapy. METHODS: We conducted a retrospective chart review of all women with surgically treated breast cancer who were referred to a provincial cancer centre for adjuvant therapy. The first cohort comprised women referred between Sept. 1, 1999, and Sept. 1, 2000 (n = 342), and the second cohort comprised women referred between Sept. 1, 2003, and Sept. 1, 2004 (n = 295). A general linear model with a stepwise selection was used to identify dominant factors that influenced elapsed times; covariates included cohort period, age at diagnosis, place of residence, disease stage, type of surgery, type of adjuvant therapy, distance to cancer centre, median household income and mean education level. RESULTS: The overall median time from disease detection to the start of first adjuvant therapy for the combined cohorts was 96 days (quartiles 76, 122); this interval was longer for patients in the second cohort (90 v. 102 days, p < 0.001). For the combined cohorts, significantly more patients saw a radiation oncologist within the recommended time from date of surgery than did patients referred to a medical oncologist (82.7% v. 51.7%; p < 0.001). Patients who received adjuvant radiation therapy as their first adjuvant treatment waited longer from the date of definitive surgery to the start of treatment than did patients who received chemotherapy or hormonal treatment (77 v. 48 or 42 days; p < 0.001). INTERPRETATION: The median elapsed time from the detection of breast cancer to the start of first adjuvant therapy was longer in the second cohort (referred in 2003/04) than in the first cohort (referred in 1999/2000). The proportion of patients whose first oncology consultation was within the recommended timeframe varied significantly according to type of oncology specialist, favouring radiation oncology. Despite this difference in access, patients whose first adjuvant therapy was systemic therapy experienced significantly shorter elapsed times from surgery to the start of adjuvant therapy than did patients whose first adjuvant therapy was radiation therapy.

Length of survival of patients with cancer in hospice: a retrospective analysis of patients treated at a major cancer center versus other practice settings.

This is a retrospective study of the length of survival (LOS) in hospice of patients with cancer treated at a major cancer center compared to other treatment sites. Of 670 patients, the 185 (28%) treated at a major cancer center had unique characteristics, including higher median Palliative Performance Score (PPS) at the time of hospice enrollment (45 versus 40, p = 0.009), and longer median LOS in hospice (35 versus 21 days, p = 0.02: log rank test). Additional variables that predicted longer LOS were higher PPS, Medicare or Medicaid, self-referral, unmarried status, and non-executed advance directives. After adjusting survival for PPS with a Cox proportional hazard model, the hazard ratio for PPS remained statistically significant (95% confidence interval [CI]: 0.95-0.97] while that for the treatment site was not (95% CI: 0.73-1.04]. The performance status, and not the treatment site, was the dominant predictor of the LOS of patients with cancer in hospice.

Endocrine therapy for breast cancer prevention in high-risk women: clinical and economic considerations.

The global burden of breast cancer highlights the need for primary prevention strategies that demonstrate both favorable clinical benefit/risk profile and good value for money. Endocrine therapy with selective estrogen-receptor modulators (SERMs) or aromatase inhibitors (AIs) has been associated with a favorable clinical benefit/risk profile in the prevention of breast cancer in women at high risk of developing the disease. The available endocrine therapy strategies differ in terms of their relative reductions of breast cancer risk, potential side effects, and upfront drug acquisition costs, among others. This review highlights the clinical trials of SERMs and AIs for the primary prevention of breast cancer, and the cost-effectiveness /cost-utility studies that have examined their "value for money" in various health care jurisdictions.

EXercise to prevent AnthrCycline-based Cardio-Toxicity (EXACT) in individuals with breast or hematological cancers: a feasibility study protocol.

BACKGROUND: Anthracyclines (AC), widely used and effective anticancer agents, are known to induce both acute and chronic declines in cardiovascular health, ranging in severity from asymptomatic, subclinical dysfunction to substantial cardiomyopathy leading to congestive heart failure and death. There is substantial evidence that physical activity, higher levels of cardiorespiratory fitness, and exercise therapy can help prevent cardiovascular disease. Moreover, animal studies have shown that exercise performed concomitantly with AC treatment may attenuate early cardiac damage that results from AC exposure. Our primary objective is to assess the feasibility of a 12-week aerobic exercise training (AET) program in patients receiving AC-based chemotherapy. METHODS/DESIGN: This is a prospective, single-arm (pre-post-test design), feasibility study of a supervised 12-week progressive, light-to-moderate to moderate-to-vigorous intensity AET program for patients (18-65 years) receiving AC chemotherapeutic treatment for a primary/non-recurrent breast cancer or hematological malignancy. Both feasibility (e.g., participant recruitment, program adherence, safety) and intervention outcome (e.g., biological markers of cardiotoxicity, aerobic capacity, quality of life) measures will be collected. The AET program will include two, 45-min community-based exercise sessions (treadmill or cycle) per week for a total of 12 weeks. All exercise sessions will be supervised by trained exercise specialists. DISCUSSION: Data from the EXACT study will be evaluated to determine the need to refine patient recruitment methods and general acceptability of the AET program. Preliminary data on the effects of the AET intervention on pertinent cardiac and health outcomes will also be evaluated and used to inform future studies in terms of the most appropriate outcome measure(s) to adopt and sample size estimation. TRIAL REGISTRATION: ClinicalTrails.gov, NCT02471053.

Differential expression of survivin-2B and survivin-DeltaEx3 is inversely associated with disease relapse and patient survival in non-small-cell lung cancer (NSCLC).

Although it was observed that inhibition of the antiapoptotic protein survivin expression in lung cancer cells induces apoptosis, the expression and role of survivin variants (survivin-2B and survivin-DeltaEx3) in lung cancer have not yet been characterized. We analyzed 24 non-small-cell lung cancer (NSCLC) samples by semi-quantitative RT-PCR. Surprisingly, our results revealed that high-level expression of survivin-2B is significantly associated with the patient category of "no relapse and alive" (p-value<0.0001). In contrast, high-level expression of survivin-DeltaEx3 is highly associated with the patient category of "relapse and dead" (p-value<0.0001). Consistent with this observation, exogenous expression of survivin-2B in A549 lung cancer cells inhibited cell growth, disrupted the mitochondria potential, and induced apoptotic cell death, while expression of survivin-DeltaEx3 protected the mitochondria potential and facilitated cell survival. These findings provide evidence that survivin-2B and survivin-DeltaEx3 play opposite roles in disease relapse and NSCLC cell survival, which is likely through the differential modulation of mitochondrial potential. Thus, controlling the differential expression of survivin-2B and survivin-DeltaEx3 may represent novel approaches for cancer therapeutics in NSCLC.

Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations.

In the absence of specific therapy, the 15%-20% of breast cancers demonstrating human epidermal growth-factor receptor 2 (HER2) protein overexpression and/or gene amplification are characterized by a more aggressive phenotype and poorer prognosis compared to their HER2-negative counterparts. Trastuzumab (Herceptin), the first anti-HER2-targeted therapy, has been associated with improved survival outcomes in HER2-positive breast cancer. However, many patients with early stage disease continue to relapse, and metastatic disease remains incurable. In order to further improve these outcomes, several novel HER2-targeted agents have recently been developed. Pertuzumab (Perjeta), a monoclonal antibody against the HER2 dimerization domain, has also been associated with improved patient outcomes in clinical trials, and has recently been approved in combination with chemotherapy and trastuzumab for neoadjuvant therapy of early stage, HER2-positive breast cancer and first-line treatment of metastatic disease. This review briefly summarizes pertuzumab's clinical development as well as the published evidence supporting its use, and highlights some of the currently unanswered questions that will influence pertuzumab's incorporation into clinical practice.