Recurrence rates in patients with HER2+ breast cancer who achieved a pathological complete response after neoadjuvant pertuzumab plus trastuzumab followed by adjuvant trastuzumab: a real-world evidence study.

PURPOSE: This study assessed real-world risk of invasive disease recurrence (IDR) and associated factors in patients with human epidermal growth factor receptor-2 positive (HER2+) early breast cancer (BC) with pathological complete responses (pCR) after neoadjuvant pertuzumab plus trastuzumab (nPT) plus chemotherapy, followed by adjuvant trastuzumab (aT). METHODS: Patients with HER2+ BC with pCR after nPT from 2013 to 2015 who received aT were identified in the US Oncology Network and followed until IDR or censoring. Kaplan-Meier and Cox regression methods were used to assess invasive disease-free survival (iDFS) and correlation between iDFS and patient characteristics. RESULTS: A total of 217 pCR patients' charts were reviewed; median age was 52 years. Most had stage IIA or IIB disease (62%), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 (84%), tumor size > 2 cm (75%), positive nodes (N+, 62%) and negative estrogen and progesterone receptor (ER- and PR-) expression (52%). Four-year iDFS rates were 90.0% overall (95% CI 84.6%, 93.6%), 86.2% for the N+ cohort and 96.0% for the N- cohort. Cox regression suggested that age, body mass index, ECOG PS, N+ status, stage T3 or T4, and ER+ or PR+ status were risk factors for IDR but were not statistically significant. CONCLUSIONS: Consistent with previous studies, this real-world study observed that patients with HER2+ BC showing pCR with nPT remain at risk for IDR, especially with node-positive disease at diagnosis. Alternatives to adjuvant trastuzumab alone, including combined trastuzumab and pertuzumab, should be considered to improve outcomes for initially N+ patients showing pCR with nPT.

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive breast cancer: A multidisciplinary approach.

Pertuzumab plus trastuzumab, administered intravenously (IV) with chemotherapy, is standard treatment for HER2-positive metastatic or high-risk early breast cancer. Pertuzumab and trastuzumab are administered over 1-2.5 h traditionally; however, the need for IV infusions places a strain on medical centers with respect to scheduling, preparation, and administration. A novel fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PHESGO®, PH FDC SC) can be administered in approximately 5-8 min. PH FDC SC was non-inferior to IV pertuzumab plus trastuzumab in terms of pertuzumab and trastuzumab serum levels in the phase III FeDeriCa study, which enrolled 500 patients with HER2-positive early breast cancer. Total pathologic complete response rates were comparable after PH FDC SC (59.7%) or IV pertuzumab plus trastuzumab (59.5%), as was the incidence of grade ≥3 (48.8% vs 52.8%) and serious adverse events (16.1% vs 17.9%). The results of a phase II clinical trial (PHranceSCa) showed that a majority of patients (85%) preferred PH FDC SC treatment over IV pertuzumab plus trastuzumab. A US multicenter expanded access study (NCT04395508) is evaluating the safety of PH FDC SC administered at home by nurse providers in patients receiving maintenance HER2-targeted therapy every 3 weeks. This product takes much less time to administer than IV pertuzumab-trastuzumab and has the potential to alleviate time constraints for patients and busy clinics. In this review we provide an overview of PH FDC SC, and discuss our experience in preparing and administering this product to patients with HER2-positive breast cancer during clinical trials.

Evaluating femoral augmentation to prevent geriatric hip fracture: A scoping review of experimental methods.

Various femoral augmentation designs have been investigated over the past decade for the prevention of geriatric hip fracture. The experimental methods used to evaluate the efficacy of these augmentations have not been critically evaluated or compared in terms of biofidelity, robustness, or ease of application. Such parameters have significant relevance in characterizing future clinical success. In this study we aimed to use a scoping review to summarize the experimental studies that evaluate femoral augmentation approaches, and critically evaluate commonly applied protocols and identify areas for concordance with the clinical situation. We conducted a literature search targeting studies that used experimental test methods to evaluate femoral augmentation to prevent geriatric fragility fracture. A total of 25 studies met the eligibility criteria. The most commonly investigated augmentation to date is the injection of bone cement or another material that cured in situ, and a popular subsequent method for biomechanical evaluation was to load the augmented proximal femur until fracture in a sideways fall configuration. We noted limitations in the clinical relevance of sideways fall scenarios being modeled and large variance in the concordance of many of the studies identified. Our review brings about recommendations for enhancing the fidelity of experimental methods modeling clinical sideways falls, which include an improved representation of soft tissue effects, using outcome metrics beyond load-to-failure, and applying loads inertially. Effective augmentations are encouraging for their potential to reduce the burden of hip fracture; however, the likelihood of this success is only as strong as the methods used in their evaluation.

The efficacy of femoral augmentation for hip fracture prevention using ceramic-based cements: A preliminary experimentally-driven finite element investigation.

Femoral fractures due to sideways falls continue to be a major cause of concern for the elderly. Existing approaches for the prevention of these injuries have limited efficacy. Prophylactic femoral augmentation systems, particularly those involving the injection of ceramic-based bone cements, are gaining more attention as a potential alternative preventative approach. We evaluated the mechanical effectiveness of three variations of a bone cement injection pattern (basic ellipsoid, hollow ellipsoid, small ellipsoid) utilizing finite element simulations of sideways fall impacts. The basic augmentation pattern was tested with both high- and low-strength ceramic-based cements. The cement patterns were added to the finite element models (FEMs) of five cadaveric femurs, which were then subject to simulated sideways falls at seven impact velocities ranging from 1.0 m/s to 4.0 m/s. Peak impact forces and peak acetabular forces were examined, and failure was evaluated using a strain-based criterion. We found that the basic HA ellipsoid provided the highest increases in both the force at the acetabulum of the impacted femur ("acetabular force", 55.0% ± 22.0%) and at the force plate ("impact force", 37.4% ± 15.8%). Changing the cement to a weaker material, brushite, resulted in reduced strengthening of the femur (45.2% ± 19.4% acetabular and 30.4% ± 13.0% impact). Using a hollow version of the ellipsoid appeared to have no effect on the fracture outcome and only a minor effect on the other metrics (54.1% ± 22.3% acetabular force increase and 35.3% ± 16.0% impact force increase). However, when the outer two layers of the ellipsoid were removed (small ellipsoid), the force increases that were achieved were only 9.8% ± 5.5% acetabular force and 8.2% ± 4.1% impact force. These results demonstrate the importance of supporting the femoral neck cortex to prevent femoral fractures in a sideways fall, and provide plausible options for prophylactic femoral augmentation. As this is a preliminary study, the surgical technique, the possible effects of trabecular bone damage during the augmentation process, and the effect on the blood supply to the femoral head must be assessed further.

Impact of Pertuzumab and Ado-Trastuzumab Emtansine on Cumulative Avoidance of Recurrence Among Women Treated for Locally Advanced, Inflammatory, or Early-Stage Nonmetastatic HER2-Positive Breast Cancer in the United States.

INTRODUCTION: We assessed the impact of HER2-positive early breast cancer (EBC) treatment landscape changes following the introduction of pertuzumab and ado-trastuzumab emtansine (T-DM1) on cumulative population-level recurrences avoided since 2013 (first pertuzumab approval for EBC in the United States; US). METHODS: We constructed a multi-year epidemiologic population treatment-impact model to estimate annual recurrences between 2013 and 2031. Parameters were: BC incidence; stage I-III proportion; HER2-positive disease proportion; treatment proportions for neoadjuvant-only, adjuvant-only, and neoadjuvant-adjuvant continuation; and therapeutic agent proportions within each of those settings (chemotherapy only, trastuzumab ± chemotherapy, pertuzumab with trastuzumab ± chemotherapy, or T-DM1). The primary endpoint was cumulative recurrences, estimated by incorporating extrapolated clinical trial data for each regimen of interest into the model under four scenarios. RESULTS: Approximately 889,057 women were predicted to be diagnosed with stage I-III HER2-positive BC from 2006 to 2031 in the US and potentially indicated for HER2-targeted treatment. In steady-state equilibrium, the model estimated that real-world utilization of pertuzumab and T-DM1 will reduce the population-level number of recurrences by approximately 32%, with 7226 recurrences predicted in 2031 based on current utilization rates. In different modeled scenarios, use of neoadjuvant pertuzumab, continuation of pertuzumab in the adjuvant setting, and T-DM1 in the adjuvant setting in women with residual disease after neoadjuvant treatment were all predicted to reduce the number of recurrences. CONCLUSION: Given the improvement of HER2-targeted treatments, alongside increases in BC disease burden, we expect that the population-level impact of HER2-targeted treatments will accelerate over the next decade. Our results suggest that utilization of HER2-targeted treatments in the US has the potential to change the epidemiology of HER2-positive EBC by preventing a substantial number of women from experiencing disease recurrence. These improvements may help to inform our understanding of the future disease and economic burden of HER2-positive BC in the US.

We predicted whether two treatments for a type of breast cancer called "HER2-positive," that had not yet spread from the breast, could be used to avoid the cancer coming back in women in the United States (US), using computer modeling. The model estimated that approximately 889,057 women were predicted to be diagnosed with this type of breast cancer from 2006 to 2031, and that use of the treatments pertuzumab and ado-trastuzumab emtansine (T-DM1) would reduce the number of breast cancers that came back by around 32%. Treating with pertuzumab before surgery, continuing pertuzumab treatment after surgery, and giving T-DM1 after surgery (in the event that some of the breast cancer remained after being treated before surgery) were all predicted to reduce the number of breast cancers that come back. Overall, we expect use of pertuzumab and T-DM1 to keep lowering the number of breast cancers that come back over the next decade in the US.

Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data.

The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progressive central nervous system (CNS) metastases following radiotherapy. Primary analysis confirmed CNS objective response rate (ORR) was 11% (95% confidence interval [CI]: 3-25); clinical benefit rate (CBR) was 68% (4 months) and 51% (6 months). We report final efficacy data after a further 21-months of follow-up, updated safety, survival, and patient-reported outcomes (PROs). Patients received standard-dose pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Primary endpoint: confirmed ORR (CNS) per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary endpoints were response duration, CBR, progression-free survival (PFS), overall survival (OS), safety, and PROs. By clinical cut-off, 39 patients had completed or discontinued treatment. Confirmed ORR (CNS) was 11% (95% CI: 3.0-25.4). Median CNS-PFS was 4.6 months (95% CI: 4.0-8.9), as was median CNS-PFS or systemic PFS (95% CI: 4.0-8.9); median OS was 27.2 months (95% CI: 16.1-not reached). CBR in the CNS was 51% (19 patients, 95% CI: 34.4-68.1) at 6 months. Two patients remained on treatment until study closure, achieving stable disease for 4.1 and 4.8 years. Treatment-related grade 3/4 adverse events occurred in 7.7% of patients. Patients with confirmed partial response or stable disease (≥4 months) in the CNS had stable PROs over time. Pertuzumab plus high-dose trastuzumab represents a reasonable non-chemotherapeutic treatment option for selected patients with HER2-positive MBC with CNS metastases.

Assessment of the Cost-Effectiveness of HER2-Targeted Treatment Pathways in the Neoadjuvant Treatment of High-Risk HER2-Positive Early-Stage Breast Cancer.

INTRODUCTION: This study aims to assess differences in costs and benefits of treatment strategies for high-risk human epidermal growth factor receptor 2 positive (HER2+) early-stage breast cancer (ESBC). METHODS: We used a hybrid decision-tree/Markov model to simulate costs and outcomes across six health states: Invasive disease-free, non-metastatic recurrence, remission, first-line and second-line metastatic cancer, and death. We considered several strategies, defined by four attributes: (1) Neoadjuvant targeted therapy (infused pertuzumab and trastuzumab (PH) versus subcutaneous fixed-dose combination (FDC) of pertuzumab and trastuzumab versus trastuzumab alone (H)); (2) adjuvant targeted therapy if pathological complete response (pCR) is achieved (PH, FDC, or H); (3) adjuvant targeted therapy (T-DM1 or H) in the case of residual disease (RD); and (4) use of branded or biosimilar H. Transition probabilities were derived from relevant clinical trials. We included drug costs and costs associated with adverse events and administration. Health state utilities were obtained from clinical trials and the literature. RESULTS: Strategies not containing T-DM1 were dominated (worse outcomes and greater costs) by strategies containing T-DM1. Among strategies with pertuzumab continuation in the case of pCR and T-DM1 in the case of RD, use of FDC was dominant (equivalent outcomes and lower costs), relative to strategies using infused therapies, regardless of biosimilar versus branded trastuzumab. Adjuvant continuation of FDC was also cost-effective (better outcomes at reasonable cost increases) relative to strategies which discontinued pertuzumab following pCR. CONCLUSION: Dual targeted therapy via FDC (with transition to T-DM1 in the case of RD) is a cost-effective treatment strategy in high-risk HER2+ ESBC.

Prophylactic augmentation implants in the proximal femur for hip fracture prevention: An in silico investigation of simulated sideways fall impacts.

Femoral fractures from sideways falls in the elderly are associated with significant rates of morbidity and mortality. Approaches to prevent these catastrophic injuries include pharmacological treatments, which have limited efficacy. Prophylactic femoral augmentation systems are a promising alternative that are gaining prominence by addressing the most debilitating osteoporosis-related fracture. We have developed finite element models (FEMs) of a novel experimental sideways fall simulator for cadavers. By virtue of the range of specimens and injury outcomes, these FEMs are well-suited to the evaluation of such implants. The purpose of this study was to use the FEMs to evaluate the mechanical effectiveness of three different prophylactic femoral augmentation systems. Models of the Y-Strut® (Hyprevention®, Pessac, France), Gamma Nail® (Stryker, Kalamazoo, USA), and a simple lag screw femoral fracture implant systems were placed into FEMs of five cadaveric pelvis-femur constructs embedded in a soft tissue surrogate, which were then subject to simulated sideways falls at seven impact velocities. Femur-only FEMs were also evaluated. Peak impact forces and peak acetabular forces were examined, and failure was evaluated using a strain-based criterion. We found that the femoral augmentation systems increased the peak forces prior to fracture, but were unable to prevent fracture for severe impacts. The Gamma Nail® system consistently produced the largest strength increases relative to the unaugmented femur for all five specimens in both the pendulum-drop FEMs and the femur-only simulations. In some cases, the same implant appeared to cause fractures in the acetabulum. The femur-only FEMs showed larger force increases than the pendulum-drop simulations, which suggests that the results of the femur-only simulations may not represent sideways falls as accurately as the soft tissue-embedded pendulum-drop simulations. The results from this study demonstrate the ability to simulate a high energy phenomenon and the effect of implants in an in silico environment. The results also suggest that implants could increase the force applied to the proximal femur during impact. Fracture outcomes from the tested implants can be used to inform the design of future devices, which reaffirms the value of modelling with biofidelic considerations in the implant design process. To the authors' knowledge, this is the first paper to use more complex biofidelic FEMs to assess prophylactic femoral augmentation methods.

Pertuzumab Plus High-Dose Trastuzumab in Patients With Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study.

PURPOSE: Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS: In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS: Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION: Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

Subject-specific ex vivo simulations for hip fracture risk assessment in sideways falls.

The risk of hip fracture of a patient due to a fall can be described from a mechanical perspective as the capacity of the femur to withstand the force that it experiences in the event of a fall. So far, impact forces acting on the lateral aspect of the pelvic region and femur strength have been investigated separately. This study used inertia-driven cadaveric impact experiments that mimic falls to the side from standing in order to evaluate the subject-specific force applied to the hip during impact and the fracture outcome in the same experimental model. Eleven fresh-frozen pelvis-femur constructs (6 female, 5 male, age = 77 years (SD = 13 years), BMI = 22.8 kg/m2 (SD = 7.8 kg/m2), total hip aBMD = 0.734 g/cm2 (SD = 0.149 g/cm2)), were embedded into soft tissue surrogate material that matched subject-specific mass and body shape. The specimens were attached to metallic lower-limb constructions with subject-specific masses and subjected to an inverted pendulum motion. Impact forces were recorded with a 6-axis force plate at 10,000 Hz and three dimensional deflections in the pelvic region were tracked with two high-speed cameras at 5000 Hz. Of the 11 specimens, 5 femur fractures and 3 pelvis fractures were observed. Three specimens did not fracture. aBMD alone did not reliably separate femur fractures from non-fractures. However, a mechanical risk ratio, which was calculated as the impact force divided by aBMD, classified specimens reliably into femur fractures and non-fractures. Single degree of freedom models, based on specimen kinetics, were able to predict subject-specific peak impact forces (RMSE = 2.55% for non-fractures). This study provides direct evidence relating subject-specific impact forces and subject-specific strength estimates and improves the assessment of the mechanical risk of hip fracture for a specific femur/pelvis combination in a sideways fall.

Long-term health-related burden of adult congenital heart diseases in Hong Kong.

Aims: This study aimed to examine the long-term clinical and economic burden of adults with congenital heart disease (ACHD) in Hong Kong. Methods: It retrospectively analyzed 336 consecutive ACHD patients who attended the Adult Congenital Heart Clinic between January 1, 2009 and December 31, 2014. Direct medical costs and clinical outcomes over the 5 years were calculated and documented. The economic evaluation was from the hospital's perspective. Results: The median age of ACHD patients was 47 (31-62) years old, with female predominance (61.5%). Ventricular and atrial septal defects accounted for 70% and severe ACHD for 10% of the study cohort. The prevalence of arrhythmia and heart failure increased with the complexity of CHD. The total mean annual cost for managing each ACHD patient was USD 2,913. The annual cost of management of simple ACHD was USD 2,638 vs complex ACHD (USD 6,425) (p = 0.013). Conclusions: This study demonstrated severe ACHD patients accounted for higher cardiovascular morbidities in arrhythmias and heart failure with a higher cost of management.

Experimental validation of finite element predicted bone strain in the human metatarsal.

Metatarsal stress fracture is a common injury observed in athletes and military personnel. Mechanical fatigue is believed to play an important role in the etiology of stress fracture, which is highly dependent on the resulting bone strain from the applied load. The purpose of this study was to validate a subject-specific finite element (FE) modeling routine for bone strain prediction in the human metatarsal. Strain gauge measurements were performed on 33 metatarsals from seven human cadaveric feet subject to cantilever bending, and subject-specific FE models were generated from computed tomography images. Material properties for the FE models were assigned using a published density-modulus relationship as well as density-modulus relationships developed from optimization techniques. The optimized relationships were developed with a 'training set' of metatarsals (n=17) and cross-validated with a 'test set' (n=16). The published and optimized density elasticity equations provided FE-predicted strains that were highly correlated with experimental measurements for both the training (r2≥0.95) and test (r2≥0.94) sets; however, the optimized equations reduced the maximum error by 10% to 20% relative to the published equation, and resulted in an X=Y type of relationship between experimental measurements and FE predictions. Using a separate optimized density-modulus equation for trabecular and cortical bone did not improve strain predictions when compared to a single equation that spanned the entire bone density range. We believe that the FE models with optimized material property assignment have a level of accuracy necessary to investigate potential interventions to minimize metatarsal strain in an effort to prevent the occurrence of stress fracture.

Effects of footwear and stride length on metatarsal strains and failure in running.

BACKGROUND: The metatarsal bones of the foot are particularly susceptible to stress fracture owing to the high strains they experience during the stance phase of running. Shoe cushioning and stride length reduction represent two potential interventions to decrease metatarsal strain and thus stress fracture risk. METHODS: Fourteen male recreational runners ran overground at a 5-km pace while motion capture and plantar pressure data were collected during four experimental conditions: traditional shoe at preferred and 90% preferred stride length, and minimalist shoe at preferred and 90% preferred stride length. Combined musculoskeletal - finite element modeling based on motion analysis and computed tomography data were used to quantify metatarsal strains and the probability of failure was determined using stress-life predictions. FINDINGS: No significant interactions between footwear and stride length were observed. Running in minimalist shoes increased strains for all metatarsals by 28.7% (SD 6.4%; p<0.001) and probability of failure for metatarsals 2-4 by 17.3% (SD 14.3%; p≤0.005). Running at 90% preferred stride length decreased strains for metatarsal 4 by 4.2% (SD 2.0%; p≤0.007), and no differences in probability of failure were observed. INTERPRETATIONS: Significant increases in metatarsal strains and the probability of failure were observed for recreational runners acutely transitioning to minimalist shoes. Running with a 10% reduction in stride length did not appear to be a beneficial technique for reducing the risk of metatarsal stress fracture, however the increased number of loading cycles for a given distance was not detrimental either.

Advanced colorectal cancer: current treatment and nursing management with economic considerations.

Colorectal cancer is one of the most common cancers affecting men and women in the United States. In 2005, 10% of all new cancer cases in men will be colorectal; for women, 11% of new cases will be colorectal. The disease is the third most frequent cancer occurring in both sexes. Colorectal cancer also is the third most frequent cause of death for men and women, and more than 56,000 cancer deaths in 2005 will be attributed to colorectal cancer. Chemotherapy options for treatment of the disease remained relatively stagnant until the approval of irinotecan in 1996 followed by capecitabine, oxaliplatin, and the new targeted agents. The new agents have improved efficacy of treatment for colorectal cancer and the lives of patients with advanced disease. With the new options for treatment come increased nursing and patient-teaching responsibilities, as well as increased costs associated with the newer drugs in the armamentarium of chemotherapy agents. Formulary budgets are seeing dramatic rises in expenditures for the new, targeted therapy treatments; discussion of the most appropriate therapies may be considered. This article will discuss epidemiology of colorectal cancer, treatment options in advanced colorectal cancer, and nursing care crucial to patients undergoing chemotherapy. Discussion of economic impact also will be presented.