A Randomized, Single-Blind Study Evaluating the Effect of a Bone Pain Education Video on Reported Bone Pain in Patients with Breast Cancer Receiving Chemotherapy and Pegfilgrastim.

BACKGROUND: Mild-to-moderate bone pain is the most commonly reported adverse event associated with pegfilgrastim. AIMS: To investigate the effect of bone pain education on pegfilgrastim-related bone pain in patients with breast cancer receiving chemotherapy and pegfilgrastim. DESIGN: Randomized, single-blind study. SETTINGS: Forty-eight community oncology clinics throughout the United States. PARTICIPANTS: Three hundred women ≥18 years of age with newly diagnosed stage I -III breast cancer, who were planning ≥4 cycles of neoadjuvant or adjuvant chemotherapy with pegfilgrastim support starting in cycle 1. METHODS: Patients were randomized 1:1 to view a general education DVD on chemotherapy side effects (GE-DVD) or a DVD on bone pain following chemotherapy and pegfilgrastim (BP-DVD). Patients recorded severity of bone pain on a scale of 0-10, location of pain, and use of bone pain medications (i.e., analgesics, antihistamines, and nonsteroidal anti-inflammatory drugs) for 5 days, beginning on the day of pegfilgrastim administration, in each of the first four chemotherapy cycles. RESULTS: Patient-reported maximum bone pain was similar in the two groups (GE-DVD vs BP-DVD: cycle 1, 3.2 vs. 3.5, p = .3479; across all cycles, 4.1 vs. 4.6, p = .2196). Other measures of bone pain were also similar between the groups. Bone pain was highest in cycle 1 but decreased and then remained stable in subsequent cycles. Bone pain medication use was similar in both groups and was highest in cycle 1. CONCLUSIONS: The bone pain-specific education evaluated here did not improve perceptions of bone pain reported in this patient population.

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim.

PURPOSE: Filgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports. METHODS: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes. RESULTS: A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53-0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37-0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29-5.27 in CIN). Additional efficacy and safety outcomes are described within indications. CONCLUSIONS: This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim.

PURPOSE: Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on pegfilgrastim-associated bone pain. METHODS: In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I-III breast cancer and an ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2-4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles. RESULTS: Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all-grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment-related AEs and discontinuations than naproxen. CONCLUSIONS: Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ; NCT01712009.

The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.

PURPOSE: Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs. METHODS: A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines. RESULTS: The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes. CONCLUSIONS: Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES).

BACKGROUND: Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]). PATIENTS AND METHODS: Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period. RESULTS: A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300). CONCLUSION: Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

Burden of Chemotherapy-Induced Febrile Neutropenia Hospitalizations in US Clinical Practice, by Use and Patterns of Prophylaxis with Colony-Stimulating Factor.

INTRODUCTION: Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice. METHODS: A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred. RESULTS: Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable. CONCLUSIONS: In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.

Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies.

PURPOSE: Chemotherapy-induced neutropenia (CIN) may increase infection risk for cancer patients; however, there is limited understanding on the quantitative relationships between severity and duration of CIN and infection risk. METHODS: This study combined individual data from adult cancer patients receiving no granulocyte colony-stimulating factor during the first chemotherapy cycle in six trials. We used area over the curve (AOC) of absolute neutrophil count (ANC) time-response curve (below different thresholds) to measure the combined effect of severity and duration of CIN. Time-dependent Cox proportional hazards models quantified the hazard of first infection associated with duration of grade 4 or grade 3/4 CIN and the hazard associated with AOC. RESULTS: We analyzed data from 271 patients who had small cell lung cancer, non-Hodgkin's lymphoma, head and neck cancer, or breast cancer; 63.8 % of the patients had advanced cancer, and 77.5 % received chemotherapy regimens with high risk of febrile neutropenia. In the first cycle, 18.8 % of the patients had infection-related hospitalizations. Each additional day patients had grade 3/4 or grade 4 CIN was associated with 28 % (95 % CI 7, 51 %) and 30 % (95 % CI 10, 54 %) increased risk of infection-related hospitalization, respectively. Each unit increase in AOC (day × 10(9)/L ANC), with threshold of ANC < 0.5 × 10(9)/L, was associated with a significantly increased risk of infection-related hospitalization (hazard ratio 1.98; 95 % CI 1.35, 2.90). CONCLUSIONS: Infection risk increases dramatically with each additional day of grade 3 or 4 CIN. Interventions limiting CIN severity and duration are of critical importance to reduce infection risk in cancer patients receiving chemotherapy.

Trajectory of absolute neutrophil counts in patients treated with pegfilgrastim on the day of chemotherapy versus the day after chemotherapy.

PURPOSE: Risk of infection increases with severity and duration of chemotherapy-induced neutropenia (CIN). Pegfilgrastim is approved for use on the day after chemotherapy to reduce incidence of infection, as manifested by febrile neutropenia (FN), in patients receiving myelosuppressive chemotherapy. In this study, we compared severity and duration of absolute neutrophil count (ANC) suppression in patients who received pegfilgrastim on the same day as chemotherapy versus the next day. METHODS: We combined individual patient data from four Amgen-sponsored clinical trials in which patients with cancer were randomized to receive pegfilgrastim either the same day as chemotherapy or the next day. Severity and duration of ANC suppression were calculated using area over the curve (AOC, the area over the ANC-time response curve and below a given clinical threshold). AOC of ANC and incidences of CIN and FN were compared by day of pegfilgrastim use. RESULTS: The analysis included 95 same-day patients and 97 next-day patients. Despite similar ANC at baseline, ANC at nadir was higher among next-day patients than same-day patients. Mean AOC of ANC (cutoff 0.5 × 10(9)/L) among next-day patients was lower by 0.30 (95 % confidence interval: 0.16, 0.43) 10(9)/L × day than same-day patients in cycle 1. Next-day patients had lower incidences of CIN than same-day patients, but there were no significant differences in incidences of FN. CONCLUSIONS: Patients who received pegfilgrastim the day after chemotherapy had less severe and shorter suppression of ANC than patients who received pegfilgrastim the same day as chemotherapy.

Annual patient and caregiver burden of oncology clinic visits for granulocyte-colony stimulating factor therapy in the US.

OBJECTIVE: Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. METHODS: Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I-III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. RESULTS: Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ∼$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ∼$450 per patient. LIMITATIONS: Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. CONCLUSIONS: The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families.

Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis in US clinical practice.

PURPOSE: Accumulating evidence suggests that not all cancer chemotherapy patients who receive first-cycle pegfilgrastim prophylaxis continue to receive it in subsequent cycles and that these patients may be subsequently at higher risk of febrile neutropenia (FN). Additional evidence from US clinical practice is warranted. METHODS: Data from two US private healthcare claims repositories were employed. The source population comprised adults who received "intermediate-risk" or "high-risk" chemotherapy regimens for solid cancers or non-Hodgkin's lymphoma and first-cycle pegfilgrastim prophylaxis. From the source population, all patients who did not receive second-cycle pegfilgrastim prophylaxis ("comparison patients") were matched (1:1) to those who received it ("pegfilgrastim patients") based on cancer, regimen, and propensity score. Odds ratios (OR) for FN-broad and narrow definitions-during the second chemotherapy cycle were estimated for comparison patients versus pegfilgrastim patients using generalized estimating equations. RESULTS: A total of 2245 comparison patients (5.3 % of source population) were matched to pegfilgrastim patients; cohorts were well-balanced on baseline characteristics. Second-cycle FN incidence proportions for comparison and pegfilgrastim patients were 3.8 versus 2.2 % based on broad definition and 2.6 versus 0.8 % based on narrow definition; corresponding OR were 1.7 (95 % CI 1.2-2.5, p = 0.002) and 3.5 (95 % CI 2.0-6.0, p < 0.001). Results were similar within cancer/regimen-subgroups and were robust when using alternative methods for confounding adjustment. CONCLUSIONS: In this retrospective evaluation of cancer chemotherapy patients who received first-cycle pegfilgrastim prophylaxis in US clinical practice, a clinically relevant minority did not receive second-cycle prophylaxis. Second-cycle FN odds among this subset were significantly higher than they were among those who continued prophylaxis.

Comorbidities among patients with cancer who do and do not develop febrile neutropenia during the first chemotherapy cycle.

Patients receiving myelosuppressive chemotherapy with certain comorbidities are at increased risk of febrile neutropenia. A comprehensive evaluation of febrile neutropenia-related comorbidities across cancers is needed. This study compared comorbidity prevalence among patients with cancer who did and did not develop febrile neutropenia during the first chemotherapy cycle. This case-control study used administrative claims from adult patients with non-Hodgkin lymphoma or breast, lung, colorectal, ovarian, or gastric cancer who received chemotherapy between 2007 and 2012. Each patient who developed febrile neutropenia (case) was matched with up to four patients without febrile neutropenia (controls) by cancer type, metastasis, chemotherapy regimen, age group, and sex. For each comorbidity (identified in the year before chemotherapy began), the adjusted odds ratio (aOR) for febrile neutropenia by cancer type was evaluated using conditional logistic regression models adjusted for potential confounding factors. Of 31,331 eligible patients, 672 developed febrile neutropenia in the first chemotherapy cycle. A total of 3312 febrile neutropenia cases and matched controls were analyzed. Across tumor types, comorbidity prevalence was higher in patients who developed febrile neutropenia than in those without febrile neutropenia. Among patients with breast cancer, osteoarthritis was more prevalent in patients with febrile neutropenia (aOR, 1.85; 95% CI, 1.07 to 3.18). Among patients with non-Hodgkin lymphoma, renal disease was more prevalent in patients with febrile neutropenia (aOR, 2.25; 95% CI, 1.23 to 4.11). Patients who developed febrile neutropenia in the first chemotherapy cycle presented with comorbidities more often than otherwise similar patients who did not develop febrile neutropenia. These findings warrant further investigation and support the inclusion of comorbidities into febrile neutropenia risk models.

Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.

BACKGROUND: Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. METHODS: A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. RESULTS: Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. CONCLUSIONS: In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.

A review of relative dose intensity and survival in patients with metastatic solid tumors.

Studies have shown that in the curative setting patients with cancer receiving chemotherapy at higher relative dose intensity (RDI) had better clinical outcomes than those receiving treatment at lower RDI. However, the impact of RDI in advanced/metastatic disease remains unclear. A review of the literature was performed to evaluate the relationship between RDI and survival in patients with metastatic lung, breast, or ovarian cancer receiving chemotherapy. Few studies attempted to specifically associate RDI with survival in a systematic way. Findings from studies that analyzed overall survival with a prespecified RDI threshold support the emerging perception that maintaining an RDI≥85% has a favorable impact on survival. Nonetheless, these studies were limited by their retrospective nature. More studies are needed to further evaluate the impact of maintaining planned chemotherapy dose intensity on outcomes in metastatic solid tumors.

Presence of valvular calcification predicts the response to cinacalcet: data from the ADVANCE study.

BACKGROUND AND AIM OF THE STUDY: Cardiac valve calcification (CVC) and coronary artery calcification (CAC) appear to be linked pathogenetically, and both are associated with a poor prognosis among patients with chronic kidney disease on dialysis (CKD-5D). Little is known, however, about factors that affect the progression of CVC and CAC. METHODS: A post-hoc analysis was performed of the ADVANCE study to assess whether patients with CVC are more prone to CAC progression, and whether CVC predicts the response to different treatments for secondary hyperparathyroidism. RESULTS: Subjects were randomized to treatment with either cinacalcet and low doses of vitamin D analogs or larger, varying doses of vitamin D. Among 235 subjects, aortic valve or mitral valve calcification was detected in 108 (46%) and 118 (50%), respectively; 69 subjects (29%) had calcification of both valves. CVC was associated both with baseline CAC and CAC progression (p < 0.05). Subjects with aortic valve calcification who were treated with cinacalcet and low doses of vitamin D experienced less progression of CAC than subjects given larger, varying doses of vitamin D (adjusted OR: 0.26; 95% CI: 0.10, 0.64). This effect was greater in subjects with larger CAC burden at baseline. CONCLUSION: The study findings suggest that CVC is a predictor of CAC progression and, potentially, of greater cardiovascular vulnerability. Treatment with cinacalcet combined with low doses of vitamin D slowed the progression of CAC compared to therapy using larger, varying doses of vitamin D.

Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer.

PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is approved as monotherapy for the treatment of metastatic colorectal cancer. We evaluated the association of tumor EGFR expression levels with outcomes in patients with chemorefractory metastatic colorectal cancer. EXPERIMENTAL DESIGN: Two phase II, multicenter, single-arm, open-label studies enrolled chemorefractory patients with tumors expressing low/negative (1-9%/<1%; Low/Negative EGFR study) or high (> or =10%; High EGFR study) levels of EGFR. Patients received panitumumab 6 mg/kg every two weeks until disease progression or intolerance. End points included objective response rate (per response evaluation criteria in solid tumors), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses by tumor KRAS status were carried out. RESULTS: A total of 203 patients (Low/Negative EGFR) and 185 patients (High EGFR) enrolled in the studies. The overall response rate was 5.7% [95% confidence interval (95% CI), 2.6-10.5] in patients with low/negative EGFR and 4.2% (95% CI, 1.6-9.0) in patients with high EGFR; the response rate at week 16 was 4% in both studies (all partial responses). Median PFS times were 8.1 weeks (95% CI, 7.1-12.6), 8.1 weeks (95% CI, 7.4-11.1), and 7.3 weeks (95% CI, 7.1-7.6) in patients with negative, low, and high levels of EGFR expression, respectively. PFS and OS were longer in patients with wild-type KRAS than those with mutant KRAS. As expected, most adverse events were skin related. CONCLUSIONS: These studies confirm previous reports that tumor EGFR expression levels are not associated with efficacy with an anti-EGFR antibody and that anti-EGFR antibody therapy should be limited to those patients whose tumors express wild-type KRAS.

Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone.

BACKGROUND: Identifying predictive biomarkers is important to optimally treat patients. This analysis evaluated the association of K-ras, BRAF, and PIK3CA gene mutations with tumor resistance to panitumumab alone. PATIENTS AND METHODS: From 3 phase II panitumumab metastatic colorectal cancer (mCRC) studies, 62 of 533 patient samples were available. Mutations were identified from genomic DNA by sequencing. RESULTS: Of the 62 samples, 24 (38.7%) harbored a K-ras mutation, and 38 (61.3%) were wild type. In the wild-type K-ras group, 11% of patients had a partial response (PR), 53% had stable disease (SD), and 37% had progressive disease (PD). In the mutant K-ras group, 21% of patients had SD, and 79% of patients had PD; there were no responses. The absence of a K-ras mutation was associated with response to panitumumab (PR vs. SD vs. PD; P = .0028). The hazard ratio for wild-type versus mutant K-ras was 0.4 (95% CI, 0.2-0.7) for progression-free survival and 0.5 (95% CI, 0.3-0.9) for overall survival. Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation. CONCLUSION: These data suggest that patients with mCRC with activating K-ras mutations are less likely to respond to panitumumab alone. The small sample size limits us from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.

Metaplastic breast cancer: clinical significance.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare poorly differentiated breast cancer characterized by coexistence of ductal carcinoma with areas of matrix producing, spindle-cell, sarcomatous, or squamous differentiation; ER/PR/HER2 negativity; and a reputation for poor outcome. METHODS: The Swedish Cancer Institute prospective breast cancer database (> 6500 patients; 1990-2005) has 24 MBC cases that were compared with typical breast cancer cases matched for age, date of diagnosis, stage, and ER/PR/HER2 status. RESULTS: The mean metaplastic primary tumor diameter was 2.5 cm. The histological/nuclear grade was high in 21 of 24 cases. No patient had distant metastasis. ER and/or PR receptor status was negative in all cases. HER2 was negative in 10 of 11 cases tested. EGFR (HER1) was positive in 7 of 7 cases tested. All patients had sentinel and/or axillary lymph node dissection and surgical resection; 18 received chemotherapy and 22 had radiation therapy. Four patients had distant recurrences 5 to 88 months from diagnosis. Five-year survival was 83% (95% confidence interval, 66-100%). Comparison with matched typical breast cancer cases revealed no major significant difference in multidisciplinary treatment patterns, recurrence, or survival. CONCLUSION: MBC is associated with poor prognostic indicators, but outcomes comparable with matched typical breast cancer cases can be achieved with routine aggressive multidisciplinary care. Increased, expression of EGFR (HER1) provides an opportunity for targeted tumor therapy.