Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m2  days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75-H →wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients' cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Changes in the use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in patients with cancer amidst regulatory and reimbursement changes.

PURPOSE: Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions. METHODS: Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation. RESULTS: Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs. CONCLUSION: Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling.

Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine.

We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥ 5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients' primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single-agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54-86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients' cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients' cancers had variants of unknown significance in these pathways. Mutations in PIK3CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients' tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients' cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER-positive, endocrine therapy-pretreated, HER2-negative metastases, are supported by preclinical data showing that sensitivity to 5-fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER-positive, HER2-negative breast cancers may predict for highly durable responses to capecitabine.

Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

BACKGROUND: Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. METHODS: This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. FINDINGS: 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3-4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. INTERPRETATION: A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2-amplified early breast cancer, irrespective of TOP2A status. FUNDING: Sanofi.

Benchmarks for value in cancer care: an analysis of a large commercial population.

PURPOSE: Cancer costs are increasing at an unprecedented rate. Key cost drivers include chemotherapy, hospital admissions/emergency room visits, and aggressive end-of-life care. We sought to evaluate these costs in a commercial payer population in collaboration with consultants from Milliman. PATIENTS AND METHODS: We used a retrospective analysis of Medstat 2007 to evaluate chemotherapy costs and use. Included patients had a cancer diagnosis; received chemotherapy during the evaluation period; had at least 1 day of coverage between January 1 and December 31, 2007 (medical and prescription coverage); was younger than age 70, and had active employment or was the spouse of an active employee. Costs are allowed amounts and are trended until 2009. Admission rates and emergency room visits are reported. Hospice use and chemotherapy during the last 14 and 30 days of life were also evaluated. RESULTS: In this commercial population of 14 million patients, 0.68% had claims for a cancer diagnosis; approximately 22% of those received chemotherapy during the study time period. Patients with cancer receiving chemotherapy averaged $111,000 per year in total medical and pharmacy costs. The average hospitalization rate for any reason was 1 admission/yr. Approximately 40% (or 0.4 admits/year) were identified as being chemotherapy related. Of the 3.5% of patients who died in the hospital, 51% received chemotherapy within 30 days of death. CONCLUSION: Understanding the costs of cancer care offers opportunities to formulate a strategic plan to control cancer costs and maintain quality care. Comprehensive cancer solutions to address the full spectrum of care will facilitate improved quality and patient outcomes.

Real-time reverse linkage using polar body analysis for preimplantation genetic diagnosis in female carriers of de novo mutations.

BACKGROUND: Single cell diagnosis for preimplantation genetic diagnosis (PGD) requires simultaneous analysis of multiple linked polymorphic markers in addition to mutation analysis in order to reduce misdiagnosis. This type of analysis requires building family haplotypes spanning at least two generations. We present three childless couples in whom the female was a de novo mutation carrier in the Duchenne Muscular Dystrophy (DMD), incontinentia pigmenti (IKBKG) or Neurofibromatosis type 2 (NF2) genes, precluding linkage prior to the PGD cycle. We constructed haplotypes based on linked polymorphic markers in these families and performed concurrent diagnosis enabling embryo transfer from the first PGD cycle. METHODS: Informative markers flanking the DMD, IKBKG and NF2 genes were used to construct non-linked haplotypes. Polar bodies 1 (PB1) and 2 (PB2) were biopsied and analyzed to determine allelic association between the mutation and markers in multiplex PCR reactions. RESULTS: For each family, the first PGD cycle allowed the establishment of linked haplotypes based on homozygous PB1 and PB2 analysis; however, no embryos were available for transfer. Subsequent cycles, when performed, confirmed this linkage. A mutation-free child was born to the family affected with DMD and an ongoing pregnancy (32 weeks) was achieved with the carrier of the IKBKG deletion. CONCLUSIONS: PB analysis for reverse linkage in real-time coupled with the PGD cycle is a powerful tool for diagnosis and linkage between markers and de novo mutations for maternal autosomal dominant or X-linked disorders. Simultaneous amplification of multiple informative markers in conjunction with the mutation allows the building of familial haplotypes and accurate PGD analysis.

PGD on a recombinant allele: crossover between the TSC2 gene and 'linked' markers impairs accurate diagnosis.

OBJECTIVE: Accounting for possible recombinations in developing an accurate preimplantation genetic diagnosis (PGD) protocol based on familial haplotypes. METHODS: Haplotypes were constructed from genomic DNA in a family where the male was affected with tuberous sclerosis complex (TSC). Embryos were biopsied at day 3, and single blastomeres were analyzed by multiplex polymerase chain reactions (PCRs) including multiple microsatellite markers and single-cell sequencing. RESULTS: Informative markers used in the initial haplotype analysis, based on the genomic DNA of the parents and affected child, were analyzed in the first PGD cycle. All embryos appeared to show recombination and none were transferred. Prior to the next cycle, the parents of the affected male were included in the haplotype analysis, demonstrating that the affected child had a recombinant allele. In the second PGD cycle, two non-recombinant intragenic single nucleotide polymorphisms (SNPs) were used with the TSC2 mutation and four microsatellite markers for a second PGD cycle. In this cycle two wild-type embryos were transferred, resulting in the birth of a healthy girl carrying the wild-type TSC2 allele. CONCLUSIONS: PGD analysis requires the use of more than one meiosis for constructing accurate haplotypes. Testing for multiple closely linked markers and the familial mutation are necessary to detect recombination events and enable precise diagnosis.

Simultaneous preimplantation genetic diagnosis for Tay-Sachs and Gaucher disease.

Preimplantation genetic diagnosis (PGD) for single gene defects is described for a family in which each parent is a carrier of both Tay-Sachs (TS) and Gaucher disease (GD). A multiplex fluorescent polymerase chain reaction protocol was developed that simultaneously amplified all four familial mutations and 10 informative microsatellite markers. In one PGD cycle, seven blastomeres were analysed, reaching a conclusive diagnosis in six out of seven embryos for TS and in five out of seven embryos for GD. Of the six diagnosed embryos, one was wild type for both TS and GD, and three were wild type for GD and carriers of TS. Two remaining embryos were compound heterozygotes for TS. Two transferable embryos developed into blastocysts (wt/wt and wt GD/carrier TS) and both were transferred on day 5. This single cycle of PGD resulted in a healthy live child. Allele drop-out (ADO) was observed in three of 34 reactions, yielding an 8% ADO rate. The occurrence of ADO in single cell analysis and undetected recombination events are primary causes of misdiagnosis in PGD and emphasize the need to use multiple polymorphic markers. So far as is known, this is the first report of concomitant PGD for two frequent Ashkenazi Jewish recessive disorders.

Adjuvant chemotherapy with doxorubicin and cyclophosphamide in women with rapidly proliferating node-negative breast cancer.

This prospective clinical trial was designed to assess the impact of adjuvant chemotherapy in women with rapidly proliferating node-negative breast cancer. This group has been predicted to have a 5-year disease-free survival (DFS) of 70% without adjuvant chemotherapy. In this study, 449 women with rapidly proliferating breast cancer (91% measured by S-phase fraction and 9% by histochemistry) received adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC) plus tamoxifen for estrogen receptor-positive or progesterone receptor-positive cancer. The 5-year DFS was 90% (+/- 2%) and the 5-year overall survival was 94% (+/- 1%). At a median follow-up of 62 months, the strategy of administering 6 cycles of AC to women with T2 N0 cancer and 3 cycles in those with smaller T1 N0 cancers appeared to eliminate tumor size as a potential prognostic factor. Adjuvant chemotherapy with AC appears effective in reducing recurrence rates for women with rapidly proliferating node-negative breast cancer.