ABSTRACT
Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).
ABSTRACT
PURPOSE: Aurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan. METHODS: In this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20-60 mg was administered orally twice per day on days 1-3 and 8-10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD. RESULTS: A total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1-3 and 8-10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer. CONCLUSION: In contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azepines/therapeutic use , Irinotecan/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Cohort Studies , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Young AdultABSTRACT
PURPOSE: Current treatment guidelines for male breast cancer are guided by female-only trials despite data suggesting distinct clinicopathologic differences between sexes. We sought to evaluate whether radiation therapy (RT) after lumpectomy was associated with equivalent survival among men > 70 years of age with stage I, estrogen receptor (ER) positive tumors, as seen in women from the Cancer and Leukemia Group B (CALGB) 9343 trial. METHODS: We performed a retrospective analysis of 752 stage I, ER-positive male breast cancer patients ≥ 70 years who were treated with hormone therapy and surgery, with or without RT, from the National Cancer Database between 2004 and 2014. Patients were categorized based on surgery and RT (lumpectomy alone, lumpectomy with RT, and mastectomy alone). Multivariable Cox proportional hazards regression analysis was used to compare overall survival between treatment groups. RESULTS: Most patients underwent total mastectomy, with only 32.6% treated with lumpectomy. Of those who underwent lumpectomy, 72.7% received adjuvant RT. In multivariate analysis, there was no statistical difference in overall survival when comparing lumpectomy alone and lumpectomy with RT (aHR 0.72 [95% CI 0.38-1.37], p = 0.31) or when comparing lumpectomy (alone or with RT) and mastectomy (aHR 1.28 [95% CI 0.88-1.87], p = 0.20). CONCLUSIONS: In this national sample of elderly men with ER-positive early-stage disease treated with endocrine therapy, there were no significant differences in overall survival when comparing lumpectomy alone and lumpectomy with RT, or lumpectomy (alone or with RT) and mastectomy. These results suggest that less aggressive treatment may be appropriate for a subset of male breast cancer patients.
Subject(s)
Breast Neoplasms , Mastectomy, Segmental , Aged , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Female , Hormones , Humans , Male , Mastectomy , Neoplasm Staging , Radiotherapy, Adjuvant , Retrospective Studies , Survival RateABSTRACT
T-cell large granular lymphocyte (LGL) leukemia is a rare indolent neoplasm primarily treated with immunosuppression. Few therapies and no consensus exist for the optimal treatment of T-cell LGL leukemia refractory to immunosuppressive therapy. Here, we report a case of relapsed/refractory T-cell LGL treated with belinostat. A 57-year-old male presented with lymphocytosis and anemia and was found to have T-cell LGL, requiring frequent packed red blood cell transfusions. He was initially treated with methotrexate with no response after 7 months. He was then switched to cyclosporine and cyclophosphamide and experienced transfusion independence for 42 months before disease relapse. He was then started on belinostat with noted subsequent transfusion independence for greater than 15 months to date and decreased disease involvement on bone marrow biopsy. To our knowledge, this is the first reported case of belinostat use in relapsed/refractory T-cell LGL leukemia which resulted in a durable clinical and biologic response.
Subject(s)
Antineoplastic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Hydroxamic Acids/therapeutic use , Leukemia, Large Granular Lymphocytic/diagnosis , Leukemia, Large Granular Lymphocytic/drug therapy , Sulfonamides/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Biopsy , Drug Resistance, Neoplasm , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Male , Middle Aged , Recurrence , Retreatment , Sulfonamides/pharmacology , Symptom Assessment , Therapeutics , Treatment OutcomeSubject(s)
Prostatic Neoplasms , Recombinational DNA Repair , DNA Repair/genetics , Humans , Male , PlatinumABSTRACT
BACKGROUND: Radiotherapy is used to treat many adolescent and young adult (AYA) and childhood cancer patients and is a risk factor for secondary breast cancer. While premenopausal breast cancer is inherently more aggressive, no studies to date have evaluated the characteristics and breast cancer-specific survival (BCSS) of premenopausal secondary breast cancer after radiotherapy in AYA and childhood cancer survivors. METHODS: Female patients ages 12 to 50 diagnosed with primary breast cancer from 1988 to 2014 (n = 107,751) were obtained from the California Cancer Registry and compared with similar aged patients with secondary breast cancer who were treated with radiotherapy for their primary tumor (n = 1,147) from ages 12 to 39. We examined BCSS using multivariable Cox proportional hazards regression. RESULTS: The secondary breast cancer cohort was more likely to be Hispanic or Black, be 35 to 45 years of age, have earlier stage tumors, be higher grade, have no lymph node involvement, and be hormone receptor negative. All women showed worse BCSS for large tumor size, lymph node involvement, and hormone receptor-negative status. BCSS was worse for women with secondary breast cancer both overall (hazard ratio, 1.98; 95% confidence interval, 1.77-2.23) and in all subgroups considered. Associations were most pronounced in Hispanics, Asian/Pacific Islanders, and younger women, as well as those with earlier stage, lymph node-negative, and hormone receptor-positive disease. CONCLUSIONS: BCSS is significantly decreased among all survivors of childhood and AYA cancer treated with radiotherapy that develop a secondary breast cancer, including women with good prognostic features. IMPACT: Therefore, we may need to consider alternative and even more aggressive treatment in what were considered low-risk populations previously.
Subject(s)
Breast Neoplasms/radiotherapy , Adolescent , Adult , Cancer Survivors , Child , Humans , Middle Aged , Treatment Outcome , Young AdultSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/administration & dosage , Bortezomib/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/analogs & derivatives , Febrile Neutropenia/chemically induced , Female , Humans , Hydroxyurea/administration & dosage , Kaplan-Meier Estimate , Male , Middle Aged , Neoplastic Cells, Circulating , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Progression-Free Survival , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Current treatment guidelines for male breast cancer are predominantly guided by female-only clinical trials. With scarce research, it is unclear whether breast-conserving therapy (BCT) is equivalent to mastectomy in men. We sought to compare overall survival (OS) among male breast cancer patients who underwent BCT versus mastectomy. METHODS: We performed a retrospective analysis of 8445 stage I-II (T1-2 N0-1 M0) male breast cancer patients from the National Cancer Database (2004-2014). Patients were grouped according to surgical and radiation therapy (RT). BCT was defined as partial mastectomy followed by RT. Multivariable and inverse probability of treatment-weighted (IPTW) Cox proportional hazards models were used to compare OS between treatment groups, controlling for demographic and clinicopathologic characteristics. RESULTS: Most patients underwent total mastectomy (61.2%), whereas 18.2% underwent BCT, 12.4% underwent total mastectomy with RT, and 8.2% underwent partial mastectomy alone. In multivariable and IPTW models, partial mastectomy alone, total mastectomy alone, and total mastectomy with RT were associated with worse OS compared with BCT (p < 0.001 all). Ten-year OS was 73.8% for BCT and 56.3, 58.0 and 56.3% for other treatment approaches. Older age, higher T/N stage, histological grade, and triple-negative receptor status were associated with poorer OS (p < 0.05). Subgroup analysis by stage demonstrated similar results. CONCLUSIONS: In this national sample of male breast cancer patients, BCT was associated with greater survival. The underlying mechanisms of this association warrant further study, because more routine adoption of BCT in male breast cancer appears to translate into clinically meaningful improvements in survival.
Subject(s)
Breast Neoplasms, Male/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , Databases, Factual , Mastectomy, Segmental/mortality , Mastectomy/mortality , Aged , Breast Neoplasms, Male/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival RateABSTRACT
Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents.
ABSTRACT
Venous thromboembolism (VTE) is a common complication of malignancy. This is related to the underlying cancer and thrombogenic effects of various therapies. Compared with VTE in patients without malignancies, cancer-associated thrombosis is associated with increased mortality, recurrence, and bleeding while on anticoagulants. These worse outcomes are due to a complex interplay between the underlying cancer, host response, antitumor therapies, and interactions between anticoagulants and cancer drugs. Primary prevention of VTE may decrease morbidity and possibly even improve cancer-related survival, but studies to date have not clearly identified a patient population that might be of most benefit nor consistently shown a survival benefit to anticoagulation.
Subject(s)
Neoplasms/complications , Venous Thromboembolism/complications , Humans , Neoplasms/blood , Survival Analysis , Venous Thromboembolism/physiopathologyABSTRACT
INTRODUCTION: The human multidrug resistance gene ATP-binding cassette B1 (ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anticancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene that may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C-->T, 2677G-->T and 3435C-->T, have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related. METHODS: In this study, 95 individuals representative of the entire ethnic make-up of the USA were compared with 101 individuals from an Ashkenazi-Jewish population. These individuals were analyzed by genomic sequencing and polymerase chain reaction, using restriction fragment length polymorphisms, to calculate their genotype frequencies. RESULTS: A total of 25 SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared with those listed by the National Center for Biotechnological Information. Frequencies of the 1236C-->T and 2677G-->T/A/C SNPs were similar for the US and Ashkenazi populations (64.2 and 60.4%, respectively for 1236C-->T [chi2: 0.30; p < or = 1]; 55.8 and 64.4%, respectively for 2677G-->T/A/C [chi2: 1.49; p < or = 1]), but were different for 3435C-->T (24.2% for the US population and 69.3% for the Ashkenazi population [chi2: 39.927; p < or = 0.001]). The 1236T/ 2677T/3435T haplotype occurred in 23.6% (standard error: 0.013) of the Ashkenazi population. CONCLUSION: The SNP at location 3435C-->T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Ethnicity/genetics , Haplotypes/genetics , Polymorphism, Single Nucleotide/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Genes, MDR/genetics , Genetic Predisposition to Disease , Genotype , Humans , Jews/genetics , Phenotype , Polymerase Chain ReactionABSTRACT
In vitro packaging of plasmid DNA using recombinant SV40 capsid proteins is a potentially useful procedure that overcomes some restrictions of the other SV40 systems such as the requirement for SV40 sequences and the limitation in size of DNA that can be packaged. The in vitro packaging system uses the four SV40 proteins (VP1, VP2, VP3, and agno) or VP1 only. The ability to confer drug resistance by three ABC transporter genes (MDR 1, MRP 1, or MXR) was determined using the surrogate fluorescent substrates rhodamine-123 or calcein AM and their specific inhibitors, or by using specific antibodies to the transporters to detect cell surface expression by fluorescence-activated cell sorter analysis (FACS). A green fluorescent protein plasmid (EGFP-C1) was also used to monitor gene transfer. The packaged plasmids ranged in size from 4.2 to 17.6 kb, and only slightly affected particle size as determined by electron microscopy. When 9.5 kb and larger plasmids were packaged using all SV40 proteins, MDR1 expression was decreased compared to VP1 alone. The size of the 15.2 kb DNA after packaging was the same as the original DNA. Packaging with SV40 capsid proteins in vitro does not require any SV40 sequences. Using either the MDR1 or the GFP gene we could demonstrate enhanced expression when cells were pretreated with phorbol 12-myristate 13-acetate (PMA) at low concentrations. Interferon-gamma did not alter expression. We conclude that in vitro packaging is more flexible then previously realized, permitting packaging of at least 17 kb plasmid DNA without the requirement for any viral sequences. This system combines efficient gene delivery of the SV40 viral vector with the presumed safety of nonviral vectors.