Summary Background NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would ...improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. Methods In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c–3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2 ) with addition of capecitabine (825 mg/m2 oral twice daily days 1–14, 75 mg/m2 docetaxel) or with addition of gemcitabine (1000 mg/m2 days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2 and 600 mg/m2 intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov , number NCT00408408. Findings Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0–5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 95% CI 0·49–0·88; p=0·004) but did not significantly increase disease-free survival (0·80 0·63–1·01; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3–4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 17%; grade 4, 37 6%), hand-foot syndrome (grade 3, 63 11%), and hypertension (grade 3, 60 10%; grade 4, two <1%) and in the non-bevacizumab group were neutropenia (grade 3, 98 16%; grade 4, 36 6%), fatigue (grade 3, 53 9%), and hand-foot syndrome (grade 3, 43 7%). Interpretation The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. Funding National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.
Summary Background Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the ...thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. Methods In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30×109 /L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50×109 /L to 200×109 /L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count ≥50×109 /L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov , numbers NCT00102323 and NCT00102336. Findings A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% 95% CI 23·4–52·8, p=0·0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% 38·7–73·7, p<0·0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0·0001). Patients given romiplostim achieved platelet counts of 50×109 /L or more on a mean of 13·8 (SE 0·9) weeks (mean 12·3 1·2 weeks in splenectomised group vs 15·2 1·2 weeks in non-splenectomised group) compared with 0·8 (0·4) weeks for those given placebo (0·2 0·1 weeks vs 1·3 0·8 weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. Interpretation Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.
The addition of bevacizumab to neoadjuvant combination chemotherapy significantly increased the percentage of patients with a pathological complete response. The effect was stronger in the ...estrogen-receptor–positive subgroup than in the hormone-receptor–negative subgroup.
Neoadjuvant chemotherapy has become established as a reasonable alternative to adjuvant chemotherapy for operable breast cancer, since it can increase the rates of breast-conserving surgery
1
–
3
and decrease the need for complete axillary lymph-node dissection.
4
–
6
Neoadjuvant chemotherapy also offers the potential for rapidly testing regimens that may improve response rates and therefore may be likely to improve the outcomes in patients. Although alterations in neoadjuvant chemotherapy that increase the rates of pathological complete response may not necessarily improve survival,
5
,
7
the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial (ClinicalTrials.gov number, NCT00002707) of neoadjuvant . . .
Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with
loss. Given the predominance ...of
mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas.
Eligible patients whose tumors screened positively for
mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy.
Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with
mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events.
GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive
-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.
Background
NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical ...complications after surgery in patients who did or did not receive bev.
Methods
A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry.
Results
Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test
p
= 0.008), but most were grade 1–2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test
p
= 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test
p
= 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson,
p
= 0.11).
Conclusions
Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.
Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast ...cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.
Introduction:
Despite the availability of many effective agents, multiple myeloma is characterized by repeated cycles of treatment response and relapse, and remains incurable in almost all patients. ...Efforts to optimize treatment are complicated by variation in disease biology and by the combinatorial complexity inherent in assembling, sequencing and administering multi-agent regimens. Determining which strategies provide maximal therapeutic benefit requires deploying a variety of multi-agent regimens in a range of settings and assessing long-term outcomes; information that cannot be readily discerned from clinical trials. Here we present results from a real-world database that comprehensively tracks all treatments and responses in patients with multiple myeloma.
Methods:
Since March 2017, All4Cure has hosted an online platform for patients with multiple myeloma, clinicians and researchers that has been initially focused in the Pacific Northwest. Medical records from consenting patients are collected and information regarding all treatments and responses graphically displayed on their de-identified dashboards. A discussion panel allows for asynchronous communication between members of All4Cure's community of patients, clinicians and researchers (currently numbering over 1600 participants). There is no charge to patients who participate in All4Cure, and clinicians and researchers are neither charged nor paid for their participation. A summarized real-world database describes the lines of therapy that each patient has received, treatment start and stop dates, and responses in accordance with International Myeloma Working Group (IMWG) criteria.
Results:
The overall profile of patients with multiple myeloma enrolled in All4Cure (N=555) was benchmarked against myeloma patients from the National Program of Cancer Registries (NPCR) (diagnosis year 2017; N=25,895). Patients in all 50 States and D.C. were included in the comparison, and those with monoclonal gammopathy of undetermined significance (MGUS) were not considered. Myeloma patients enrolled in All4Cure are younger at diagnosis or start of treatment (median 61 versus between 65 and 69), more likely to be white (90.3% versus 73.5%), and more likely to reside in Washington State (41.2% versus 2%) compared to the NPCR cohort, reflecting participation influenced by geographic location as described above.
After enrollment, All4Cure patients are followed longitudinally throughout the entirety of their disease course, with fewer than 2% having been lost to follow up. To gain insights uniquely available from the All4Cure database and to inform the future direction for our research, we focus our exploratory data analysis on the All4Cure cohort of patients who started treatment in June 2015 or later (N=299). Despite the relatively recent start of the All4Cure database, this timeframe allows up to 6 years of observation following the start of treatment, since the survival rates for the first 1-2 years of treatment are generally very high. Consistent with prior knowledge, increasing age and disease stage are associated with increased morality, as are high-risk cytogenetics such as 17p-, t(4:14) and t(14;16).
We further explored the potential impact of early lines of therapy on long-term disease control. While the current literature is mixed on the merits of aggressive treatments in early lines of therapy in terms of overall survival, insights from our data suggest that more aggressive front-line therapies (such as SCT) are associated with improved disease control over time, although this is evolving with the impact of novel therapies and in particular the use of triplet and now quadruplet induction regimens and adapting treatment to achieve measurable residual disease (MRD) negativity.
Conclusions:
Even with the current limitations regarding the size and representativeness of All4Cure's database, these preliminary results support the validity of this approach for gaining insight into the treatments and outcomes of patients with multiple myeloma in real-world settings.
Blau: Oncopeptides: Other: Oncopeptides is an All4Cure customer. Blau: All4Cure: Current equity holder in publicly-traded company. Richter: Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Richardson: Secura Bio: Consultancy; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.
Abstract
Background Metastatic triple negative breast cancer (mTNBC) is an inherently diverse disease and while molecular classification of mTNBC has assisted in treatment decisions, if based on only ...an initial biopsy, it does not take into account the evolution of metastatic cancer. Characterization of emerging metastases is needed to reveal both new resistance or sensitivity to available therapeutics. The goal of “Intensive Trial of OMics in Cancer (ITOMIC) - Intensive Longitudinal Monitoring in Subjects With Triple-Negative Breast Cancer” (NCT01957514) - was to determine the feasibility of longitudinal collection of patient biopsies that would be subjected to molecular analysis to provide actionable, relevant and timely information to guide treatment decisions.Methods Multiple biopsies were collected longitudinally, including pre- and post-treatment, from 29 mTNBC patients enrolled in the ITOMIC study and subjected to multi-dimensional molecular profiling including WES, WGS, cancer gene panel sequencing, RNA-seq, and proteomics and/or IHC for tumor biomarkers. This information was used to guide iterative, patient- and tumor- individualized treatment recommendations made by a multi-institutional ITOMIC Tumor Board (ITB) and conveyed to each subject’s oncologist.Results Longitudinal biopsy collection was found to be safe. Molecular profiling revealed that 2 of an original 31 enrolled subjects likely had lung cancer rather than mTNBC, supporting the merit of repeated tissue analysis. While the other 29 subjects had all been given a diagnosis of mTNBC before entering the trial, estrogen receptor, progesterone receptor, and/or HER2 were found to be over-expressed in at least one sample for 12 subjects; appearance of receptor positivity suggests targeted therapy may be effective. Tumor evolution in response to the first on-study treatment for most subjects (cisplatin) was revealed by copy number alterations, changes in single nucleotide variants, and insertions/deletions in pre-/post-treatment biopsies. Over the course of the study, the ITB convened 54 times and 39 of 182 recommended treatments were evaluated and accessed through either an existing clinical trial, a single patient IND, approved off label or label indication. While not all ITB treatment recommendations were followed, 24 subjects did receive at least one ITB-recommended drug, frequently as part of a clinical trial. Currently, for 27 subjects (2 withdrew) median survival is ~31 months. There are 4 surviving patients in treatment with a remarkable median survival of >51 months.Conclusion Collection and molecular analysis of multiple biopsies during the course of patient’s disease, shown here to be safe and feasible, provides information vital to appropriate treatment choice and reveals new targets for and resistance to therapy in metastatic TNBC.
Citation Format: Kimberly A Burton, Eric Q Konnick, Sibel Blau, Michael O Dorschner, Julie Gralow, Rahul Parulkar, Elisabeth Mahen, Patricia Spilman, Stephanie Parker, Francis M Senecal, Colin Pritchard, Christopher Szeto, Jing Zhu, Vijayakrishna K Gadi, Stephen C Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Carl Anthony Blau. Multidimensional molecular profiling of repeated metastatic TNBC biopsies in the intensive trial of omics safely guides treatment decisions abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-13.
Background:
Here we describe an online network of patients with cancer, clinicians and researchers, layered on top of a comprehensive real world database of treatments and outcomes, continuously ...updated in near real time, and initially focused on multiple myeloma.
Methods:
Patients with multiple myeloma register at www.all4cure.com and sign HIPAA release forms to provide access to all of their medical records from all of the institutions from which they have received care. From the medical records, a structured dataset of treatments and lab results is extracted by a myeloma-dedicated team for display on each patient's de-identified, personalized dashboard. A discussion panel allows more than 1200 participating patients, clinicians and researchers to post comments or questions regarding each patient's specific circumstances. For each patient, lines of therapy and responses are determined according to IMWG and published criteria (Blood 2015 126: 921-922). Here we report initial results from the treatments and responses among patients with multiple myeloma and plasma cell leukemia.
Results:
A total of 493 patients includes 26 with monoclonal gammopathy of undetermined significance (MGUS), 51 with smoldering myeloma, 408 with multiple myeloma, and 8 with primary plasma cell leukemia. Among patients with multiple myeloma, 42 (10.3%) had antecedent MGUS and/or smoldering myeloma. The average age is 65.6 (+/- 9.7). 50.9% are male and 49.1% are female. 42 states in the U.S. and 8 other countries are represented. Two patients with multiple myeloma had not started treatment by the time of this report. The remaining 414 patients with multiple myeloma or plasma cell leukemia received 1 to 16 lines of therapy. Among the 414 patients that received at least one line of therapy, a remarkable 89 distinct first line therapies were administered. The most common first line therapies were lenalidomide, bortezomib, dexamethasone (n=92), cyclophosphamide, bortezomib, dexamethasone (n=50), lenalidomide, bortezomib, dexamethasone + autologous stem cell transplant + lenalidomide maintenance (n=41), lenalidomide and dexamethasone (n=29), and bortezomib and dexamethasone (n=22). 62 patients received a first line therapy that was not received by any other patient in our database. This variation was attributable to participation in clinical trials, variation in the availability of drugs over time and different geographic locations, and the very large number of distinct combinations associated with multi-agent regimens.
Seventy six percent of patients with multiple myeloma or plasma cell leukemia received a second line of therapy, 52% received a third line of therapy, 34% received a fourth line of therapy, 23% received a fifth line of therapy, and 18% received a sixth line of therapy. We observed a trend toward a decline in favorable responses with successive lines of therapy (Table 1) consistent with previous reports, with a correlation coefficient between the line of therapy and overall response rate of -0.74. Among the 76 patients who received 6 or more lines of therapy (247 lines of therapy in total), only 7 achieved stringent complete responses (sCRs), of which 5 were associated with a CAR-T therapy. Table 1 also shows a trend toward more rapid changes in treatment associated with later lines of therapy. 57 of 493 patients (12%) are deceased.
Conclusions:
Our findings reveal remarkable variation in the treatment of myeloma and provide a potentially valuable resource of up to date and current clinical features, prognosis, treatments, side effects, and outcomes of patients with myeloma in the real world.
Table 1. Summary of lines of therapy and outcomes across 414 patients with multiple myeloma and plasma cell leukemia. The percentages of patients achieving sCR, ≥ PR (overall response rate - ORR), and ≥MR (clinical benefit rate - CBR) are shown for each line of therapy. Also depicted is the interval mortality and the mean and median number of days between the beginning of a line therapy and the beginning of the next line of therapy.
Display omitted
Richter:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy; X4 pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive biotechnologies: Consultancy; Secura bio: Consultancy; Astra Zeneca: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy. Chhun:All4Cure: Current Employment. Zheng:All4Cure: Current Employment. Piboonvaranggoon:All4Cure: Current Employment. Mallick:All4Cure: Current Employment. Wren:All4Cure: Current Employment. Nam:All4Cure: Current Employment. Lopez Barquilla:All4Cure: Current equity holder in private company. Blau:All4Cure: Current equity holder in private company. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Other; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees. Blau:All4Cure: Current Employment, Current equity holder in private company.
Neoadjuvant chemotherapy can increase the rates of breast-conserving surgery in patients with operable breast cancer and is a reasonable alternative to adjuvant chemotherapy. Several trials have ...shown that adding bevacizumab (an antiangiogenic monoclonal antibody against vascular endothelial growth factor A) and the antimetabolites capecitabine and gemcitabine to taxanes can improve outcomes in patients with metastatic breast cancer.This trial investigated whether adding capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide in women with operable human epidermal growth factor receptor 2 (HER2)–negative breast cancer, would increase the rates of pathological complete response in the breast.The pathological response after the addition of bevacizumab to these neoadjuvant chemotherapy regimens also was investigated; this was the primary end point of this study.A total of 1206 women with primary operable HER2-negative breast cancer were randomly assigned to 1 of 3 neoadjuvant chemotherapy regimens(1) docetaxel (100 mg/m of body-surface area), administered on day 1 in 4 cycles every 3 weeks, followed by doxorubicin-cyclophosphamide (60 mg and 600 mg/m, respectively), administered every 3 weeks (docetaxel group); (2) capecitabine (825 mg/m), administered twice daily on days 1 through 14, added to docetaxel (75 mg/m), administered on day 1 in 4 cycles, followed by doxorubicin-cyclophosphamide (docetaxel-capecitabine group); or (3) gemcitabine (1000 mg/m), administered intravenously on days 1 and 8, added to docetaxel (75 mg/m), administered on day 1 in 4 cycles, followed by treatment with doxorubicin-cyclophosphamide for 4 cycles (docetaxel-gemcitabine group). Patients also were randomized to receive or not receive bevacizumab (15 mg per kg of body weight), administered every 3 weeks, with each of the first 6 cycles of chemotherapy.Compared with adding docetaxel therapy alone, the addition of capecitabine or gemcitabine did not significantly increase the rate of pathological complete response in the breast (32.7% with docetaxel, 29.7% with docetaxel-capecitabine, and 31.8% with docetaxel-gemcitabine; P = 0.69). Addition of capecitabine or gemcitabine increased toxic effects, specifically, the hand-foot syndrome, neutropenia, and mucositis. Adding bevacizumab was associated with a significant increase in the rate of pathological complete response in the breast (with and without bevacizumab34.5 vs 28.2%, respectively; P = 0.02). The greatest benefit of adding bevacizumab was found in the patient subgroup with hormone receptor–positive tumors; there was a weaker effect in the hormone receptor–negative subgroup.These findings show that the addition of bevacizumab to neoadjuvant chemotherapy is associated with a small but significant increase in the rate of pathological complete response.
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