Publications by authors named "William M Sikov"

32 Publications

Factors Associated with Nodal Pathologic Complete Response Among Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Results of CALGB 40601 (HER2+) and 40603 (Triple-Negative) (Alliance).

Ann Surg Oncol 2021 Apr 5. Epub 2021 Apr 5.

Department of Surgery, Division of Surgical Oncology, Yale Cancer Center, New Haven, CT, USA.

Background: De-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) requires careful patient selection. We seek to determine predictors of nodal pathologic complete response (ypN0) among patients treated on CALGB 40601 or 40603, which tested NAC regimens in HER2+ and triple-negative breast cancer (TNBC), respectively.

Patients And Methods: A total of 760 patients with stage II-III HER2+ or TNBC were analyzed. Those who had axillary surgery before NAC (N = 122), or who had missing pretreatment clinical nodal status (cN) (N = 58) or ypN status (N = 41) were excluded. The proportion of patients with ypN0 disease was estimated for those with and without breast pathologic complete response (pCR) according to pretreatment nodal status.

Results: In 539 patients, the overall ypN0 rate was 76.3% (411/539) to 93.2% (245/263) in patients with breast pCR and 60.1% (166/276) with residual breast disease (RD) (P < 0.0001). For patients who were cN0 pretreatment, the ypN0 rate was 88.8% (214/241), 96.3% (104/108) with breast pCR, and 82.7% (110/133) with RD. For patients who were cN1, 66.2% (157/237) converted to ypN0, 91.7% (111/121) with breast pCR and 39.7% (46/116) with RD. For patients who were cN2/3, 65.6% (40/61) converted to ypN0, 88.2% (30/34) with breast pCR and 37.0% (10/27) with RD. On multivariable analysis, only pretreatment clinical nodal status and breast pCR/RD were associated with ypN0 status (both P < 0.0001).

Conclusions: Breast pCR and pretreatment nodal status are predictive of ypN0 axillary nodal involvement, with < 5% residual nodal disease among cN0 patients who experience breast pCR. These findings support the incorporation of axillary surgery de-escalation strategies into NAC trials.
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http://dx.doi.org/10.1245/s10434-021-09897-wDOI Listing
April 2021

Cryoablation and Immunotherapy for Breast Cancer: Overview and Rationale for Combined Therapy.

Radiol Imaging Cancer 2021 Mar 26;3(2):e200134. Epub 2021 Feb 26.

Department of Diagnostic Imaging, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (H.C.R.T., R.C.W.); Department of Diagnostic Imaging, Women and Infants Hospital of Rhode Island, Providence, RI (R.C.W.); Program in Women's Oncology, Warren Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI (W.M.S.); and Department of Diagnostic Radiology, Wayne State University, Ascension Providence Rochester Hospital, Rochester Hills, Mich (P.J.L.).

Cryoablation is a well-tolerated outpatient procedure that has been used to treat metastatic sites as well as small breast cancers in patients who are considered poor candidates for surgery. Recent studies suggest that cell disruption caused by cryoablation may increase the expression and immunogenicity of tumor neoantigens, which could enhance the ability of the immune system to recognize and attack cancer cells at both local and distant sites. Such an approach might broaden the role of immunotherapy for the treatment of breast cancer, which has previously demonstrated limited response to these agents, likely owing to the modest immunogenicity of most breast cancer subtypes. If cryoablation can induce a systemic tumor-specific response, it could enhance tumor susceptibility to immunotherapy agents. This review briefly summarizes the necessary components for generating an immune response against tumor cells, reviews the tumor microenvironment of breast cancer, describes the rationale for and limitations of immune checkpoint inhibition, highlights the potential for cryoablation to induce a systemic tumor-specific immune response, and describes the rationale for combining cryoablation and immune checkpoint inhibitors for the treatment of breast cancer. Ablation Techniques, Breast, Neoplasms-Primary, Percutaneous, Tumor Microenvironment, Tumor Response, Ultrasonography © RSNA, 2021.
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http://dx.doi.org/10.1148/rycan.2021200134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011444PMC
March 2021

Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Apr;7(4):603-608

The University of Texas MD Anderson Cancer Center, Houston.

Importance: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood.

Objective: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC.

Design, Setting, And Participants: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019.

Interventions: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib.

Main Outcomes And Measures: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR.

Results: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin.

Conclusions And Relevance: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC.

Trial Registration: ClinicalTrials.gov Identifier: NCT02032277.
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http://dx.doi.org/10.1001/jamaoncol.2020.7310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893540PMC
April 2021

Breast Conservation After Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: Surgical Results From the BrighTNess Randomized Clinical Trial.

JAMA Surg 2020 03 18;155(3):e195410. Epub 2020 Mar 18.

Department of Breast Surgery, Helios Klinikum Berlin-Buch, Berlin, Germany.

Importance: Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer.

Objectives: To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC).

Design, Setting, And Participants: This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019.

Interventions: Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide.

Main Outcomes And Measures: Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed.

Results: Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38).

Conclusions And Relevance: This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT02032277.
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http://dx.doi.org/10.1001/jamasurg.2019.5410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990971PMC
March 2020

Early assessment with magnetic resonance imaging for prediction of pathologic response to neoadjuvant chemotherapy in triple-negative breast cancer: Results from the phase III BrighTNess trial.

Eur J Surg Oncol 2020 02 5;46(2):223-228. Epub 2019 Oct 5.

Helios Klinikum Berlin-Buch, Berlin, Germany.

Introduction: The ability of breast magnetic resonance imaging (MRI) to predict pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) varies across biological subtypes. We sought to determine how well breast MRI findings following initial treatment on the phase III BrighTNess trial correlated with pCR in patients with triple negative breast cancer (TNBC).

Methods: Baseline and mid-treatment imaging and pathologic response data were available in 519 patients with stage II-III TNBC who underwent NST as per protocol. MRI complete response (mCR) was defined as disappearance of all target lesion(s) and MRI partial response (mPR) as a ≥50% reduction in the largest tumor diameter.

Results: Overall, mCR was demonstrated in 116 patients (22%), whereas 166 (32%) had mPR and 237 (46%) had stable/progressive disease (SD/PD). The positive predictive value (PPV), negative predictive value, and overall accuracy of the mid-treatment MRI for pCR were 78%, 56%, and 61%, respectively; accuracy did not differ significantly between gBRCA mutation carriers and non-carriers (52% vs. 63%, p = 0.10). When compared to patients with SD/PD, those with mPR or mCR were 3.35-fold (95% CI 2.07-5.41) more likely to have pCR at surgery. MRI response during NST was significantly associated with eligibility for breast-conserving surgery following completion of treatment (93.1% for mCR vs. 81.6% for SD/PD, p < 0.001).

Conclusions: Complete response on mid-treatment MRI in the BrighTNess trial had a PPV of 78% for demonstration of pCR after completion of NST in TNBC. However, a substantial proportion of patients with mPR or SD/PD also achieved a pCR.

Clinical Trial Registration: NCT02032277.
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http://dx.doi.org/10.1016/j.ejso.2019.10.002DOI Listing
February 2020

Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)-Positive Breast Cancer.

JAMA Netw Open 2019 04 5;2(4):e192561. Epub 2019 Apr 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Importance: There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer.

Objective: To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy.

Design, Setting, And Participants: In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019.

Main Outcomes And Measures: Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting.

Results: In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002).

Conclusions And Relevance: A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481453PMC
April 2019

Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.

Lancet Oncol 2018 04 28;19(4):497-509. Epub 2018 Feb 28.

National Surgical Adjuvant Breast and Bowel Project Foundation, Pittsburgh, PA, USA; Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA.

Background: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer.

Methods: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277.

Findings: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]).

Interpretation: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S1470-2045(18)30111-6DOI Listing
April 2018

Prechemotherapy Education: Reducing Patient Anxiety Through Nurse-Led Teaching Sessions
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Clin J Oncol Nurs 2018 02;22(1):76-82

Background: Patients with cancer experience stress surrounding diagnosis and treatment. Many cancer centers employ a nurse-led education session to alleviate patient anxiety and confusion.
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Objectives: The goal was to evaluate the effect of a nurse-led chemotherapy teaching session on patients' knowledge, anxiety, and preparedness for 
cancer-directed therapy.
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Methods: After discussing treatment with their oncologist, participants completed a survey assessing their perceived understanding of various treatment topics. After, they underwent a teaching session with an oncology nurse. The survey was readministered when patients returned for their first and second treatment cycles.
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Findings: Significant increases were observed in patients' understanding of their treatment schedule, potential adverse effects, and antiemetic medication regimen by the first cycle of therapy and a reduction in treatment-related anxiety by the second cycle of therapy.
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http://dx.doi.org/10.1188/18.CJON.76-82DOI Listing
February 2018

Which patients with early-stage triple-negative breast cancer should receive a platinum?

Authors:
William M Sikov

Clin Adv Hematol Oncol 2017 Jul;15(7):510-514

Breast Health Center, Women and Infants Hospital of Rhode Island, and Warren Alpert Medical School of Brown University, Providence, Rhode Island.

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July 2017

A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I.

Support Care Cancer 2017 11 27;25(11):3407-3416. Epub 2017 May 27.

Department of Oncology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.

Purpose: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS.

Methods: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN.

Results: Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02).

Conclusions: Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.
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http://dx.doi.org/10.1007/s00520-017-3760-2DOI Listing
November 2017

Informed consent in oncology clinical trials: A Brown University Oncology Research Group prospective cross-sectional pilot study.

PLoS One 2017 24;12(2):e0172957. Epub 2017 Feb 24.

The Brown University Oncology Research Group, Providence, Rhode Island, United States of America.

Background: Informed consent forms (ICFs) for oncology clinical trials have grown increasingly longer and more complex. We evaluated objective understanding of critical components of informed consent among patients enrolling in contemporary trials of conventional or novel biologic/targeted therapies.

Methods: We evaluated ICFs for cancer clinical trials for length and readability, and patients registered on those studies were asked to complete a validated 14-question survey assessing their understanding of key characteristics of the trial. Mean scores were compared in groups defined by trial and patient characteristics.

Results: Fifty patients, of whom half participated in trials of immunotherapy or biologic/targeted agents and half in trials of conventional therapy, completed the survey. On average, ICFs for industry-originated trials (N = 9 trials) were significantly longer (P < .0001) and had lower Flesch ease-of-reading scores (P = .003) than investigator-initiated trials (N = 11). At least 80% of patients incorrectly responded to three key questions which addressed the experimental nature of their trial therapy, its purported efficacy and potential risks relative to alternative treatments. The mean objective understanding score was 76.9±8.8, but it was statistically significantly lower for patients who had not completed high school (P = .011). The scores did not differ significantly by type of cancer therapy (P = .12) or trial sponsor (P = .38).

Conclusions: Many participants enrolled on cancer trials had poor understanding of essential elements of their trial. In order to ensure true informed consent, innovative approaches, such as expanded in-person counseling adapted to the patient's education level or cultural characteristics should be evaluated across socio-demographic groups.

Trial Registration: Clinicaltrials.gov NCT01772511.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325585PMC
August 2017

Feasibility Assessment of Patient Reporting of Symptomatic Adverse Events in Multicenter Cancer Clinical Trials.

JAMA Oncol 2017 Aug;3(8):1043-1050

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: In cancer clinical trials, symptomatic adverse events (AEs), such as nausea, are reported by investigators rather than by patients. There is increasing interest to collect symptomatic AE data via patient-reported outcome (PRO) questionnaires, but it is unclear whether it is feasible to implement this approach in multicenter trials.

Objective: To examine whether patients are willing and able to report their symptomatic AEs in multicenter trials.

Design, Setting, And Participants: A total of 361 consecutive patients enrolled in any 1 of 9 US multicenter cancer treatment trials were invited to self-report 13 common symptomatic AEs using a PRO adaptation of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) via tablet computers at 5 successive clinic visits. Patient adherence was tracked with reasons for missed self-reports. Agreement with clinician AE reports was analyzed with weighted κ statistics. Patient and investigator perspectives were elicited by survey. The study was conducted from March 15, 2007, to August 11, 2011. Data analysis was performed from August 9, 2013, to March 21, 2014.

Results: Of the 361 patients invited to participate, 285 individuals enrolled, with a median age of 57 years (range, 24-88), 202 (74.3%) female, 241 (85.5%) white, 73 (26.8%) with a high school education or less, and 176 (64.7%) who reported regular internet use (denominators varied owing to missing data). Across all patients and trials, there were 1280 visits during which patients had an opportunity to self-report (ie, patients were alive and enrolled in a treatment trial at the time of the visit). Self-reports were completed at 1202 visits (93.9% overall adherence). Adherence was highest at baseline and declined over time (visit 1, 100%; visit 2, 96%; visit 3, 95%; visit 4, 91%; and visit 5, 85%). Reasons for missing PROs included institutional errors in 27 of 48 (56.3%) of the cases (eg, staff forgetting to bring computers to patients at visits), patients feeling "too ill" in 8 (16.7%), patient refusal in 8 (16.7%), and internet connectivity problems in 5 (10.4%). Patient-investigator CTCAE agreement was moderate or worse for most symptoms (most κ < 0.05), with investigators reporting fewer AEs than patients across symptoms. Most patients believed that the system was easy to use (234 [93.2%]) and useful (230 [93.1%]), and investigators thought that the patient-reported AEs were useful (133 [94.3%]) and accurate (119 [83.2%]).

Conclusions And Relevance: Participants in multicenter cancer trials are willing and able to report their own symptomatic AEs at most clinic visits and report more AEs than investigators. This approach may improve the precision of AE reporting in cancer trials.
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http://dx.doi.org/10.1001/jamaoncol.2016.6749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553624PMC
August 2017

Axillary Management of Stage II/III Breast Cancer in Patients Treated with Neoadjuvant Systemic Therapy: Results of CALGB 40601 (HER2-Positive) and CALGB 40603 (Triple-Negative).

J Am Coll Surg 2017 Apr 13;224(4):688-694. Epub 2017 Jan 13.

Department of Surgery, Brigham and Women's Hospital, Boston, MA.

Background: Management of the axilla in stage II/III breast cancer undergoing neoadjuvant systemic therapy (NST) is controversial. To understand current patterns of care, we collected axillary data from 2 NST trials: HER2-positive (Cancer and Leukemia Group B [CALGB] 40601) and triple-negative (CALGB 40603).

Study Design: Axillary evaluation pre- and post-NST was per the treating surgeon and could include sentinel node biopsy. Post-NST, node-positive patients were recommended to undergo axillary lymph node dissection (ALND). We report pre-NST histopathologic nodal evaluation and post-NST axillary surgical procedures with correlation to clinical and pathologic nodal status.

Results: Seven hundred and forty-two patients were treated, 704 had complete nodal data pre-NST and post-NST. Pre-NST, 422 (60%) of 704 patients underwent at least 1 procedure for axillary node evaluation (total of 468 procedures): fine needle aspiration (n = 234; 74% positive), core needle biopsy (n = 138; 72% positive), and sentinel node biopsy (n = 96; 33% positive). Pre-NST, 304 patients were considered node-positive. Post-NST, 304 of 704 patients (43%) underwent sentinel node biopsy; 44 were positive and 259 were negative (29 and 36 patients, respectively, had subsequent ALND). Three hundred and ninety-one (56%) patients went directly to post-NST ALND and 9 (1%) pre-NST node-positive patients had no post-NST axillary procedure. Post-NST, 170 (24%) of the 704 patients had residual axillary disease. Agreement between post-NST clinical and radiologic staging and post-NST histologic staging was strongest for node-negative (81%) and weaker for node-positive (N1 31%, N2 29%), with more than half of the clinically node-positive patients found to be pathologic negative (p < 0.001).

Conclusions: Our results suggest there is no widely accepted standard for axillary nodal evaluation pre-NST. Post-NST staging was highly concordant in patients with N0 disease, but poorly so in node-positive disease. Accurate methods are needed to identify post-NST patients without residual axillary disease to potentially spare ALND.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5616181PMC
April 2017

Systemic Therapies for Nonmetastatic Breast Cancer: The Role of Neoadjuvant and Adjuvant Chemotherapy and the Use of Endocrine Therapy.

Clin Obstet Gynecol 2016 12;59(4):756-771

*Dana-Farber Cancer Institute †Harvard Medical School ‡Massachusetts General Hospital Cancer Center, Boston, Massachusetts §Program in Women's Oncology, Women and Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, Rhode Island.

Breast cancer is a heterogenous disease, comprised of at least 3 major subtypes: hormone receptor-positive/HER2-(HR+), HER2+, and HR-/HER2-(triple negative) breast cancers. The medical management of each subype is distinct. In this article, we review contemporary data supporting the use of chemotherapy, endocrine therapy and biologic therapies, especially HER2-directed agents, in the adjuvant and neoadjuvant setting in patients with newly diagnosed nonmetastatic (stage I-III) breast cancer.
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http://dx.doi.org/10.1097/GRF.0000000000000237DOI Listing
December 2016

Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II-III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance).

Breast Cancer Res Treat 2016 11 4;160(2):297-304. Epub 2016 Oct 4.

Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601).

Methods: The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR).

Results: Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not.

Conclusions: Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed.
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http://dx.doi.org/10.1007/s10549-016-4006-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189982PMC
November 2016

Impact of race, ethnicity, and BMI on achievement of pathologic complete response following neoadjuvant chemotherapy for breast cancer: a pooled analysis of four prospective Alliance clinical trials (A151426).

Breast Cancer Res Treat 2016 08 22;159(1):109-18. Epub 2016 Jul 22.

Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

Previous studies demonstrated poor response to neoadjuvant systemic therapy (NST) for breast cancer among black women and women who are overweight or obese, but this may be due to chemotherapy underdosing. We assessed associations of race, ethnicity, and body mass index (BMI) with pathologic complete response (pCR) in clinical trial populations. 1797 women enrolled in four NST trials (CALGB 40601, 40603; ACOSOG Z1041, Z1071) were included. Tumor subtypes were defined by estrogen receptor (ER) and HER2 status. Logistic regression generated odds ratios (OR) and 95 % confidence intervals (CI) for the associations of race, ethnicity, and BMI with in-breast pCR adjusting for subtype, study arm, lymph node status, tumor size, and tumor grade. 253 (14.1 %) were black, 199 (11.1 %) Hispanic, 520 (28.9 %) overweight, and 743 (41.4 %) obese. Compared to whites, Blacks and Hispanics were more likely to be obese and Blacks were more likely to have triple-negative cancer. pCR rates differed significantly by tumor subtype. In multivariate analyses, neither race (black vs white: OR 1.18, 95 % CI 0.85-1.62) nor ethnicity (Hispanic vs non-Hispanic; OR 1.30, 95 % CI 0.67-2.53) were significant predictors of pCR overall or by subtype. Overweight and obese women had lower pCR rates in ER+/HER2+, but higher pCR rates in ER-/HER2+ cancers. There was no difference in pCR according to race or ethnicity. Overall, there was no major difference in pCR rates by BMI. These findings suggest that pCR with optimally dosed NST is a function of tumor, rather than patient, biology.
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http://dx.doi.org/10.1007/s10549-016-3918-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011019PMC
August 2016

Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

BMC Cancer 2016 Apr 18;16:274. Epub 2016 Apr 18.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.

Background: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.

Methods: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.

Results: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

Conclusions: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
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http://dx.doi.org/10.1186/s12885-016-2302-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835834PMC
April 2016

Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015.

Semin Radiat Oncol 2016 Jan 4;26(1):59-70. Epub 2015 Sep 4.

Program in Women׳s Oncology, Breast Health Center, Women and Infants Hospital of Rhode Island and Alpert Medical School of Brown University, Providence, RI. Electronic address:

Standard management of early stage and advanced breast cancer has been improved over the past few years by knowledge gained about the biology of the disease, results from a number of eagerly anticipated clinical trials and the development of novel agents that offer our patients options for improved outcomes or reduced toxicity or both. This review highlights recent major developments affecting the systemic therapy of breast cancer, broken down by clinically relevant patient subgroups and disease stage, and briefly discusses some of the ongoing controversies in the treatment of breast cancer and promising therapies on the horizon.
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http://dx.doi.org/10.1016/j.semradonc.2015.09.005DOI Listing
January 2016

How high a bar to change neoadjuvant therapy for triple-negative breast cancer?

J Comp Eff Res 2015 Aug;4(4):293-6

Program in Women's Oncology, Women & Infants Hospital of Rhode Island & Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA.

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http://dx.doi.org/10.2217/cer.15.29DOI Listing
August 2015

Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: surgical results from CALGB 40603 (Alliance).

Ann Surg 2015 Sep;262(3):434-9; discussion 438-9

*Department of Surgery, Brigham and Women's Hospital, Boston, MA †Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC ‡Department of Medical Oncology Women and Infants Hospital and Alpert Medical School of Brown University, Providence, RI §Alliance Statistics and Data Center, MD Anderson Cancer Center, Houston, TX ¶Department of Medical Oncology, Maine Center for Cancer Medicine, Scarborough, ME ∥Department of Medical Oncology, City of Hope Medical Center, Los Angeles, CA **Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY ††Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and ‡‡Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Objective: To assess the efficacy of neoadjuvant systemic therapy (NST) at increasing the rate of successful breast-conserving therapy (BCT) in triple negative breast cancer.

Background: Inducing tumor regression to permit BCT is often cited to support administration of NST. To quantify this benefit, we conducted a surgical companion study to CALGB40603, a randomized phase II, 2×2 factorial trial of neoadjuvant paclitaxel ± carboplatin ± bevacizumab (B) followed by doxorubicin plus cyclophosphamide ± B in stage II-III triple negative breast cancer.

Methods: Before and after NST, treating surgeons evaluated BCT candidacy by clinico-radiographic criteria; surgery performed was at surgeon and patient discretion. We measured (1) conversion rates from BCT-ineligible to BCT-eligible, (2) surgical choices in BCT candidates, and (3) rates of successful BCT with tumor-free margins.

Results: Four hundred four patients were assessable for surgical outcomes. Two hundred nineteen (54%) were BCT candidates before NST. One hundred ninety-seven (90%) remained BCT candidates after NST, of whom 138 (70%) chose BCT, which was successful in 130 (94%). Of 185 (46%) who were not BCT candidates before NST, 78 (42%) converted to candidates with NST. Of these, 53 (68%) chose BCT with a 91% (48/53) success rate. The overall BCT-eligibility rate rose from 54% to 68% (275/404) with NST. Addition of carboplatin, B, or both increased conversion rates.

Conclusions: This is the first study to document prospectively a 42% conversion rate from BCT-ineligible to BCT-eligible, resulting in a 14% absolute increase in BCT eligibility. BCT was successful in 93% of patients who opted for it, but 31% of BCT-eligible patients still chose mastectomy.
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http://dx.doi.org/10.1097/SLA.0000000000001417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710511PMC
September 2015

I will recommend a clinical trial-if I can.

Authors:
William M Sikov

Am Soc Clin Oncol Educ Book 2015 :44-6

From the Program in Women's Oncology, Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, Rhode Island.

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http://dx.doi.org/10.14694/EdBook_AM.2015.35.44DOI Listing
February 2016

Relevance of pCR in breast cancer trials.

Authors:
William M Sikov

Oncology (Williston Park) 2014 Oct;28(10):884, 886

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October 2014

Assessing the role of platinum agents in aggressive breast cancers.

Authors:
William M Sikov

Curr Oncol Rep 2015 Feb;17(2)

Women and Infants Hospital, Breast Health Center, 101 Dudley Street, Providence, RI, 02905, USA,

As anticipated by their structure and mechanism of action, platinum analogs exhibit clinically significant antitumor activity in the more aggressive forms of breast cancer, both alone and in combination with other cytotoxic agents and targeted therapies. In early-stage human epidermal growth factor receptor-2 (HER2)-positive breast cancer, the administration of carboplatin together with a taxane (usually docetaxel) and trastuzumab (and pertuzumab in the neoadjuvant setting) is a standard of care regimen. In BRCA1 mutation carriers, neoadjuvant treatment with single-agent cisplatin results in a high pathologic complete response (pCR) rate. In both BRCA-mutated and sporadic triple-negative breast cancer, the addition of carboplatin to neoadjuvant chemotherapy significantly increases pCR rates. Despite these encouraging results, many questions remain about the role of platinum analogs in these patient populations, including their optimal doses and schedules, and utility in patients with advanced stage disease. A number of these questions are addressed by ongoing trials.
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http://dx.doi.org/10.1007/s11912-014-0428-7DOI Listing
February 2015

Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma.

Br J Haematol 2015 May 22;169(3):352-5. Epub 2015 Jan 22.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20-negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V-EPOCH) in three patients with PBL; two were HIV-positive and one was HIV-negative. All three patients obtained a durable complete response to V-EPOCH with survival times of 24, 18 and 12 months respectively.
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http://dx.doi.org/10.1111/bjh.13300DOI Listing
May 2015

Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance).

J Clin Oncol 2015 Jan 4;33(1):13-21. Epub 2014 Aug 4.

William M. Sikov, Miriam Hospital and Alpert Medical School of Brown University, Providence, RI; Donald A. Berry, University of Texas MD Anderson Cancer Center, Houston, TX; Charles M. Perou and Lisa A. Carey, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill; Constance T. Cirrincione, Alliance Statistical Center, Durham; Charles S. Kuzma, Southeast Cancer Control Consortium, Winston-Salem, NC; Baljit Singh, New York University Medical Center; Elisa R. Port, Mount Sinai Medical Center; Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; Sara M. Tolaney, Mehra Golshan, Jennifer R. Bellon, and Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA; Timothy J. Pluard, Washington University-St Louis Medical Center, St Louis, MO; George Somlo, City of Hope Comprehensive Cancer Center, Duarte; Deborah Collyar, Patient Advocates in Research, Danville, CA; and Olwen M. Hahn, University of Chicago Medical Center, Chicago, IL.

Purpose: One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab.

Patients And Methods: Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed.

Results: Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated.

Conclusion: In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.
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http://dx.doi.org/10.1200/JCO.2014.57.0572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268249PMC
January 2015

Dual HER2-targeting without chemotherapy and estrogen deprivation in the neoadjuvant setting.

Authors:
William M Sikov

Gland Surg 2014 Feb;3(1):81-4

Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Trastuzumab has had a major impact on outcomes in HER2-positive breast cancer, but innate or acquired resistance to it is recognized as a problem that can limit its effectiveness. Given its locus of action, the oral tyrosine kinase inhibitor lapatinib would be expected to counteract many of the proposed mechanisms of trastuzumab resistance. It has demonstrated activity in trastuzumab-resistant patients, and neoadjuvant studies in HER2+ patients have demonstrated higher pathologic complete response (pCR) rates with the addition of lapatinib to trastuzumab and chemotherapy. TBCRC006 was a phase II neoadjuvant trial that studied the efficacy of the lapatinib and trastuzumab combination without concurrent chemotherapy, but with estrogen deprivation therapy in ER+ patients. In 65 patients with T2-3 HER2+ cancers, the overall pCR rate was 27%, including 36% in ER-tumors. A total 54% of ER+/HER2+ patients had either a pCR or were downstaged to T <1 cm. Correlative studies on tissue obtained prior to and during neoadjuvant therapy are underway. These results suggest that a significant fraction of HER2+ patients will respond to dual HER2-targeted therapy without cytotoxic chemotherapy, and that antihormonal therapy to block ER/HER2 'crosstalk' may be necessary to achieve optimal responses in ER+/HER2+ patients.
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http://dx.doi.org/10.3978/j.issn.2227-684X.2013.09.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115768PMC
February 2014

Neoadjuvant, anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative, early-stage breast cancer: a multicentric analysis of feasibility and rates of pathologic complete response.

Chemotherapy 2013 13;59(5):387-94. Epub 2014 May 13.

Women's Department, West-German Cancer Center, Comprehensive Cancer Center, University Hospital of Essen, Essen, Germany.

Background: Triple-negative breast cancer (TNBC) attracts a disproportionate share of intensive research because of its poor prognosis. Standard anthracycline- and taxane-based regimens still yield an unsatisfactorily low rate of pathologic complete response (pCR). The pCR rate is a recognized surrogate marker for good long-term survival.

Methods: A multicentric, retrospective study was conducted including all patients not willing to undergo or not suitable for an anthracycline-based regimen. Six cycles of docetaxel 75 mg/m(2) and carboplatin AUC 6 q3w were administered. The primary endpoint was pCR (ypT0/ypTis + ypN0) and near-pCR (≤5 mm residual disease). The secondary endpoint was feasibility (CTCAE version 4.03 criteria) and adherence to treatment.

Results: Six cycles of carboplatin AUC 6 and docetaxel 75 mg/m(2) resulted in a high pCR rate of 50% and a combined pCR/near-pCR rate of 70%. Grade 3 and 4 toxicities were rare events and 28 of 30 (93%) patients completed all 6 cycles. No toxicity-related treatment discontinuation and no febrile neutropenia were registered.

Conclusion: This chemotherapy regimen provides a highly effective and feasible strategy for patients not willing to receive or not suitable for an anthracycline-based treatment (cardiac ejection fraction <65% or age >65 years). Combinations of platinum compounds with taxanes and anthracyclines may be also desirable in TNBC.
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http://dx.doi.org/10.1159/000362756DOI Listing
January 2015

Adjuvant chemotherapy in T1a/bN0 HER2-positive or triple-negative breast cancers: application and outcomes.

Breast 2013 Oct 13;22(5):793-8. Epub 2013 Mar 13.

The Warren Alpert Medical School of Brown University, Providence, RI 02912, USA; The Cancer Center at Memorial Hospital of Rhode Island, 111 Brewster St., Pawtucket, RI 02860, USA.

We assessed practice patterns and the impact of systemic adjuvant therapy on human epidermal growth factor receptor 2 (HER2)-positive or triple-negative, node-negative breast cancers up to 10 mm in size. Records of 161 patients identified among 1415 cases diagnosed in our institutions between 2000 and 2010 were assessed for factors associated with recommendation for chemotherapy and survival outcomes. Adjuvant chemotherapy was recommended in 53% of patients, more commonly in patients with younger age, stage T1b, high grade, HER2+/ER- status and diagnosis after 2006. With a median follow-up of 54 months, the 5-year cumulative incidence of recurrence was 5.3% and overall survival was 93.2%. Age less than 40 and presence of lymphovascular invasion (LVI) were associated with higher risk of recurrence. In a univariate analysis administration of adjuvant chemotherapy was not associated with a significantly better recurrence rate (P = 0.33).
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http://dx.doi.org/10.1016/j.breast.2013.02.014DOI Listing
October 2013

Clinical trials in triple negative breast cancer.

Breast Dis 2010 ;32(1-2):123-36

Department of Hematology-Oncology, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease against which targeted therapies that significantly improve the prognosis for hormone receptor-positive and HER2-overexpressing breast cancers are ineffective. This article summarizes our current understanding of the biology of TNBC as it relates to the efficacy of standard and investigational therapies. It reviews promising preliminary results that have been achieved with chemotherapeutic agents including the platinum analogs and agents that inhibit DNA repair by targeting poly ADP-ribose polymerase (PARP), while anti-angiogenic therapies and those that target the epidermal growth factor receptor (EGFR) have had more limited success. Agents that target a number of other pathways which appear to influence the biologic aggressiveness of TNBC, including src and PI3K, are in early stage clinical trials. As we learn more about TNBC, and which of its characteristics determine treatment response and resistance, we should become better able to select appropriate therapies for biologically defined patient subgroups, and reduce the clinical burden of this disease.
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http://dx.doi.org/10.3233/BD-2010-0310DOI Listing
February 2012

Phase I trial examining addition of gemcitabine to CHOP in intermediate grade NHL.

Cancer Chemother Pharmacol 2011 Oct 15;68(4):1075-80. Epub 2011 Jul 15.

Department of Hematology/Oncology, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA.

Purpose: Gemcitabine induces a 20% response as single-agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas.

Methods: Patients received CHOP plus gemcitabine at 500 mg/m(2) (Cohort 1) or 750 mg/m(2) (Cohort 2) on days 1 and 4 of each 21-day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose-limiting toxicity.

Results: Between April 2002 and May 2004, 10 patients were enrolled and completed the study treatment (6 in Cohort 1, 4 in Cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia, and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose-limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction in gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%.

Conclusions: This Phase I trial concludes that gemcitabine 500 mg/m(2) on days 1 and 4 of each 21-day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL.
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http://dx.doi.org/10.1007/s00280-011-1702-0DOI Listing
October 2011