MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial.

BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study.

BACKGROUND: Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models. METHODS: The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. RESULTS: Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination. CONCLUSIONS: The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL.

PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

PURPOSE: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS: The panel considered peer-reviewed reports published in English. RECOMMENDATIONS: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline.

PURPOSE: To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS: Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS: Patients with newly diagnosed BC and BRCA1/2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines.

Association of 70-Gene Signature Assay Findings With Physicians' Treatment Guidance for Patients With Early Breast Cancer Classified as Intermediate Risk by the 21-Gene Assay.

IMPORTANCE: Among patients who undergo the 21-gene assay (21-GA), 39% to 67% receive an intermediate risk result and may receive ambiguous treatment guidance. The 70-gene signature assay (70-GS) may be associated with physicians' treatment decisions in this population with early breast cancer. OBJECTIVE: To determine whether 70-GS findings are associated with physicians' decisions about adjuvant treatment and confidence in their recommendations and to evaluate the dichotomous (high- vs low-risk) and continuous distribution of 70-GS indices among this group of patients with intermediate risk. DESIGN, SETTING, AND PARTICIPANTS: The Prospective Study of MammaPrint in Breast Cancer Patients With an Intermediate Recurrence Score (PROMIS trial) was an impact study conducted from May 20, 2012, through December 31, 2015, that enrolled 840 patients with early-stage breast cancer and a 21-gene assay recurrence score of 18 to 30. Patients were treated in 58 US institutions. INTERVENTIONS: The 70-GS result was given to physicians before adjuvant treatment. MAIN OUTCOMES AND MEASURES: Change in physician treatment decision before vs after receiving the 70-GS result. With a treatment change of greater than 20%, the odds ratio (OR) was applied. RESULTS: Among the 840 patients who underwent 70-GS classification (mean age, 59 years; range, 27-93 years), 374 (44.5%) had a low-risk and 466 (55.5%) had a high-risk result. The distribution of 70-GS indices did not correlate with recurrence score within the 21-GA intermediate range, with 70-GS low- and high-risk patients observed at every recurrence score. A significant change in adjuvant treatment was associated with receiving the 70-GS classifications with an OR of 0.64 (95% CI, 0.50-0.82; McNemar test, P < .001) for all patients. Among the low-risk patients, 108 of 374 (28.9%) had chemotherapy removed from their treatment recommendation; among the high-risk patients, 171 of 466 (36.7%) had chemotherapy added. Results of the 70-GS were associated with the physician's adjuvant treatment recommendation; 409 high-risk patients (87.8%) were recommended to receive adjuvant chemotherapy, and 339 low-risk patients (90.6%) were recommended no chemotherapy. Physicians reported having greater confidence in their treatment recommendation in 660 cases (78.6%) based on 70-GS results. CONCLUSIONS AND RELEVANCE: The 70-GS provides clinically actionable information regarding patients classified as intermediate risk by the 21-GA and was associated with a change in treatment decision in 282 of these patients (33.6%). Chemotherapy was added or withheld by the treating physician based on the results of the 70-GS test. Physicians reported more confidence with their treatment recommendation after receiving 70-GS results.

Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis.

BACKGROUND: Trastuzumab targets the human epidermal growth factor receptor 2 oncogene and in combination with first-line therapy results in significantly improved survival outcomes and has thus become standard of care in both adjuvant and metastatic settings. While it is estimated that 1% to 4% of patients treated with trastuzumab will develop heart failure and ∼10% will experience a reduction in left ventricular ejection fraction (LVEF), the patient risk factors associated with trastuzumab-induced cardiotoxicity (TIC) are unclear. This meta-analysis aims to consolidate previously published data to identify the risk factors most likely leading to TIC. METHODS: A search of the MEDLINE literature database using the keywords trastuzumab/Herceptin, risk factors, outcomes, cardiac, cardiotoxicity, cardiomyopathy, LVEF, and chemotherapy was performed. Only prospective/retrospective human studies were included, with additional studies excluded if they reported baseline LVEF > 68%, a cohort of <50 patients, or results that were not stratified based on cardiotoxic events. Pooled odds ratio (OR) and 95% confidence interval (CI) for each potential risk factor were calculated, with heterogeneity of data and samples explored using random-effects modeling. RESULTS: Data were collected from 17 articles, capturing 6527 patients. Hypertension (OR 1.61, 95% CI 1.14-2.26; P < 0.01), diabetes (OR 1.62; 95% CI 1.10-2.38; P < 0.02), previous anthracycline use (OR 2.14; 95% CI 1.17-3.92; P < 0.02), and older age (P = 0.013) were all shown to be associated with TIC. CONCLUSION: Cardiac performance should be closely monitored in women treated with trastuzumab. Recognizing potential risk factors along with careful attention to symptoms/LVEF measurements could minimize the occurrence of TIC in this population.

Multimodality Imaging in Cardiooncology.

Cardiotoxicity represents a rising problem influencing prognosis and quality of life of chemotherapy-treated patients. Anthracyclines and trastuzumab are the drugs most commonly associated with development of a cardiotoxic effect. Heart failure, myocardial ischemia, hypertension, myocarditis, and thrombosis are typical manifestation of cardiotoxicity by chemotherapeutic agents. Diagnosis and monitoring of cardiac side-effects of cancer treatment is of paramount importance. Echocardiography and nuclear medicine methods are widely used in clinical practice and left ventricular ejection fraction is the most important parameter to asses myocardial damage secondary to chemotherapy. However, left ventricular ejection decrease is a delayed phenomenon, occurring after a long stage of silent myocardial damage that classic imaging methods are not able to detect. New imaging techniques including three-dimensional echocardiography, speckle tracking echocardiography, and cardiac magnetic resonance have demonstrated high sensitivity in detecting the earliest alteration of left ventricular function associated with future development of chemotherapy-induced cardiomyopathy. Early diagnosis of cardiac involvement in cancer patients can allow for timely and adequate treatment management and the introduction of cardioprotective strategies.

Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance).

PURPOSE: Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity. This trial was designed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity. PATIENTS AND METHODS: In all, 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous calcium/magnesium before and after oxaliplatin, a placebo before and after, or calcium/magnesium before and placebo after. The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 tool. RESULTS: There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy, including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale. In addition, calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy. CONCLUSION: This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity.

Feasibility of 4 cycles of docetaxel and cyclophosphamide every 14 days as an adjuvant regimen for breast cancer: a Wisconsin Oncology Network study.

INTRODUCTION: Dose-dense therapies have had a major effect on reducing toxicity and improving outcomes in breast cancer. A combination of TC every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule, with therapy completed within 10 weeks. PATIENTS AND METHODS: We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC through a regional oncology network. All women completed primary surgery before accrual, and subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24 to 48 hours after the administration of each chemotherapy cycle. RESULTS: Of 42 women enrolled, 41 were evaluable using prespecified criteria. Of these, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of neuropathy were similar to that reported previously. The rate of neutropenic fever was low (2.5%). Rash and plantar-palmar erythrodythesia were common and reached grade 3 in 4 subjects (9.8%). CONCLUSION: Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen.

Cardioncology: state of the heart.

Cardiotoxicity caused by chemotherapy is a concerning reality plaguing oncologists and cardiologists. The coexistence of cancer and cardiovascular diseases in the same patient is more common due to the aging population and improvement of chemotherapeutic drug effectiveness. We review the incidence and clinical features of cardiotoxicity caused by some of the most common chemotherapeutic drugs to provide the cardiologist with information regarding general cardiovascular toxicity, early left ventricular dysfunction detection, cardiac damage prevention and follow-up. In conclusion, awareness of this emerging problem has important clinical implications as only highly specialized care will prevent patients who successfully overcome cancer from being defeated by the side effects of anticancer therapy.

Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab.

PURPOSE: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. EXPERIMENTAL DESIGN: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). CONCLUSION: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions.

Use of echocardiography to evaluate the cardiac effects of therapies used in cancer treatment: what do we know?

Cardiologists and oncologists today face the daunting challenge of identifying patients at risk for late-onset left ventricular (LV) systolic dysfunction from the use of various chemotherapeutic agents. Currently, the most widely used method in clinical practice for monitoring the potential of chemotherapy-induced cardiotoxicity is calculation of LV ejection fraction. The use of LV ejection fraction to determine whether to continue or discontinue the use of chemotherapeutic agents is limited, because decreases in LV ejection fraction frequently occur late and can be irreversible. These limitations have led to the exploration of diastolic function and newer modalities that assess myocardial mechanics to identify sensitive and specific variables that can predict the occurrence of late systolic function. The cancer therapies associated with cardiotoxicity are reviewed in this report. Additionally, the authors evaluate the role of present-day echocardiographic parameters, complementary noninvasive imaging modalities, and biomarkers in the prediction of cardiotoxicity. The authors address the evolving role of cardioprotective agents and potential therapies to prevent or reverse the progression of LV systolic dysfunction. Finally, they provide some ideas regarding future directions to enhance the knowledge of predicting late-onset LV systolic dysfunction secondary to cancer therapy.