Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: CAPItello-291 is an ongoing phase 3 trial in which capivasertib-fulvestrant significantly improved progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291. METHODS: This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan-Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov, NCT04305496. FINDINGS: Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib-fulvestrant (n=355) or placebo-fulvestrant (n=353). The median age of the patients was 59 years (IQR 51-67) in the capivasertib-fulvestrant group and 58 years (IQR 49-66) in the placebo-fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1-16·7) for capivasertib-fulvestrant and 12·7 months (IQR 2·0-16·4) for placebo-fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of -2·5 [95% CI -4·5 to -0·6] with capivasertib-fulvestrant vs -5·6 [-7·9 to -3·4] with placebo-fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib-fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo-fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib-fulvestrant group than in the placebo-fulvestrant group (HR 2·75, 95% CI 2·01-3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools "frequently" or "almost constantly" was 29% higher at cycle 1, day 15 in the capivasertib-fulvestrant group than in the placebo-fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported "not at all" or "a little bit" of bother from treatment side-effects. INTERPRETATION: Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population. FUNDING: AstraZeneca.

Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY.

PURPOSE: The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data. METHODS: The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC. RESULTS: Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up. CONCLUSION: The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC. CLINICAL TRIAL REGISTRATION: Clinical trials registration number: NCT03286842.

A plain language summary of the CAPItello-291 study: Capivasertib in hormone receptor-positive advanced breast cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the article discussing the results of the CAPItello-291 study. In the study, participants had advanced breast cancer that could not be completely removed with surgery, and that was diagnosed as a type of breast cancer where tumor cells had hormone receptors (HR-positive) but did not have HER2 receptors (HER2-negative). All participants were also required to have previously received treatment with a type of therapy called an aromatase inhibitor (with or without a CDK4/6 inhibitor), but over time their cancer cells had still grown or spread. The CAPItello-291 study researchers wanted to find out if a treatment combination of the medications capivasertib plus fulvestrant worked better than placebo plus fulvestrant. Capivasertib is a drug that blocks the activity of a protein called AKT, which is found inside breast cancer cells. WHAT ARE THE KEY TAKEAWAYS?: The main finding was that participants who took capivasertib plus fulvestrant lived longer without their disease getting worse (progressing) compared with those treated with placebo plus fulvestrant. This is called progression-free survival. This result was seen across all participants (median progression-free survival of 7.2 months with capivasertib plus fulvestrant vs 3.6 months with placebo plus fulvestrant). It was also seen in participants whose tumors had detectable genetic alterations in genes called PIK3CA, AKT1, and/ or PTEN (median progression-free survival of 7.3 months with capivasertib plus fulvestrant vs 3.1 months with placebo plus fulvestrant). The most common side effects experienced by participants included diarrhea and different types of rash. These were as expected (given how capivasertib works). The CAPItello-291 study is still ongoing, and more results are expected to be released in the future. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor).Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

Risk of Lymphedema Following Contemporary Treatment for Breast Cancer: An Analysis of 7617 Consecutive Patients From a Multidisciplinary Perspective.

OBJECTIVE: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making. SUMMARY BACKGROUND DATA: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear. METHODS: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients. RESULTS: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients). CONCLUSIONS: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3.

BACKGROUND: Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials. MATERIALS AND METHODS: Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia. RESULTS: The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities. CONCLUSION: Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS. IMPLICATIONS FOR PRACTICE: Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.

Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations.

TAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3-4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3-4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

A pilot study on intermittent every other days of 5-dose Filgrastim compared with single Pegfilgrastim in breast Cancer patients receiving adjuvant Docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy.

Aim To compare the efficacy and safety of intermittent every other days 5-dose filgrastim with single pegfilgrastim in patients with breast cancer receiving adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy. Methods In this pilot study, Korean patients who had undergone complete resection for breast cancer and scheduled for adjuvant TAC chemotherapy were enrolled. Patients were randomized to receive either intermittent 5 doses of filgrastim (5 mcg/kg/day) or once-a-cycle pegfilgrastim (6 mg) as primary prophylaxis during the first three cycles of the TAC chemotherapy. Absolute neutrophil count (ANC) was analyzed as well. Results A total of 22 patients were randomly and equally divided into filgrastim or pegfilgrastim arms. Febrile neutropenia (FN) occurred in 1 patient in the pegfilgrastim arm (1 of 33 cycles) and none in the filgrastim arm. G3 neutropenia occurred in 1 patient (1 of 33 cycles) in the filgrastim arm and 2 patients (4 of 33 cycles) in the pegfilgrastim arm (P = 0.476). G4 neutropenia occurred in 11 patients (28 of 33 cycles) in the filgrastim arm and 9 patients (18 of 33 cycles) in the pegfilgrastim arm (P = 0.476). Except for on day 9 in cycle 3, there was no significant difference between the two groups in terms of ANC. Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim.

A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial.

Although the introduction of human epidermal growth factor receptor (HER)2-directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2-positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies. Patients received 12 mg poziotinib once daily on a 14-day on/7-day off schedule. Progression-free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30-76) and had received a median of four prior therapies including two HER2-directed therapies for advanced or metastatic cancers. The median follow-up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94-4.40 months), and median overall survival has not been reached. The most common treatment-related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. METHODS: We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. FINDINGS: Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30·0%; 95% CI 16·6-46·5) patients given afatinib alone (difference vs investigator's choice: -11·9% [95% CI -32·9 to 9·7], p=0·37), 13 (34·2%; 19·6-51·4) given afatinib plus vinorelbine (difference vs investigator's choice: -7·6% [-28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0-57·9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]). INTERPRETATION: Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned. FUNDING: Boehringer Ingelheim.

Quality of life (QoL) in metastatic breast cancer patients with maintenance paclitaxel plus gemcitabine (PG) chemotherapy: results from phase III, multicenter, randomized trial of maintenance chemotherapy versus observation (KCSG-BR07-02).

The therapeutic goals are palliative for metastatic breast cancer (MBC) and include prolongation of survival with good quality of life (QoL) and symptom control. The purpose of this study was to examine QoL among women with MBC treated on KCSG-BR07-02 with maintenance of paclitaxel plus gemcitabine (PG) chemotherapy after achieving disease control to initial six cycles of PG chemotherapy or observation. Patients were randomized to either maintenance chemotherapy or observation until progression. QoL was assessed using EORTC QLQ-C30 and BR-23. QoL at each cycle was compared between the two treatment arms using the 2-sample t test. Generalized estimating equation method was used to examine the overall difference between the two treatments in QoL. All reported p-values are 2 sided. There were no statistically significant differences between two arms in most of the component of the EORTC QLQ-C30 and BR-23 (p > 0.05). There was no significant difference between two treatments (p = 0.6094 for QLQ-C30, p = 0.5516 for BR23) at baseline, and there did not exist significant change over the cycle (p = 0.0914 for QLQ-C30, p = 0.7981 for BR23). There was no significant interaction effect between treatment and cycle (p = 0.5543 for QLQ-C30. p = 0.5817 for BR23). Maintenance PG chemotherapy in patients with MBC achieving disease control with an initial six cycles of PG chemotherapy resulted in better PFS and OS compared to observation without impeding QoL.

Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer.

BACKGROUND: This report describes the results of an analysis of patient-reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody-drug conjugate trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. METHODS: A secondary endpoint of the EMILIA study was time to symptom worsening (time from randomization to the first documentation of a ≥ 5-point decrease from baseline) as measured by the Trial Outcome Index Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy-Breast questionnaire. Predefined exploratory patient-reported outcome endpoints included proportion of patients with a clinically significant improvement in symptoms (per TOI-PFB) and proportion of patients with diarrhea symptoms (per Diarrhea Assessment Scale). RESULTS: In the T-DM1 arm, 450 of 495 patients had a baseline and ≥ 1 postbaseline TOI-PFB score versus 445 of 496 patients in the capecitabine-plus-lapatinib arm. Time to symptom worsening was delayed in the T-DM1 arm versus the capecitabine-plus-lapatinib arm (7.1 months versus 4.6 months, respectively; hazard ratio = 0.796; P = .0121). In the T-DM1 arm, 55.3% of patients developed clinically significant improvement in symptoms from baseline versus 49.4% in the capecitabine-plus-lapatinib arm (P = .0842). Although similar at baseline, the number of patients reporting diarrhea symptoms increased 1.5- to 2-fold during treatment with capecitabine and lapatinib but remained near baseline levels in the T-DM1 arm. CONCLUSIONS: Together with the EMILIA primary data, these results support the concept that T-DM1 has greater efficacy and tolerability than capecitabine plus lapatinib, which may translate into improvements in health-related quality of life.

Detection of circulating tumor cells in patients with breast cancer using the quantitative RT-PCR assay for monitoring of therapy efficacy.

Circulating tumor cells (CTCs) are an independent prognostic factor for patients with breast cancer. However, the role of CTCs in early breast cancer management is not yet clearly defined. The aim of this study was to isolate and characterize CTCs in blood sample of a breast cancer patient as a biomarker for monitoring treatments efficacy. In this study, 692 blood samples from 221 breast cancer patients and 376 healthy individuals was used to detect CTCs with multiple markers including epithelial cell adhesion molecule (EpCAM), cytokeratin (CK) 19, human epidermal growth factor (HER) 2, Ki67, human telomerase reverse transcriptase (hTERT), and vimentin using quantitative reverse transcription PCR (RT-qPCR). A total of 153 (69.2%) blood samples of 221 patients with breast cancer were found to be positive for at least one of the cancer-associated marker gene before treatment. After chemotherapy, no CTCs were found in 28 (33.3%) of the 84 blood samples analyzed for the presence of CTCs using the RT-qPCR, whereas 56 (66.7%) blood samples were still found to be positive for at least one of the markers. After completing the therapy, the CTC positivity rate decreased to 7 (20.6%) in the neoadjuvant group, whereas this increased to 7 (14%) cases in the adjuvant group. There was no statistically significant relationship between TNM stage and detection of CTC-related markers. Data from this study suggest that RT-qPCR assay for the detection of CTC markers might be useful in selecting appropriate therapeutics and for monitoring treatment efficacy in breast cancer patients.

Trastuzumab deruxtecan versus treatment of physician's choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study.

BACKGROUND: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1-2 prior lines of chemotherapy. METHODS: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66). RESULTS: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1-2. CONCLUSIONS: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03734029.

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. METHODS: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. FINDINGS: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4-37·5]; difference 21·1%, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1-32·3]) and the trastuzumab (difference -4·8%, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]). INTERPRETATION: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. FUNDING: GlaxoSmithKline.

Randomized controlled trial of standardized education and telemonitoring for pain in outpatients with advanced solid tumors.

PURPOSE: Previous studies have not defined the role of telemonitoring with educational tools in outpatients with advanced cancers. We tested the effectiveness of standardized education and telemonitoring for improving pain, distress, anxiety, depression, quality of life (QoL), and performance in outpatients with advanced cancers. METHODS: A total of 108 patients were randomly assigned to receive pain education alone (control arm) or pain education plus telemonitoring (experimental arm). Nursing specialists provided video-assisted educational material in both arms and daily telemonitoring for the first week in the experimental arm. Assessment was performed at baseline and 1 week and included evaluations of pain (Brief Pain Inventory, BPI), distress (Distress Thermometer, DT), anxiety, and depression (Hospital Anxiety and Depression Scale, HADS), QoL (QLQ-C30), and a Karnofsky score. RESULTS: Overall (n = 108), pain intensity was significantly improved at 1 week, including worst pain (7.3 to 5.7, P < 0.01) and average pain (4.6 to 3.8, P < 0.01). Additionally, anxiety (HADS score ≥ 11, 75% to 56%, P < 0.01), depression (HADS score ≥ 11, 73% to 51%, P < 0.01), QoL (fatigue and insomnia), and the Karnofsky score (32 to 66, P < 0.01) were also significantly improved at 1 week. However, the level of distress did not improve. The telemonitoring plus standardized education group showed more significant improvement in portion of pain >4 on VAS scale (35% vs. 19%, P = 0.02). CONCLUSIONS: Standardized pain education using nursing specialists is an efficient way to improve not only pain itself but also anxiety, depression, performance, and QoL. The addition of telemonitoring helps to improve pain management in the outpatient setting.

Machine Learning Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy for ER+HER2- Breast Cancer: Integrating Tumoral and Peritumoral MRI Radiomic Features.

BACKGROUND: This study aimed to predict pathologic complete response (pCR) in neoadjuvant chemotherapy for ER+HER2- locally advanced breast cancer (LABC), a subtype with limited treatment response. METHODS: We included 265 ER+HER2- LABC patients (2010-2020) with pre-treatment MRI, neoadjuvant chemotherapy, and confirmed pathology. Using data from January 2016, we divided them into training and validation cohorts. Volumes of interest (VOI) for the tumoral and peritumoral regions were segmented on preoperative MRI from three sequences: T1-weighted early and delayed contrast-enhanced sequences and T2-weighted fat-suppressed sequence (T2FS). We constructed seven machine learning models using tumoral, peritumoral, and combined texture features within and across the sequences, and evaluated their pCR prediction performance using AUC values. RESULTS: The best single sequence model was SVM using a 1 mm tumor-to-peritumor VOI in the early contrast-enhanced phase (AUC = 0.9447). Among the combinations, the top-performing model was K-Nearest Neighbor, using 1 mm tumor-to-peritumor VOI in the early contrast-enhanced phase and 3 mm peritumoral VOI in T2FS (AUC = 0.9631). CONCLUSIONS: We suggest that a combined machine learning model that integrates tumoral and peritumoral radiomic features across different MRI sequences can provide a more accurate pretreatment pCR prediction for neoadjuvant chemotherapy in ER+HER2- LABC.

Outcomes of an Acute Palliative Care Unit at a Comprehensive Cancer Center in Korea.

Background: The acute palliative care unit (APCU) bridges between active cancer treatment and hospice care. However, no study has proven the efficacy of APCU in Korea. Objective: To evaluate the first-year outcomes of the patients admitted to an APCU at a tertiary hospital in Korea. Design: The APCU admitted 205 patients between April 14, 2014, and April 30, 2015. Of these patients, 57 were evaluable for baseline and one-week follow-up Edmonton Symptom Assessment System (ESAS). Results: Of the 57 participants, 56.1% were male, with a median age of 60 years (range, 52.8-69.5 years). All patients had advanced cancer, and 42 out of 57 had terminal illnesses. The median APCU stay was 14 days (range, 10-17 days). The 42 (73.7%) patients were referred to the APCU after anticancer treatment was completed. Ten (17.5%) patients died during their stay, and 20 (35.1%) were discharged home. Among those who completed the ESAS, there were significant improvements in scores in the following symptoms: fatigue, depression, loss of appetite, and shortness of breath. Physical symptoms (pain, fatigue, nausea, drowsiness, appetite, and shortness of breath) and the total ESAS scores were significantly improved (p = 0.002 and p = 0.005, respectively). Each non-medical palliative care program, such as art and music therapy, yoga, foot massage, haircut, and body care, showed no significant differences between the group who received them and those who did not. Conclusion: During the APCU stay, the overall symptoms of inpatients were reduced. A comprehensive and multidisciplinary team approach is essential for patients who need palliative care.

Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.