Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer.

PURPOSE: Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer. METHODS: A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data. RESULTS: Personalized Signatera assays detected ctDNA ahead of clinical or radiologic relapse in 30 of the 34 patients who relapsed (patient-level sensitivity of 88.2%). Relapse was predicted with a lead interval of up to 38 months (median, 10.5 months; range, 0-38 months), and ctDNA positivity was associated with shorter relapse-free survival (P < .0001) and overall survival (P < .0001). All relapsing triple-negative patients (n = 7/23) had a ctDNA-positive test within a median of 8 months (range, 0-19 months), while the 16 nonrelapsed patients with triple-negative breast cancer remained ctDNA-negative during a median follow-up of 58 months (range, 8-99 months). The four patients who had negative tests before relapse all had hormone receptor-positive (HR+) disease and conversely, five of the 122 nonrelapsed patients (all HR+) had an occasional positive test. CONCLUSION: Serial postoperative ctDNA assessment has strong prognostic value, provides a potential window for earlier therapeutic intervention, and may enable more effective monitoring than current clinical tests such as cancer antigen 15-3. Our study provides evidence that those with serially negative ctDNA tests have superior clinical outcomes, providing reassurance to patients with breast cancer. For select cases with HR+ disease, decisions about treatment management might require serial monitoring despite the ctDNA-positive result.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition.

Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.

Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial.

PURPOSE: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC). PATIENTS AND METHODS: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers. RESULTS: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels. CONCLUSIONS: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

CDK4/6 inhibitors versus weekly paclitaxel for treatment of ER+/HER2- advanced breast cancer with impending or established visceral crisis.

PURPOSE: ER+/HER2- advanced breast cancer (ABC) with visceral crisis (VC) or impending VC (IVC) is commonly treated with chemotherapy instead of CDK4/6 inhibitors (CDK4/6i). However, there is little evidence to confirm which treatment is superior. This study compared outcomes of patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i or weekly paclitaxel. METHODS: Patients with ER+/HER2- ABC receiving first line treatment at a large tertiary UK cancer centre from 1-Mar-2017 to 30-Jun-2021 were retrospectively identified. Hospital records were screened for IVC/VC affecting the liver, lungs/mediastinum, gastrointestinal tract and/or bone marrow. Baseline demographics, clinical data and survival outcomes were recorded up to 30-Jul-2022. RESULTS: 27/396 (6.8%) patients with ABC who received CDK4/6i and 32/86 (37.2%) who received paclitaxel had IVC/VC. Median time to treatment failure (TTF), progression-free survival (PFS) and overall survival (OS) were significantly longer in the CDK4/6i compared to paclitaxel cohort: TTF 17.3 vs. 3.5 months (HR 0.33, 95%CI 0.17-0.61, p = 0.0002), PFS 17.8 vs. 4.5 months (HR 0.38, 95%CI 0.21-0.67, p = 0.002), OS 24.6 vs. 6.7 months (HR 0.37, 95%CI 0.20-0.68, p = 0.002). The median time to first improvement in IVC/VC was similar in patients receiving CDK4/6i compared to paclitaxel (3.9 vs. 3.6 weeks, p = 0.773). Disease control at 4 months was not significantly different in the CDK4/6i and paclitaxel cohorts (77.8% vs. 59.4%, p = 0.168). In multivariate analysis, treatment with CDK4/6i was independently associated with a longer PFS compared to paclitaxel (HR 0.31, 95%CI 0.12-0.78, p = 0.015). CONCLUSION: In this retrospective study, patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i had a significantly better survival compared to those treated with weekly paclitaxel. Further prospective studies that minimise possible selection bias are recommended.

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. METHODS: This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). INTERPRETATION: DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. FUNDING: Daiichi Sankyo and AstraZeneca.

Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial.

In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.

OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

BACKGROUND: In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. PATIENTS AND METHODS: Patients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). RESULTS: In the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67-1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33-0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. CONCLUSIONS: OS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.

Reinstatement of Pavlovian responses to alcohol cues by stress.

RATIONALE: Stress may contribute to relapse to alcohol use in part by enhancing reactivity to cues previously paired with alcohol. Yet, standard models of stress-induced reinstatement generally use contingent presentations of alcohol-paired cues to reinforce instrumental behaviors, making it difficult to isolate the ability of cues to invigorate alcohol-seeking. OBJECTIVE: Here we sought to test the impact of stress on behavioral responses to alcohol-paired cues, using a model of stress-induced reinstatement of Pavlovian conditioned approach, inspired by Nadia Chaudhri's work on context-induced reinstatement. METHODS: Long Evans rats were trained to associate one auditory cue with delivery of alcohol or sucrose and an alternative auditory cue with no reward. Following extinction training, rats were exposed to a stressor prior to being re-exposed to the cues under extinction conditions. We assessed the effects of yohimbine, intermittent footshock and olfactory cues paired with social defeat on responses to alcohol-paired cues and the effects of yohimbine on responses to sucrose-paired cues. RESULTS: The pharmacological stressor, yohimbine, enhanced alcohol seeking in a Pavlovian setting, but not in a cue-selective manner. Intermittent footshock and social defeat cues did not enhance alcohol seeking in this paradigm. CONCLUSIONS: While yohimbine elicited reinstatement of reward-seeking in a Pavlovian setting, these effects may be unrelated to activation of stress systems or to interactions with specific cues.

VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors - Efficacy, Safety, and Biomarker Results.

PURPOSE: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. PATIENTS AND METHODS: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. RESULTS: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. CONCLUSIONS: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results.

PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.

Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort.

The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.

Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers.

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.This article is highlighted in the In This Issue feature, p. 1.

Permanent hair loss associated with taxane chemotherapy use in breast cancer: A retrospective survey at two tertiary UK cancer centres.

PURPOSE: Taxane chemotherapy is commonly used in the management of breast cancer. Hair loss (alopecia) is an expected side effect which may have a significant effect on quality of life. Alopecia is normally temporary but permanent chemotherapy-induced alopecia (pCIA) is increasingly recognised especially following docetaxel chemotherapy. However, the prevalence following docetaxel is not well understood and there is no published literature for paclitaxel chemotherapy. The aim of this study is to investigate the prevalence and patterns of pCIA resulting from both docetaxel and paclitaxel chemotherapy at two tertiary UK cancer centres. METHODS: In collaboration between Clatterbridge Cancer Centre and The Christie NHS Foundation Trusts, a retrospective survey was conducted for breast cancer patients who had received taxane chemotherapy in the neoadjuvant and adjuvant settings. Patients who had concluded chemotherapy at least a year previously were contacted by post and invited to participate by completing a questionnaire and returning it to their treatment centre. Data collected included the incidence and pattern of pCIA using the Savin pictorial hair loss scale, and the methods used by patients to manage it. Fisher's exact test was used to compare pCIA between the docetaxel and paclitaxel cohorts. RESULTS: 383 patients responded to the survey (a 63.3% overall response rate). These comprised 245 patients receiving docetaxel and 138 patients treated with paclitaxel. pCIA was reported by 23.3% of patients receiving docetaxel and 10.1% paclitaxel (p < 0.01). Overall 16.7% of patients in both groups reported the ongoing use of products or appliances such as wigs to camouflage their pCIA. In the docetaxel group, pCIA appeared to be more frequent in post-menopausal women than peri- or pre-menopausal women (37.8%, 12.3% and 19.6% respectively [Chi-square test p < 0.01]). Also in the docetaxel group, there appeared to be a trend for more severe scalp alopecia when the patient also received an aromatase inhibitor (AI) or tamoxifen and this difference was most marked in those who had received both an AI and tamoxifen as components of their treatment regime (p = 0.04). The use of scalp cooling was only recorded in the Christie paclitaxel group (n = 12). Of these 12 patients, 83.3% reported no hair loss. While overall rates of permanent eyebrow, eyelash and nostril hair loss were low, this pattern of hair loss appeared more frequent in the paclitaxel than the docetaxel group 4.3% vs. 1.8% (p = 0.29). CONCLUSIONS: Both docetaxel and paclitaxel may cause permanent scalp hair loss, but it is significantly more prevalent with docetaxel compared with paclitaxel. IMPLICATIONS FOR CANCER SURVIVORS: Clinicians should counsel patients regarding the risk of permanent alopecia prior to embarking upon taxane chemotherapy and routinely offer scalp cooling if available. More research is required to understand the pathobiology of this important and previously under recognised long-term side effect to enable more active preventive and management approaches.

Enhancing integrated psychosocial oncology through leveraging the oncology social worker's role in collaborative care.

OBJECTIVE: The collaborative care model is effective in delivering evidence-based psychosocial oncology care. Social workers comprise the largest proportion of psychosocial oncology providers in the United States. This study describes the process and perceptions of clinical oncology social workers at a large comprehensive cancer center who transitioned to practicing as care managers within collaborative care. METHODS: We describe the process of engaging clinical oncology social workers as care managers as part of the implementation of collaborative care at the Seattle Cancer Care Alliance. We then present survey results from 2017 and 2020 of participating social workers' perceptions of the collaborative care model's advantages and disadvantages. RESULTS: Since the implementation of collaborative care at our institution, key functions of the social worker as care manager were defined. The majority of social workers surveyed in 2017 and 2020 agreed that collaborative care led to improved clinical outcomes, timely access to care, and greater patient satisfaction. They also reported professional advantages: more interdisciplinary team integration, working at the top of their licensure, and improved job satisfaction. Challenges identified included missing important patient needs and creating extra work burden for social workers. CONCLUSIONS: Oncology social workers can be successfully deployed as care managers within a collaborative care model, thus leveraging existing clinical staff to address unmet psychosocial patient needs. This model is feasible and sustainable in a large academic cancer center, requires minimal additional resources, and is favorably viewed by participating social workers in terms of perceived benefits to patients and their own professional roles.

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial.

BACKGROUND: The phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). METHODS: Patients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. RESULTS: Overall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus -3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of 'improvement' in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). CONCLUSION: HRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.