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Developments in HIV-related medicine have significant implications for the practice of oncology. Although HIV is a relatively new discipline within medicine, the identification and therapeutic targeting of HIV has been rapid. Furthermore, political lobbying has sculpted scientific research and patient care. Rational drug design has reduced morbidity and mortality to such an extent that the development of predictive surrogate endpoints has been necessary to enable randomised assessments of new protocols to continue. These studies now include the routine detection of resistance to tailor specific therapies to the patient. The involvement of affected communities in dynamically modelled studies have shown the efficacy of new, preventive strategies and debates about such approaches have improved the standard of care. In this review, we discuss what oncologists can learn from the HIV epidemic.

Background: There is incomplete information regarding evolution of antibody titers against SARS‐CoV‐2 after a two‐dose strategy vaccination with BNT162b2 in older adults in long‐term care facilities (LTCFs) with frailty, disability, or cognitive impairment. We aimed to determine IgG antibody titer loss in older adults in LTCFs. Methods: This is a multicenter longitudinal cohort study including 127 residents (90 females and 37 males) with a mean age of 82.7 years (range 65–99) with different frailty and disability profiles in two LTCFs in Albacete, Spain. Residents received two doses of BNT162b2 as per label, and antibody levels were determined 1 and 6 months after the second dose. Age, sex, previous history of coronavirus disease 2019 (COVID‐19), comorbidity (Charlson Index), performance in activities of daily living (Barthel Index), frailty (FRAIL instrument), and cognitive status were assessed. Results: The mean antibody titers 1 and 6 months after the second vaccine dose were 32,145 AU/ml (SD 41,206) and 6182 AU/ml (SD 13,316), respectively. Across all participants, the median antibody titer loss measured 77.6% (interquartile range [IQR] 23.8%). Notably, the decline of titers in individuals with pre‐vaccination COVID‐19 infection was significantly lower than in those without a history of SARS‐CoV‐2 infection (72.2% vs. 85.3%; p < 0.001). The median titer decrease per follow‐up day was 0.47% (IQR 0.14%) and only pre‐vaccination COVID‐19 was associated with lower rate of antibody decline at 6 months (hazard ratio 0.17; 95% confidence interval 0.07–0.41; p < 0.001). Frailty, disability, older age, cognitive impairment, or comorbidity were not associated with the extent of antibody loss. Conclusions: Older adults in LTCFs experience a rapid loss of antibodies over the first 6 months after the second dose of BNT162b2 vaccine. Only pre‐vaccination COVID‐19 is associated with a slower rate of antibody decrease. Our data support immunization with a third dose in this vulnerable, high‐risk population. [ABSTRACT FROM AUTHOR]

Background/Objectives: The safety and immunogenicity of the BNT162b2 coronavirus disease 2019 (COVID‐19) vaccine in older adults with different frailty and disability profiles have not been well determined. Our objective was to analyze immunogenicity of the BNT162b2 mRNA COVID‐19 vaccine in older adults across frailty and disability profiles. Design: Multicenter longitudinal cohort study. Setting and participants: A total of 134 residents aged ≥65 years with different frailty and disability profiles in five long‐term care facilities (LTCFs) in Albacete, Spain. Intervention and measurements: Residents were administered two vaccine doses as per the label, and antibody levels were determined 21.9 days (SD 9.3) after both the first and second dose. Functional variables were assessed using activities of daily living (Barthel Index), and frailty status was determined with the FRAIL instrument. Cognitive status and comorbidity were also evaluated. Results: Mean age was 82.9 years (range 65–99), and 71.6% were female. The mean antibody titers in residents with and without previous COVID‐19 infection were 49,878 AU/ml and 15,274 AU/ml, respectively (mean difference 34,604; 95% confidence interval [CI]: 27,699–41,509). No severe adverse reactions were observed, after either vaccine dose. Those with prevaccination COVID‐19 had an increased antibody level after the vaccine (B = 31,337; 95% CI: 22,725–39,950; p < 0.001). Frailty, disability, older age, sex, cognitive impairment, or comorbidities were not associated with different antibody titers. Conclusions: The BNT162b2 mRNA COVID‐19 vaccine in older adults is safe and produces immunogenicity, independently of the frailty and disability profiles. Older adults in LTCFs should receive a COVID‐19 vaccine. [ABSTRACT FROM AUTHOR]

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.Methods: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.Conclusions: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC. [ABSTRACT FROM AUTHOR]

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy. [ABSTRACT FROM AUTHOR]

Introduction: Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or 'reference' trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies. Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab. Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome. [ABSTRACT FROM AUTHOR]

Background: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.Methods: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.Findings: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).Interpretation: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.Funding: Celltrion Inc. [ABSTRACT FROM AUTHOR]

The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a 'one-size-fits-all' approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness. [ABSTRACT FROM AUTHOR]