25/Jan/2022

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening

BACKGROUND
High rates of overdiagnosis are a critical barrier to organized prostate cancer screening. Magnetic resonance imaging (MRI) with targeted biopsy has shown the potential to address this challenge, but the implications of its use in the context of organized prostate cancer screening are unknown.

METHODS
We conducted a population-based noninferiority trial of prostate cancer screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with prostate-specific antigen (PSA) levels of 3 ng per milliliter or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer (experimental biopsy group). The primary outcome was the proportion of men in the intention-to-treat population in whom clinically significant cancer (Gleason score ≥7) was diagnosed. A key secondary outcome was the detection of clinically insignificant cancers (Gleason score 6).

RESULTS
Of 12,750 men enrolled, 1532 had PSA levels of 3 ng per milliliter or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group. In the intention-to-treat analysis, clinically significant cancer was diagnosed in 192 men (21%) in the experimental biopsy group, as compared with 106 men (18%) in the standard biopsy group (difference, 3 percentage points; 95% confidence interval [CI], −1 to 7; P<0.001 for noninferiority). The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4% [41 participants] vs. 12% [73 participants]; difference, −8 percentage points; 95% CI, −11 to −5).

CONCLUSIONS
MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was noninferior to standard biopsy for detecting clinically significant prostate cancer in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer. (Funded by the Swedish Research Council and others; STHLM3-MRI ClinicalTrials.gov number, NCT03377881. opens in new tab.)

Bob T. Li, M.D., Ph.D., M.P.H., Egbert F. Smit, M.D., Ph.D., Yasushi Goto, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Hibiki Udagawa, M.D., Julien Mazières, M.D., Misako Nagasaka, M.D., Ph.D., Lyudmila Bazhenova, M.D., Andreas N. Saltos, M.D., Enriqueta Felip, M.D., Ph.D., Jose M. Pacheco, M.D., Maurice Pérol, M.D., et al., for the DESTINY-Lung01 Trial Investigators

This article was published on July 9, 2021, at NEJM.org.

Susana Ferreira

18/Jan/2022

MPTP-induced mouse model of Parkinson’s disease: A promising direction of therapeutic strategies

Among the popular animal models of Parkinson’s disease (PD) commonly used in research are those that employ neurotoxins, especially 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). This neurotoxin exerts it neurotoxicity by causing a barrage of insults, such as oxidative stress, mitochondrial apoptosis, inflammation, excitotoxicity, and formation of inclusion bodies acting singly and in concert, ultimately leading to dopaminergic neuronal damage in the substantia nigra pars compacta and striatum. The selective neurotoxicity induced by MPTP in the nigrostriatal dopaminergic neurons of the mouse brain has led to new perspectives on PD. For decades, the MPTP-induced mouse model of PD has been the gold standard in PD research even though it does not fully recapitulate PD symptomatology, but it does have the advantages of simplicity, practicability, affordability, and fewer ethical considerations and greater clinical correlation than those of other toxin models of PD. The model has rejuvenated PD research and opened new frontiers in the quest for more novel therapeutic and adjuvant agents for PD. Hence, this review summarizes the role of MPTP in producing Parkinson-like symptoms in mice and the experimental role of the MPTP-induced mouse model. We discussed recent developments of more promising PD therapeutics to enrich our existing knowledge about this neurotoxin using this model.

Musa Mustapha, Che Norma Mat Taib

This work is licensed under a Creative Commons Attribution 4.0 International License30

Parkinson’s disease

Susana Ferreira

11/Jan/2022

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer

BACKGROUND
The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.

METHODS
In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival.

RESULTS
A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P=0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P=0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.

CONCLUSIONS
Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037. opens in new tab.)

Kevin Kalinsky, M.D., William E. Barlow, Ph.D., Julie R. Gralow, M.D., Funda Meric-Bernstam, M.D., Kathy S. Albain, M.D., Daniel F. Hayes, M.D., Nancy U. Lin, M.D., Edith A. Perez, M.D., Lori J. Goldstein, M.D., Stephen K.L. Chia, M.D., Sukhbinder Dhesy-Thind, M.D., Priya Rastogi, M.D., et al.

This article was published on December 1, 2021, at NEJM.org.

Breast Cancer

Susana Ferreira

04/Jan/2022

Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial

BACKGROUND
Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients.

METHODS
IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II–IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II–IIIA population, and finally the intention-to-treat (ITT) population (stage IB–IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting).

FINDINGS
Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4–38·3) in the stage II–IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II–IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50–0·88; p=0·0039) and in all patients in the stage II–IIIA population (0·79; 0·64–0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67–0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).

INTERPRETATION
IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.

FUNDING
F Hoffmann-La Roche and Genentech.

Prof Enriqueta Felip, MD , Nasser Altorki, Prof Caicun Zhou, MD, Tibor Csőszi, MD, Ihor Vynnychenko, MD, Oleksandr Goloborodko, PhD, et al.

Lung cancer

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