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Challenges of health systems in Latin America and the Caribbean include accessibility, inequity, segmentation, and poverty. These challenges are similar in different countries of the region and transcend national borders. The increasing digital transformation of health care holds promise of more precise interventions, improved health outcomes, increased efficiency, and ultimately reduced health-care costs. In Latin America and the Caribbean, the adoption of digital health tools is in early stages and the quality of cancer registries, electronic health records, and structured databases are problematic. Cancer research and innovation in the region are limited due to inadequate academic resources and translational research is almost fully dependent on public funding. Regulatory complexity and extended timelines jeopardise the potential improvement in participation in international studies. Emerging technologies, artificial intelligence, big data, and cancer research represent an opportunity to address the health-care challenges in Latin America and the Caribbean collectively, by optimising national capacities, sharing and comparing best practices, and transferring scientific and technical capabilities., Competing Interests: Declaration of Interests CHB reports institutional research grant from Pfizer, Pharma Mar, Polyphor, Henlius Biotech, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Squibb, BioMarin, Astellas Pharma, AbbVie, Merck Sharp & Dohme, Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GlaxoSmithKline, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, and Amgen; advisory board consulting from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, Merck Sharp & Dohme, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, and GlaxoSmithKline; and stocks from MedSIR, Biomarker, and Tummi, outside the submitted work; he declares no relevant conflicts of interests related to this Series paper. AFC declares financial research support from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol Myers Squibb, and The Foundation for Clinical and Applied Cancer Research (FICMAC); he received honoraria as advisor, participated in speakers’ bureau, and gave expert testimony to Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, and FICMAC. CR reports grants or contracts from Pfizer–Lung Cancer Research Foundation (for the EMPOWER ME trial); consulting fees (for advisory board) from ArcherDX, Bristol Myers Squibb, Novartis, and Boston Pharmaceuticals; payment or honoraria for educational events from AstraZeneca, Roche, and Merck Sharp & Dohme; participation on a safety monitoring board from MD Serono; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from the International Society of Liquid Biopsy (Vice President), the International Association for the Study of Lung Cancer (Deputy Chair of the Educational Committee), European School of Oncology (Scientific Board Member), the European Society for Medical Oncology (Faculty of Advanced Lung Cancer), and research support (unpaid) from Guardant Health. EdA reports research support and grants from Roche; and grants from Libbs, Pierre Fabre, Zodiacs, Seattle Genetics, Novartis, Roche, Servier, AstraZeneca, and GlaxoSmithKline, outside the submitted work. OA reports personal fees from Pfizer, Lilly, Merck, and Bristol Myers Squibb; and grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Roche, outside the submitted work. RD declares advisory role for Roche and Boehringer Ingelheim; speaker's fees from Roche, Ipsen, Amgen, Servier, Sanofi, Libbs, and Merck Sharp & Dohme; and research grants from Merck and Pierre Fabre, outside the submitted work. EC reports honoraria for lectures and consulting or advisory role from Merck outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean., Competing Interests: Declaration of interests CHB reports institutional research grants from Pfizer, Pharma Mar, Polyphor, Henlius Biotech, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Squibb, BioMarin, Astellas Pharma, AbbVie, Merck Sharp & Dohme, Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GlaxoSmithKline, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, and Amgen; advisory board consulting from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, Merck Sharp & Dohme, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, and GlaxoSmithKline; and stocks from MedSIR, Biomarker, and Tummi, outside the submitted work; and declares that these conflicts of interest did not affect this paper. CJCE received honoraria from Merck Sharp & Dohme outside the submitted work. CV-G reports grants, personal fees, and non-financial support from Roche; personal fees from Novartis and Myriad Genetics; personal fees and non-financial support from Pfizer and Merck Sharp & Dohme Oncology; grants and personal fees from Eli Lilly and AstraZeneca, outside the submitted work. FG-D declares travel and accommodation expenses from Pfizer, Lilly, Boehringer Ingelheim, AstraZeneca, and Exelixis outside the submitted work. JSK reports part-time employment to contribute to the research and writing of this publication from Dana-Farber Cancer Institute and full-time employment as a scientific research associate from Dewpoint Therapeutics. PERL declares grants or contracts from Merck Sharp & Dohme, AstraZeneca, Merck Serono, Halozyme, Roche, Acerta Pharma, Novartis, Regeneron, Myovant Sciences, PharmaMar, Pfizer, PRA Health Sciences, Quintiles, Parexel, Bristol Myers Squibb, Medivation, Janssen, Eurofarma, Pharmaceutical Product Development, Covance, ICON Clinical Research, and Intrials; payment for expert testimony from AstraZeneca; and support for attending meetings or travel (or both) from Roche, Zodiac, and Novartis. PE reports personal fees from Eli Lilly, Novartis, and Libbs, outside the submitted work. RB-S has served as an advisor or a consultant to Eli Lilly, Merck Sharp and Dohme, and Roche; and has received honoraria from Bard Access, Bristol Myers Squib, Libbs, Eli Lilly, Novartis, Pfizer, Roche, and Zodiac; and travel and accommodation expenses from Roche and Daiichi Sankyo. TP contributed as part of her role as postdoctoral research associate at the Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. YC-G reports travel grant from Pfizer and research grant from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer., Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m 2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891., Findings: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018)., Interpretation: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need., Funding: F Hoffmann-La Roche and Genentech., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings., Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants., Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo., Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events., Funding: Wyeth, Pfizer, and Puma Biotechnology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer., Methods: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709., Findings: Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group., Interpretation: Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained., Funding: Wyeth, Pfizer, Puma Biotechnology., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response., Methods: We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358., Findings: 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events., Interpretation: Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response., Funding: GlaxoSmithKline., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Breast cancer is the most common cancer in women worldwide and 70% of breast cancer deaths occur in women from low-income and middle-income countries. Latin America has about 115,000 new cases of disease every year, with about 50,000 arising in Brazil. We examined the present status of breast cancer in Brazil as an example of the health effects of geographical, ethnic, and socioeconomic diversities on delivery of care. Our goal was to identify deficiencies that could be responsible for disparities in survival from breast cancer. We searched the English and Portuguese published work and reviewed national databases and Brazilian publications. Although the availability of publications specific to Brazil is low in general, we identified several factors that could account for disparities: delays in diagnosis due to low cancer awareness and implementation of mammography screening, unknown quality of surgery, and restricted access to radiotherapy and modern systemic therapies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)