Publications by authors named "Cristina Saura"

73 Publications

Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer.

Front Oncol 2021 20;11:710596. Epub 2021 Sep 20.

Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.
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http://dx.doi.org/10.3389/fonc.2021.710596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489403PMC
September 2021

High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer.

Clin Cancer Res 2021 Sep 30. Epub 2021 Sep 30.

Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO)

Purpose: amplification (amp) is recurrent in metastatic breast cancer (BC) and is associated with resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Multi-tyrosine kinase inhibitors (MTKI) and selective pan-FGFR inhibitors (FGFRi) are being developed for amp BC. High-level amplification and protein expression by IHC have identified BC responders to FGFRi or MTKI, respectively.

Experimental Design: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of seventeen BC patient-derived xenografts (PDXs) harboring amplification in and in ten patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.

Results: High mRNA levels but not copy number alteration (CNA) associated with FGFRi response. Treatment with MTKI showed higher response rates than with FGFRi (86% 53%), regardless of the mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRi or MTKI, and PDXs exclusively sensitive to MTKI exhibited an additional anti-angiogenic response. Consistently, clinical benefit of MTKI was not associated with high mRNA levels and it was observed in patients previously treated with anti-angiogenic drugs.

Conclusion: Tailored therapy with FGFRi in molecularly-selected metastatic BC based on high mRNA levels warrants prospective validation in luminal BC CDK4/6i-resistant patients and in TNBC patients without targeted therapeutic options.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1810DOI Listing
September 2021

Clinical consequences of BRCA2 hypomorphism.

NPJ Breast Cancer 2021 Sep 9;7(1):117. Epub 2021 Sep 9.

Genome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37-54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.
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http://dx.doi.org/10.1038/s41523-021-00322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429460PMC
September 2021

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

Breast 2021 Oct 3;59:327-338. Epub 2021 Aug 3.

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy.

Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration.

Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %).

Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.
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http://dx.doi.org/10.1016/j.breast.2021.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365381PMC
October 2021

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

Eur J Cancer 2021 Sep 9;155:168-178. Epub 2021 Aug 9.

Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Electronic address:

Purpose: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline.

Methods: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application.

Results: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%).

Conclusions: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.
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http://dx.doi.org/10.1016/j.ejca.2021.05.040DOI Listing
September 2021

Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer.

Clin Cancer Res 2021 Aug 11. Epub 2021 Aug 11.

Gustave Roussy, Villejuif, France.

Purpose: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS.

Experimental Design: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models.

Results: Four hundred and twenty samples had successful sequencing: 34.0% had mutations and 5.5% had mutations. In the combined patient populations, mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64-1.03], whereas mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54-0.82); H-score ≥240 versus <240, HR = 0.77 (0.63-0.93); HERmark positive vs. negative, HR = 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51-0.81); H-score ≥ 240, HR = 0.54 (0.41-0.72); HERmark positive, HR = 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm, HR = 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm, HR = 0.91 (0.61-1.36)].

Conclusions: mutations were associated with shorter PFS whereas higher expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1584DOI Listing
August 2021

Copy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial.

Clin Cancer Res 2021 Oct 28;27(20):5607-5618. Epub 2021 Jul 28.

Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium.

Purpose: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial.

Experimental Design: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0.

Results: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for amplification. Nevertheless, amplification ceased to be predictive once expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor-positive subgroup. 6q23-24 deletion was significantly more frequent in wild-type (WT) compared with -mutated, resulting in copy number levels significantly associated with lack of pCR only in the WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number.

Conclusions: Our analysis identified copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. expression outperformed amplification. The complexity of the 6q23-24 region warrants further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1317DOI Listing
October 2021

Long-Term Cardiac Safety and Survival Outcomes of Neoadjuvant Pegylated Liposomal Doxorubicin in Elderly Patients or Prone to Cardiotoxicity and Triple Negative Breast Cancer. Final Results of the Multicentre Phase II CAPRICE Study.

Front Oncol 2021 9;11:645026. Epub 2021 Jul 9.

Department of Medical Oncology, Institut Català d'Oncologia, IDIBELL, L'Hospitalet, Spain.

Background: The CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS).

Methods: In this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m) plus cyclophosphamide (600 mg/m) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed.

Results: Between Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%).

Conclusion: At 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity.

Trial Registration Number: ClinicalTrials.gov reference NCT00563953.
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http://dx.doi.org/10.3389/fonc.2021.645026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300427PMC
July 2021

Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer.

Breast Cancer Res Treat 2021 Sep 15;189(2):377-386. Epub 2021 Jul 15.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Purpose: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results.

Methods: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint.

Results: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged.

Conclusions: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.
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http://dx.doi.org/10.1007/s10549-021-06143-5DOI Listing
September 2021

Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis.

J Clin Oncol 2021 Oct 1;39(29):3293-3305. Epub 2021 Jul 1.

Fertility and Procreation Unit, Gynecologic Oncology Department, European Institute of Oncology IRCCS, Milan, Italy.

Purpose: Many patients and physicians remain concerned about the potential detrimental effects of pregnancy after breast cancer (BC) in terms of reproductive outcomes and maternal safety. This systematic review and meta-analysis aimed at providing updated evidence on these topics.

Methods: A systematic literature review was conducted to identify studies including patients with a pregnancy after BC (PROSPERO number CRD42020158324). Likelihood of pregnancy after BC, their reproductive outcomes, and maternal safety were assessed. Pooled relative risks, odds ratios (ORs), and hazard ratios (HRs) with 95% CIs were calculated using random effects models.

Results: Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis. BC survivors were significantly less likely to have a subsequent pregnancy compared with the general population (relative risk, 0.40; 95% CI, 0.32 to 0.49). Risks of caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88), and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33) were significantly higher in BC survivors, particularly in those with previous chemotherapy exposure, compared with the general population. No significantly increased risk of congenital abnormalities or other reproductive complications were observed. Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68). Similar results were observed after correcting for potential confounders and irrespective of patient, tumor, and treatment characteristics, pregnancy outcome, and timing of pregnancy.

Conclusion: These results provide reassuring evidence on the safety of conceiving in BC survivors. Patients' pregnancy desire should be considered a crucial component of their survivorship care plan.
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http://dx.doi.org/10.1200/JCO.21.00535DOI Listing
October 2021

Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy.

EBioMedicine 2021 Jul 20;69:103451. Epub 2021 Jun 20.

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA; Department of Medicine, University of Barcelona, Barcelona, Spain. Electronic address:

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation.

Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels.

Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy.

Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods.

Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).
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http://dx.doi.org/10.1016/j.ebiom.2021.103451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233691PMC
July 2021

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.

Oncologist 2021 08 7;26(8):e1327-e1338. Epub 2021 Jun 7.

Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania, USA.

Background: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C).

Materials And Methods: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered.

Results: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed.

Conclusion: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC.

Implications For Practice: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.
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http://dx.doi.org/10.1002/onco.13830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342591PMC
August 2021

SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer.

Front Oncol 2021 23;11:638482. Epub 2021 Apr 23.

SOLTI Innovative Cancer Research, Barcelona, Spain.

Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. EudraCT 2019-004964-23; NCT number: NCT04610528.
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http://dx.doi.org/10.3389/fonc.2021.638482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103897PMC
April 2021

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

Breast Cancer Res Treat 2021 Jul 28;188(2):449-458. Epub 2021 Apr 28.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Purpose: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study.

Methods: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points.

Results: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]).

Conclusion: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.
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http://dx.doi.org/10.1007/s10549-021-06217-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260518PMC
July 2021

Tumor Cellularity and Infiltrating Lymphocytes (CelTIL) as a Survival Surrogate in HER2-Positive Breast Cancer.

J Natl Cancer Inst 2021 Mar 31. Epub 2021 Mar 31.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.

In early-stage HER2-positive breast cancer, biomarkers that guide de-escalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a pre-specified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0%-85.0%) versus 59.7% (95% CI = 50.0%-72.0%) (hazard ratio = 0.40; 95% CI = 0.17 to 0.94), and 86.4% (95% CI = 80.0%-94.0%) vs 73.5% (95% CI = 64.0%-84.0%) (hazard ratio = 0.43; 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline TILs, hormone receptor status, pre-treatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early read-out biomarker to help de-escalate/escalate systemic therapy in HER2-positive breast cancer seem warranted.
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http://dx.doi.org/10.1093/jnci/djab057DOI Listing
March 2021

Evolution of Angiogenic Factors in Pregnant Patients with Breast Cancer Treated with Chemotherapy.

Cancers (Basel) 2021 Feb 23;13(4). Epub 2021 Feb 23.

Obstetrics and Gynecology Department, Hospital Universitari Son Espases, 07120 Palma, Spain.

High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT).

Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes.

Methods: Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls.

Results: Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1; sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover; there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth.

Conclusions: Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients; although further studies will be required to guide clinical decision-making.
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http://dx.doi.org/10.3390/cancers13040923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926500PMC
February 2021

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Apr;7(4):573-584

Division of Hematology/Oncology, Northwestern University, Chicago, Illinois.

Importance: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation.

Objective: To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC.

Design, Setting, And Participants: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019.

Interventions: Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice.

Main Outcomes And Measures: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis.

Results: A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable.

Conclusions And Relevance: In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021.

Trial Registration: ClinicalTrials.gov Identifier: NCT02492711.
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http://dx.doi.org/10.1001/jamaoncol.2020.7932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823434PMC
April 2021

Reply to T. J. A. Dekker, D.-C. Mo et al, and A. Seidman et al.

J Clin Oncol 2021 01 17;39(3):254-255. Epub 2020 Dec 17.

Cristina Saura, MD, PhD and Mafalda Oliveira, MD, PhD, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), SOLTI Breast Cancer Cooperative Group, Barcelona, Spain; Sung-Bae Kim, MD, PhD, University of Ulsan College of Medicine, Seoul, Republic of Korea; Thomas Yau, MD, MBBS, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China, Toshimi Takano, MD, Toranomon Hospital, Tokyo, Japan; and Adam Brufsky, MD, PhD, Magee-Womens Hospital of UPMC, Pittsburgh, PA.

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http://dx.doi.org/10.1200/JCO.20.02963DOI Listing
January 2021

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.

Lancet Oncol 2020 11;21(11):1455-1464

SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain.

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.

Methods: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data.

Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1).

Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.

Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.
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http://dx.doi.org/10.1016/S1470-2045(20)30450-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140650PMC
November 2020

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with -Mutant Cancers.

Clin Cancer Res 2021 01 4;27(2):447-459. Epub 2020 Nov 4.

Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, New York.

Purpose: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with -mutant cancers with the isoform-specific PI3K inhibitor taselisib.

Patients And Methods: Patients were enrolled on the basis of local mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.

Results: A total of 166 patients with -mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront ( and ) and postprogression through reactivation of the PI3K pathway (, and ). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.

Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target -mutant tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2657DOI Listing
January 2021

Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.

Breast Cancer Res 2020 11 2;22(1):120. Epub 2020 Nov 2.

Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.

Methods: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.

Results: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.

Conclusions: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.

Trial Registration: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.
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http://dx.doi.org/10.1186/s13058-020-01354-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607628PMC
November 2020

Effect of body mass index on response to neo-adjuvant therapy in HER2-positive breast cancer: an exploratory analysis of the NeoALTTO trial.

Breast Cancer Res 2020 10 27;22(1):115. Epub 2020 Oct 27.

Institut Jules Bordet and l'Universitè Libre de Bruxelles (U.LB), Brussels, Belgium.

Background: Obesity is a risk factor for breast cancer (BC) development, recurrence, and death. In view of this, we aimed to investigate the clinical value of obesity in BC patients treated with anti-HER2 therapies in the NeoALTTO trial, which randomized 455 patients to neo-adjuvant lapatinib, trastuzumab, or their combination plus paclitaxel.

Methods: Patients were classified according to their basal body mass index (BMI) into underweight (< 18.5 kg/m), normal (≥ 18.5; < 25 kg/m), overweight (≥ 25; < 30 kg/m), and obese (≥ 30 kg/m) WHO categories. Univariate and multivariate logistic regression analyses were performed using BMI as a categorical variable. Pathological complete response (pCR) and event-free survival (EFS) were the NeoALTTO primary and secondary outcomes, respectively.

Results: Among 454 patients analyzed, 14 (3%), 220 (48%), 137 (30%), and 83 (18%) were classified as underweight, normal weight, overweight, and obese, respectively; 231 (51%) and 223 (49%) had hormone receptor (HR)-positive and HR-negative primary tumors; 160 (35%) achieved pCR. In the overall patient population, no association was found between BMI groups and pCR, as we reported pCR rates of 57.1%, 35%, 30.7%, and 39.8% in underweight, normal weight, overweight, and obese cases, respectively. In contrast, in HR-positive tumors, overweight or obesity was generally associated with decreased likelihood of achieving a pCR independently of other clinical variables, including planned surgery, nodal status, and tumor size (odds ratio [OR] = 0.55, 95%CI 0.30-1.01, as compared to normal or underweight; p = 0.053); notably, no differential effect of BMI with respect to pCR was observed in HR-negative cases (odds ratio [OR] = 1.30, 95%CI 0.76-2.23, as compared to normal or underweight; p = 0.331), resulting in a statistically significant interaction between BMI and HR status (p = 0.036). There was no association between BMI and EFS neither in the overall nor in the HR-positive population, but this analysis was under-powered.

Conclusions: NeoALTTO patients overweight or obese at baseline and with HR-positive primary BC appeared less likely to achieve pCR after neo-adjuvant anti-HER2 therapies. This finding paves the way to future research in targeting the interplay between HER2/HR signaling and metabolism.
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http://dx.doi.org/10.1186/s13058-020-01356-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590445PMC
October 2020

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.

Lancet Oncol 2020 10;21(10):1283-1295

Division of Research, Peter MacCallum Cancer Center, Melbourne, VIC, Australia. Electronic address:

Background: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane.

Methods: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed.

Findings: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome).

Interpretation: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer.

Funding: F Hoffman-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(20)30465-4DOI Listing
October 2020

Evolving Landscape of Molecular Prescreening Strategies for Oncology Early Clinical Trials.

JCO Precis Oncol 2020 14;4. Epub 2020 May 14.

Cancer Genomics Lab, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Most academic precision oncology programs have been designed to facilitate enrollment of patients in early clinical trials with matched targeted agents. Over the last decade, major changes were seen both in the targetable molecular alteration landscape and in drug development trends. In this article, we describe how the Vall d'Hebron Institute of Oncology molecular prescreening program adapted to a dynamic model of biomarker-drug codevelopment. We started with a tumor-agnostic hotspot mutation panel plus in situ hybridization and immunohistochemistry of selected markers and subsequently transitioned to tumor-specific amplicon-based next-generation sequencing (NGS) tests together with custom copy number, fusion, and outlier gene expression panels. All assays are optimized for archived formalin-fixed paraffin-embedded tumor tissues without matched germline sequencing. In parallel, biomarker-matched trials evolved from a scenario of few targets and large populations (such as PI3K inhibitors in mutants) to a complex situation with many targets and small populations (such as multiple targetable fusion events). Recruitment rates in clinical trials with mandatory biomarkers decreased over the last 3 years. Molecular tumor board meetings proved critical to guide oncologists on emerging biomarkers for clinical testing and interpretation of NGS results. The substantial increase of immunotherapy trials had a major impact in target prioritization and guided clinical implementation of new markers, such as tumor mutational burden, with larger exon-based NGS assays and gene expression signatures to capture microenvironment infiltration patterns. This new multiomics era of precision oncology is expected to increase the opportunities for early clinical trial matching.
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http://dx.doi.org/10.1200/PO.19.00398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446427PMC
May 2020

Real-world effectiveness of dual HER2 blockade with pertuzumab and trastuzumab for neoadjuvant treatment of HER2-positive early breast cancer (The NEOPETRA Study).

Breast Cancer Res Treat 2020 Nov 2;184(2):469-479. Epub 2020 Sep 2.

Hospital Virgen de la Salud, Toledo, Spain.

Purpose: Neoadjuvant clinical trials with dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy demonstrated high rates of pathological complete response (pCR) in HER2-positive early breast cancer (BC). We investigated whether the benefit on pCR seen in clinical trials is confirmed in a real-world setting.

Methods: Multicenter, retrospective study in patients with HER2-positive early BC receiving neoadjuvant treatment with pertuzumab and trastuzumab in routine clinical practice (n = 243). The primary endpoint was total pCR (tpCR) (ypT0/is ypN0).

Results: A total of 243 evaluable patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes in 74.1% of patients, with single-agent taxane in 11.1% of patients and with platinum-based chemotherapy (CT) in 14.4% of patients. The tpCR rate was 66.4%:71% with anthracyclines and taxanes, 59.3% with single-agent taxane, and 48.6% with platinum-based combinations. The tpCR rate was higher among patients with hormone receptor (HR)-negative tumors (80.9%) vs HR-positive tumors (55.4%) (p < 0.001). A pCR in the breast (ypT0/is) was achieved in 67.6% of patients. Of 143 patients who showed radiological complete response (rCR) (62%), 112 (78.3%) patients also achieved tpCR. Assessment of rCR by magnetic resonance imaging (MRI) showed the highest negative predictive value (NPV) for predicting tpCR (83.5%). Breast-conserving surgery was performed in 58.7% of patients. Grade 3 and grade 4 toxicities were reported in 33 (18.2%) and 12 (6.6%) patients, respectively. No toxicity leading to death was reported.

Conclusions: This real-world analysis shows that neoadjuvant pertuzumab, trastuzumab, and chemotherapy achieve comparable or even higher rates of tpCR than those seen in clinical trials. The pCR benefit is higher in HR-negative tumors. The assessment of rCR by MRI showed the highest ability for predicting pCR. In addition, this neoadjuvant strategy confers an acceptable safety profile.
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http://dx.doi.org/10.1007/s10549-020-05866-1DOI Listing
November 2020

Neratinib plus capecitabine for the treatment of advanced HER2-positive breast cancer.

Expert Rev Anticancer Ther 2020 09 30;20(9):731-741. Epub 2020 Aug 30.

Medical Oncology Department, Vall d'Hebron Hospital , Barcelona, Spain.

Introduction: Several agents are being developed for advanced HER2-positive breast cancer, such as potent tyrosine kinase inhibitors (TKI) targeting ErbB family receptors, novel antibody-drug conjugates, higher affinity anti-HER2 antibodies, among others. Neratinib is an irreversible pan-HER (EGFR, ERBB2, and ERBB4) TKI being tested in early and advanced HER2-positive breast cancer. In the NALA trial, neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine. The main adverse event in the neratinib arm was diarrhea, which mandates for prophylactic treatment with loperamide.

Areas Covered: In this review, we analyze and discuss preclinical and clinical data with neratinib plus capecitabine. We summarize efficacy and safety results from phase I/II and III trials, and discuss this regimen within the landscape of treatment for patients with HER2-positive metastatic breast cancer progressing after two lines of HER2-directed treatment.

Expert Opinion: Neratinib plus capecitabine is a valid treatment option for patients with advanced HER2-positive breast cancer, after progression to at least two anti-HER2-based regimens. Given the multiple options that are being developed in this context, efforts should be employed to establish strong predictive biomarkers of efficacy to each drug and combination.
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http://dx.doi.org/10.1080/14737140.2020.1807947DOI Listing
September 2020

Tackling the Biological Diversity in Early Triple-Negative Breast Cancer.

Breast Care (Basel) 2020 Jun 9;15(3):205-207. Epub 2020 Jun 9.

Department of Medical Oncology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

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http://dx.doi.org/10.1159/000508969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383273PMC
June 2020

Sequential immunohistochemistry and virtual image reconstruction using a single slide for quantitative KI67 measurement in breast cancer.

Breast 2020 Oct 13;53:102-110. Epub 2020 Jul 13.

Molecular Oncology Group, Vall D'Hebron Institute of Oncology, Barcelona, Spain. Electronic address:

Objective: Ki67 is a prognostic and predictive marker in breast cancer (BC). However, manual scoring (MS) by visual assessment suffers from high inter-observer variability which limits its clinical use. Here, we developed a new digital image analysis (DIA) workflow, named KiQuant for automated scoring of Ki67 and investigated its equivalence with standard pathologist's assessment.

Methods: Sequential immunohistochemistry of Ki67 and cytokeratin, for precise tumor cell recognition, were performed in the same section of 5 tissue microarrays containing 329 tumor cores from different breast cancer subtypes. Slides were digitalized and subjected to DIA and MS for Ki67 assessment. The intraclass correlation coefficient (ICC) and Bland-Altman plot were used to evaluate inter-observer reproducibility. The Kaplan-Meier analysis was used to determine the prognostic potential.

Results: KiQuant showed an excellent correlation with MS (ICC:0.905,95%CI:0.878-0.926) with satisfactory inter-run (ICC:0.917,95%CI:0.884-0.942) and inter-antibody reproducibilities (ICC:0.886,95%CI:0.820-0.929). The distance between KiQuant and MS increased with the magnitude of Ki67 measurement and positively correlated with analyzed tumor area and breast cancer subtype. Agreement rates between KiQuant and MS within the clinically relevant 14% and 30% cut-off points ranged from 33% to 44% with modest interobserver reproducibility below the 20% cut-off (0.606, 95%CI:0.467-0.727). High Ki67 by KiQuant correlated with worse outcome in all BC and in the luminal subtype (P = 0.028 and P = 0.043, respectively). For MS, the association with survival was significant only in 1 out of 3 observers.

Conclusions: KiQuant represents an easy and accurate methodology for Ki67 measurement providing a step toward utilizing Ki67 in the clinical setting.
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http://dx.doi.org/10.1016/j.breast.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375667PMC
October 2020

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

J Clin Oncol 2020 09 17;38(27):3138-3149. Epub 2020 Jul 17.

Graduate School of Medicine, Gunma University, Gunma, Japan.

Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.

Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).

Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% 29.2%; 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; .0004). The most common all-grade adverse events were diarrhea (N+C 83% L+C 66%) and nausea (53% 42%). Discontinuation rates and HRQoL were similar between groups.

Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
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http://dx.doi.org/10.1200/JCO.20.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499616PMC
September 2020

Breast cancer during pregnancy: matched study of diagnostic approach, tumor characteristics, and prognostic factors.

Tumori 2020 Oct 6;106(5):378-387. Epub 2020 Jul 6.

Hospital Universitari Son Espases, Palma, Illes Balears, Spain.

Introduction: Breast cancer is one of the most frequently occurring cancers during pregnancy and its incidence is increasing. Many studies have shown poor outcomes, the causes of which remain unclear.

Objectives: To analyze radiologic characteristics, histology, and prognosis factors of breast cancer during pregnancy.

Methods: A total of 42 patients with breast cancer diagnosed during pregnancy (BCP) were matched with 84 patients with breast cancer of similar age who were not pregnant. Sensitivity of radiology, tumor characteristics, prognosis factors, disease-free survival, and overall survival were analyzed.

Results: The sensitivity of breast ultrasound was higher than that of mammography for both groups. Ultrasound sensitivity for cancer was 95.7% in patients with BCP versus 98% in the not pregnant group, with non-statistically significant differences. Mammography sensitivity for cancer was 56.5% in patients with BCP versus 61% in the not pregnant group, with non-statistically significant differences. The stage at diagnosis according to the TNM staging system was significantly higher in patients with BCP with stage IV cancer: 16.7% in patients with BCP versus 3.7% in the not pregnant group ( = 0.03). No statistically significant differences were observed in histologic grade, Ki-67 index, or molecular subtype. Disease-free survival and overall survival were significantly lower in patients with BCP ( = 0.002 and = 0.04). Multivariate analysis showed no difference when adjusting for stage and surrogate molecular subtype.

Conclusion: Breast ultrasound shows a high sensitivity to detect breast cancer during pregnancy. BCP is diagnosed at a higher stage than in nonpregnant women. In our series, patients with BCP had poorer outcomes than the not pregnant group. These results were not observed when adjusting for stage.
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http://dx.doi.org/10.1177/0300891620925158DOI Listing
October 2020
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