Publications by authors named "Mafalda Oliveira"

59 Publications

Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification.

Cancer Res 2022 04;82(8):1646-1657

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

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies.

Significance: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612637PMC
April 2022

LitKDM2 study: the impact of health Literacy and knowledge about the disease on the metabolic control of type 2 diabetes mellitus.

Acta Diabetol 2022 Jun 19;59(6):819-825. Epub 2022 Mar 19.

Family Health Unit St. André de Canidelo, R. das Fábricas, 282, 4400-712, Vila Nova de Gaia, Portugal.

Aims: Diabetes mellitus (DM) is a common chronic disease with serious individual and socioeconomic consequences. Low health literacy (HL) has been associated with higher morbimortality. Health knowledge about DM (HK-DM) may also influence individual health. We aimed to assess HL and HK-DM in patients with type 2 DM and their associations with metabolic control.

Methods: Our sample comprised 194 diabetic patients from a primary care health centre. We collected clinical and demographic data and applied two validated questionnaires, the Newest Vital Sign (NST) and Diabetes Knowledge Test (DKT), to assess HL and HK-DM, respectively. Metabolic control was defined as HbA1c < 7.0%. Participants were classified according to the NST as having "high likelihood of limited HL" (HLL-HL), "possibility of limited HL" (PL-HL), or "adequate HL" (A-HL) and by the DKT as having "low", "average" and "good" HK. Statistical analysis included logistic regression models, using p < 0.05 as a cut-off for statistical significance.

Results: Overall, 72.7 and 34.7% of participants had HLL-HL and low HK-DM, respectively. A-HL (OR = 6.02; 95% CI: 1.691-21.450) and PL-HL (OR = 4.78; 95% CI: 1.350-16.899) were significantly associated with better metabolic control than HLL-HL. We did not find a significant association between HK-DM and metabolic control.

Conclusions: HL seems to be associated with better metabolic control. We also found a high prevalence of illiteracy and scarce knowledge about DM. Primary care physicians should promote HL to help patients achieve better metabolic control.
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http://dx.doi.org/10.1007/s00592-022-01875-2DOI Listing
June 2022

Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: A systematic review and meta-analysis.

Cancer Treat Rev 2022 Mar 18;104:102362. Epub 2022 Feb 18.

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

Circulating tumor DNA (ctDNA) is increasingly being used as a biomarker in early breast cancer (EBC). We performed a systematic review and meta-analysis to investigate the prognostic value of ctDNA in patients with EBC treated with neoadjuvant therapy (NAT). We searched Medline, Web of Science and Embase for observational or interventional studies that included patients with EBC undergoing NAT, reported outcomes related to the predefined endpoints, and had full text articles available. Study selection followed the PRISMA guidelines and quality assessment the REMARK tool for biomarker studies. Primary endpoint was impact of ctDNA detection in different time points (baseline, on-treatment, and after NAT) on relapse-free survival (RFS) and overall survival (OS). Secondary endpoints included the association of ctDNA detection with pathologic complete response (pCR), and the positive and negative predictive value of ctDNA detection in predicting residual disease after NAT. From the 2908 studies initially identified, 11 met the eligibility criteria and were included in the meta-analysis. Detection of ctDNA, both at baseline and after completion of NAT, significantly associated to worse RFS (HR 4.22, 95% CI: 1.29-13.82 and HR 5.67, 95% CI: 2.73-11.75, respectively) and worse OS (HR 19.1, 95% CI: 6.9-53.04 and HR 4.00, 95% CI: 1.90-8.42, respectively). In contrast, detection of ctDNA did not associate with the probability of achieving a pCR. Our results suggest that ctDNA assessment during NAT for EBC merits further evaluation as a stratification risk factor in prospective trials, in order to better individualize patient's treatment.
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http://dx.doi.org/10.1016/j.ctrv.2022.102362DOI Listing
March 2022

Botulinum Toxin Type A Injection in the Treatment of Postparetic Facial Synkinesis: An Integrative Review.

Am J Phys Med Rehabil 2022 03;101(3):284-293

From the Department of Physical Medicine and Rehabilitation, Centro Hospitalar Universitário de São João, Porto, Portugal.

Abstract: This study aimed to review the recent literature about botulinum toxin type A treatment patterns, including muscle targets, doses, duration of effect, adverse effects, and clinical outcomes in patients with postparetic synkinesis. A bibliographic research of studies published in the last 10 yrs was carried out on PubMed database, using the medical subject heading terms: botulinum toxin and synkinesis. English-language cohort studies or randomized controlled trials about botulinum toxin type A treatment on patients with postparetic synkinesis were eligible for inclusion. Ten studies met the inclusion criteria, seven prospective studies, two retrospective studies, and one randomized controlled trial, involving 23-99 patients. The target facial muscles included frontalis, corrugator supercilli, orbicularis oculi, levator labii superioris, zygomaticus major, orbicularis oris, risorius, buccinator, depressor anguli oris, depressor labii inferioris, mentalis, and platysma. The dose of onabotulinumtoxinA administered per injection site ranged between 0.5 and 10 U. Adverse effects were rare and temporary. The mean duration of onabotulinumtoxinA effect ranges from 66 days to 4 mos. There was a statistically significant improvement in posttreatment evaluation, both in objective and subjective assessments. There is scientific evidence of the benefit of botulinum toxin type A treatment for postparetic synkinesis, but there is lack of standardized treatment protocols.
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http://dx.doi.org/10.1097/PHM.0000000000001840DOI Listing
March 2022

Aneurysmal Bone Cyst Presenting as Fragility Fracture: A Case Report Focused on the Rehabilitation Approach.

Cureus 2022 Jan 12;14(1):e21145. Epub 2022 Jan 12.

Physical Medicine and Rehabilitation Department, Centro Hospitalar Universitário de São João, Porto, PRT.

Aneurysmal bone cysts are rare lesions, comprising one to six percent of primary bone tumors. Despite benign, those may be locally aggressive. We report a pediatric case with an atypical presentation. The patient was a seven-year-old boy, admitted to an emergency room due to right inguinal pain, without a history of trauma. The symptoms had acute onset and worsened gradually for five days. Radiographs revealed a cystic lesion on the proximal right femur and two longitudinal fractures. After further diagnostic work-up and given the probable diagnosis of an aneurysmal bone cyst, surgical treatment was performed. The diagnosis was then confirmed by histopathological analysis. After surgery, the patient maintained severe pain, having an important range of motion (ROM) and muscular strength reduction on the affected limb. As so, the patient engaged in a daily tailored Physical Medicine and Rehabilitation (PMR) program, for four months. After concluding the treatment plan, the patient was asymptomatic: recovery of both ROM and muscular strength was achieved, as well as the ability to return to previous daily-life activities. This is a paradigmatic case in which a rare condition with a rare presentation was displayed after several others were ruled out, requiring a multidisciplinary approach.
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http://dx.doi.org/10.7759/cureus.21145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832383PMC
January 2022

Facemasks during aerobic exercise: Implications for cardiac rehabilitation programs during the Covid-19 pandemic.

Rev Port Cardiol (Engl Ed) 2021 12;40(12):957-964

Department of Physical Medicine & Rehabilitation, Centro Hospitalar e Universitário de São João, Porto, Portugal.

Introduction And Objectives: During the COVID-19 pandemic, among the safety measures adopted, use of facemasks during exercise training sessions in cardiac rehabilitation programs raised concerns regarding possible detrimental effects on exercise capacity. Our study examined the cardiorespiratory impact of wearing two types of the most common facemasks during treadmill aerobic training.

Methods: Twelve healthy health professionals completed three trials of a symptom-limited Bruce treadmill protocol: Without a mask, with a surgical mask and with a respirator. Perceived exertion and dyspnea were evaluated with the Borg Scale of Perceived Exertion and the Borg Dyspnea Scale, respectively. Blood pressure, heart rate and arterial oxygen saturation (SpO2) were measured at each 3-minute stage.

Results: Using a surgical mask or a respirator resulted in a shorter duration of exercise testing. At peak capacity, using a respirator resulted in higher levels of dyspnea and perceived exertion compared to not wearing a facemask. A significant drop in SpO2 was present at the end of exercise testing only when using a respirator. There were no differences in either chronotropic or blood pressure responses between testing conditions.

Conclusions: Professionals involved in cardiac rehabilitation should be aware of the cardiorespiratory impact of facemasks. Future studies should assess whether exposure to these conditions may impact on the overall results of contemporary cardiac rehabilitation programs.
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http://dx.doi.org/10.1016/j.repce.2021.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673478PMC
December 2021

Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer.

Clin Cancer Res 2022 Mar;28(5):993-1003

Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial.

Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points.

Results: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment.

Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2498DOI Listing
March 2022

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial.

Breast Cancer Res Treat 2022 Feb 3;191(3):565-576. Epub 2021 Dec 3.

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

Purpose: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC).

Methods: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).

Results: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%).

Conclusion: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.
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http://dx.doi.org/10.1007/s10549-021-06450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831286PMC
February 2022

Neoadjuvant eribulin in HER2-negative early-stage breast cancer (SOLTI-1007-NeoEribulin): a multicenter, two-cohort, non-randomized phase II trial.

NPJ Breast Cancer 2021 Nov 25;7(1):145. Epub 2021 Nov 25.

Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Eribulin prolongs overall survival in patients with pre-treated advanced breast cancer. However, no biomarker exists to prospectively select patients who will benefit the most from this drug. SOLTI-1007-NeoEribulin is a phase II, open-label, two-cohort, exploratory pharmacogenomic study in patients with clinical stage I-II HER2-negative breast cancer receiving neoadjuvant eribulin monotherapy treatment. Primary objective was to explore the association of baseline tumor gene expression with pathological complete response in the breast (pCR) at surgery. Key secondary objectives were pCR rates in all patients and according to HR status, gene expression changes during treatment and safety. One-hundred one hormonal receptor-positive (HR + ) and seventy-three triple-negative breast cancer (TNBC) patients were recruited. The pCR rates were 6.4% in all patients, 4.9% in HR + disease and 8.2% in TNBC. The TNBC cohort was interrupted due to a progression disease rate of 30.1%. The pCR rates differed according to intrinsic subtypes: 28.6% in HER2-enriched, 11.1% in Normal-like, 7.9% in Luminal B, 5.9% in Basal-like and 0% in Luminal A (HER2-enriched vs. others odds ratio = 7.05, 95% CI 1.80-42.14; p-value = 0.032). Intrinsic subtype changes at surgery occurred in 33.3% of cases, mostly (49.0%) Luminal B converting to Luminal A or Basal-like converting to Normal-like. Baseline tumor-infiltrating lymphocytes (TILs) were significantly associated with pCR. Eribulin showed a good safety profile with a low response and pCR rates. Patients with HER2-negative disease with a HER2-enriched profile may benefit the most from eribulin. In addition, significant biological activity of eribulin is observed in Luminal B and Basal-like subtypes.
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http://dx.doi.org/10.1038/s41523-021-00351-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616926PMC
November 2021

First Nationwide Molecular Screening Program in Spain for Patients With Advanced Breast Cancer: Results From the AGATA SOLTI-1301 Study.

Front Oncol 2021 4;11:744112. Epub 2021 Nov 4.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

Background: The SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain.

Methods: DNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments. The primary objective was to determine the success of matching somatic DNA alteration to an experimental drug/drug class.

Results: Between September 2014 and July 2017, 305 patients with ABC from 10 institutions were enrolled. Tumor sequencing was successful in 260 (85.3%) patients. Median age was 54 (29-80); most tumors were hormone receptor-positive/HER2-negative (74%), followed by triple-negative (14.5%) and HER2-positive (11.5%). Ninety-seven (37%) tumor samples analyzed proceeded from metastatic sites. Somatic mutations were identified in 163 (62.7%) patients, mostly in (34%), (22%), (5%), (3%), and (3%) genes. Significant enrichment of mutation was observed in metastatic versus primary samples (9% 2%; p=0.01). Genome-driven cancer therapy was recommended in 45% (n=116) of successfully screened patients, 11% (n=13) of whom finally received it. Among these patients, 46.2% had a PFS of ≥6 months on matched therapy.

Conclusions: AGATA is the first nationwide molecular screening program carried out in Spain and we proved that implementing molecular data in the management of ABC is feasible. Although these results are promising, only 11% of the patients with genome-driven cancer therapy received it.
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http://dx.doi.org/10.3389/fonc.2021.744112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600133PMC
November 2021

High mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer.

Clin Cancer Res 2022 01 30;28(1):137-149. Epub 2021 Sep 30.

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

Purpose: amplification (amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for amp breast cancer. High-level amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, 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 17 breast cancer patient-derived xenografts (PDXs) harboring amplification in and in 10 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) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high mRNA levels and was observed in patients previously treated with antiangiogenic drugs.

Conclusions: Tailored therapy with FGFRis in molecularly selected MBC based on high mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1810DOI Listing
January 2022

Facemasks during aerobic exercise: Implications for cardiac rehabilitation programs during the Covid-19 pandemic.

Rev Port Cardiol 2021 Dec 22;40(12):957-964. Epub 2021 Sep 22.

Department of Physical Medicine & Rehabilitation, Centro Hospitalar e Universitário de São João, Porto, Portugal.

Introduction And Objectives: During the COVID-19 pandemic, among the safety measures adopted, use of facemasks during exercise training sessions in cardiac rehabilitation programs raised concerns regarding possible detrimental effects on exercise capacity. Our study examined the cardiorespiratory impact of wearing two types of the most common facemasks during treadmill aerobic training.

Methods: Twelve healthy health professionals completed three trials of a symptom-limited Bruce treadmill protocol: Without a mask, with a surgical mask and with a respirator. Perceived exertion and dyspnea were evaluated with the Borg Scale of Perceived Exertion and the Borg Dyspnea Scale, respectively. Blood pressure, heart rate and arterial oxygen saturation (SpO2) were measured at each 3-minute stage.

Results: Using a surgical mask or a respirator resulted in a shorter duration of exercise testing. At peak capacity, using a respirator resulted in higher levels of dyspnea and perceived exertion compared to not wearing a facemask. A significant drop in SpO2 was present at the end of exercise testing only when using a respirator. There were no differences in either chronotropic or blood pressure responses between testing conditions.

Conclusions: Professionals involved in cardiac rehabilitation should be aware of the cardiorespiratory impact of facemasks. Future studies should assess whether exposure to these conditions may impact on the overall results of contemporary cardiac rehabilitation programs.
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http://dx.doi.org/10.1016/j.repc.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455281PMC
December 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 11 11;27(21):5818-5827. 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.

Patients And Methods: 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
November 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

Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Medical Oncology Department, Vall d'Hebron Hospital, 08035 Barcelona, Spain.

Development of brain metastases can occur in up to 30-50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain metastases; however, screening for brain metastases is not currently recommended due to the lack of robust evidence to support survival benefit. In recent years, several novel anti-HER2 agents have led to significant improvements in the outcomes of HER2-positive metastatic breast cancer. Despite these advances, brain and leptomeningeal metastases from HER2-positive breast cancer remain a significant cause of morbidity and mortality, and their optimal management remains an unmet need. This review presents an update on the current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer and discusses the open questions in the field.
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http://dx.doi.org/10.3390/cancers13122927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230933PMC
June 2021

Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative.

Cancer Discov 2021 11 28;11(11):2796-2811. Epub 2021 Jun 28.

Sahlgrenska University Hospital, Gothenburg, Sweden.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for and somatic mutations. Metastases were enriched in , and mutations; and amplifications; and deletions. An increase in clonality was observed in driver genes such as and . Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with and/or mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR/HER2 cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1647DOI Listing
November 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

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

N Engl J Med 2021 04;384(16):1529-1541

From the Division of Medical Oncology, Massachusetts General Hospital Cancer Center (A. Bardia), and the Department of Medical Oncology, Dana-Farber Cancer Institute (S.M.T.) - both in Boston; the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H.); the Medical Oncology Department and the Department of Drug Development and Innovation, Institut Curie, Paris (D.L.), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (F.D.), and the Department of Medical Oncology, Centre Eugène Marquis, Rennes (V.D.) - all in France; the Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven (K.P.), and the Clinical Trials Conduct Unit (P.A.), Institut Jules Bordet-Université Libre de Bruxelles (M.J.P.), Brussels - all in Belgium; the Medical Oncology Department and Breast Cancer Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (M.O.), and the International Breast Cancer Center, Quiron Group (J.C.) - all in Barcelona; Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (A. Brufsky); Ohio State University Wexner Medical Center, Columbus (S.D.S.); Columbia University Irving Medical Center (K.K.) and Memorial Sloan Kettering Cancer Center (T.T.) - both in New York; Northside Hospital, Atlanta (A.B.Z.); Florida Cancer Specialists, Tampa (R.W.); Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (F.L.); Rocky Mountain Cancer Centers, Greenwood Village, CO (S.D.); Baylor University Medical Center and Texas Oncology, Dallas (J.O.); Segal Cancer Centre, Jewish General Hospital, Montreal (C.F.); Barts Cancer Institute, Queen Mary University of London, London (P.S.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (L.A.C.); Gianni Bonadonna Foundation, Milan (L.G.); the Department of Medicine and Research, Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany (S.L.); Immunomedics, Morris Plains, NJ (D.M.G., Q.H., M.S.O., L.M.I.); and the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.).

Background: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.

Methods: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.

Results: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.

Conclusions: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).
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http://dx.doi.org/10.1056/NEJMoa2028485DOI Listing
April 2021

PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.

Br J Cancer 2021 04 15;124(9):1581-1591. Epub 2021 Mar 15.

Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance.

Methods: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway.

Results: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment.

Conclusions: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.
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http://dx.doi.org/10.1038/s41416-021-01293-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076303PMC
April 2021

Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor-Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2-Based Therapy.

Clin Cancer Res 2021 06 25;27(11):3116-3125. Epub 2021 Feb 25.

Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

Purpose: We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer.

Experimental Design: Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS).

Results: A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 ( = 0.012).

Conclusions: In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172481PMC
June 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

Palbociclib combined with endocrine therapy in heavily pretreated HR/HER2 advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

Breast 2020 Dec 13;54:286-292. Epub 2020 Nov 13.

Hospital Universitario Virgen de Valme, Sevilla, Spain.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR/HER2) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017.

Patients And Methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR/HER2 mBC who had progressed on ≥4 treatments for advanced disease were eligible.

Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia.

Conclusions: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.
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http://dx.doi.org/10.1016/j.breast.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695980PMC
December 2020

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

Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer.

JCO Precis Oncol 2020 Nov;4:1012-1024

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Purpose: Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with -altered tumors. We report findings from the extensive translational research program.

Patients And Methods: Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored.

Results: Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating or mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases.

Conclusion: These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.
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http://dx.doi.org/10.1200/PO.19.00396DOI Listing
November 2020

Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR, HER2 Advanced Breast Cancer.

Clin Cancer Res 2020 12 30;26(24):6417-6428. Epub 2020 Sep 30.

Department of Breast Medical Oncology, Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).

Patients And Methods: Postmenopausal women with hormone receptor-positive (HR), human epidermal growth factor receptor 2-negative (HER2), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.

Results: Patients ( = 116) received triplet therapy ( = 83 in the dose-escalation phase; = 33 in the dose-expansion phase). A dose-dependent drug-drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.

Conclusions: Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR, HER2 ABC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489181PMC
December 2020

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER Breast Cancer.

Cancer Cell 2020 10 24;38(4):516-533.e9. Epub 2020 Sep 24.

Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Cancer Centre, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge UK. Electronic address:

PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.
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http://dx.doi.org/10.1016/j.ccell.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562820PMC
October 2020

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial.

Clin Cancer Res 2020 11 16;26(22):5820-5829. Epub 2020 Sep 16.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.

Patients And Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.

Results: Seventy-one patients were recruited ( = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; = 0.003).

Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0844DOI Listing
November 2020
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