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10 pages, 874 KiB

Open AccessArticle

Methods and Designs of Modern Breast Cancer Confirmatory Trials

by Julien Péron, Thibaut Reverdy, Colette Smenteck, Marion Cortet, Benoît You and Gilles Freyer

Cancers 2021, 13(11), 2757; https://doi.org/10.3390/cancers13112757 - 2 Jun 2021

Viewed by 2132

Abstract

Background: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to [...] Read more.

Background: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to describe the changes in methods and designs of breast cancer confirmatory trials. Methods: All phase III randomized trials published between 2001 and 2020 and assessing systemic BC therapies were included. Trials’ main characteristics, endpoints, and statistical methods were collected using a standardized data extraction form. Results: A total of 347 randomized controlled trials (RCTs) met the inclusion criteria. While most older trials (79%) included all subtypes of breast cancer, most recent trials populations were limited to one large intrinsic BC subgroup (69%). The use of gatekeeping testing strategies increased dramatically from 9% to 71%. The use of overall survival (OS) as an endpoint in the trials increased over time, but its use as a primary endpoint remained infrequent. The inclusion of OS testing in a hierarchical sequence in case of positive testing of a tumor-centered or composite endpoint appeared to have become the new standard. Conclusion: Our findings indicate some improvements in the quality of the evidence-base supporting new breast cancer drugs. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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12 pages, 2722 KiB

Open AccessArticle

Patient-Reported Outcomes of Palbociclib Plus Exemestane with GnRH Agonist versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer: A Prospective, Open-Label, Randomized Phase ll Trial (KCSG-BR 15-10)

by Soohyeon Lee, Seock-Ah Im, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Kyoung Eun Lee, Hee Kyung Ahn, Moon Hee Lee, Hee-Jun Kim, Han Jo Kim, Jong In Lee, Su-Jin Koh and Yeon Hee Park

Cancers 2020, 12(11), 3265; https://doi.org/10.3390/cancers12113265 - 5 Nov 2020

Cited by 10 | Viewed by 3006

Abstract

In the era of CDK4/6 inhibitors in hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, few trials have been specifically studied to compare quality of life between palbociclib plus endocrine therapy (ET) and cytotoxic chemotherapy exclusively in premenopausal women. We aimed to evaluate differences [...] Read more.

In the era of CDK4/6 inhibitors in hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, few trials have been specifically studied to compare quality of life between palbociclib plus endocrine therapy (ET) and cytotoxic chemotherapy exclusively in premenopausal women. We aimed to evaluate differences of patient report outcomes (PROs) between palbociclib plus ET and capecitabine. PROs were assessed using EORTC QLQ-C30 at baseline, every 6 weeks, and the end of treatment. All EORTC QLQ-30 scores were maintained from baseline to the end of treatment. Patients treated palbociclib plus ET arm experienced delay in time-to-deterioration of physical functioning (HR = 0.58, 95% CI, 0.36 to 0.84, p = 0.0058), nausea and vomiting (HR = 0.48; 95% CI, 0.32 to 0.73, p = 0.0005), and diarrhea (HR = 0.42; 95% CI, 0.27 to 0.65, p = 0.001). There was a numeric trend for worsening of insomnia (HR = 1.43; 95% CI, 0.96 to 2.16, p = 0.079) and favoring of appetite loss (HR = 0.69, 95% CI, 0.44 to 1.07, p = 0.09) in the palbociclib plus ET arm. Premenopausal patients with palbociclib plus ET maintained QoL without compromising treatment efficacy. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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Review

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24 pages, 403 KiB

Open AccessReview

Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives

by Romain Varnier, Christophe Sajous, Solène de Talhouet, Colette Smentek, Julien Péron, Benoît You, Thibaut Reverdy and Gilles Freyer

Cancers 2021, 13(19), 4840; https://doi.org/10.3390/cancers13194840 - 28 Sep 2021

Cited by 13 | Viewed by 3323

Abstract

The development of gene expression signatures since the early 2000′s has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early [...] Read more.

The development of gene expression signatures since the early 2000′s has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early breast cancer. However, many questions remain unanswered about their predictive ability, reproducibility and external validity in specific populations. They also represent a new hope to tailor (neo)adjuvant systemic treatment, adjuvant radiation therapy, hormone therapy duration and to identify a subset of patients who might benefit from CDK4/6 inhibitor adjuvant treatment. This review will highlight these particular issues, address the remaining questions and discuss the ongoing and future trials. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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15 pages, 576 KiB

Open AccessReview

PET/MRI for Staging the Axilla in Breast Cancer: Current Evidence and the Rationale for SNB vs. PET/MRI Trials

by Rosa Di Micco, Letizia Santurro, Maria Luisa Gasparri, Veronica Zuber, Giovanni Cisternino, Sara Baleri, Manuela Morgante, Nicole Rotmensz, Carla Canevari, Francesca Gallivanone, Paola Scifo, Annarita Savi, Patrizia Magnani, Ilaria Neri, Nadia Ferjani, Elena Venturini, Claudio Losio, Isabella Sassi, Giampaolo Bianchini, Pietro Panizza, Luigi Gianolli and Oreste Davide Gentilini Show full author list Hide full author list

Cancers 2021, 13(14), 3571; https://doi.org/10.3390/cancers13143571 - 16 Jul 2021

Cited by 9 | Viewed by 2569

Abstract

Axillary surgery in breast cancer (BC) is no longer a therapeutic procedure but has become a purely staging procedure. The progressive improvement in imaging techniques has paved the way to the hypothesis that prognostic information on nodal status deriving from surgery could be [...] Read more.

Axillary surgery in breast cancer (BC) is no longer a therapeutic procedure but has become a purely staging procedure. The progressive improvement in imaging techniques has paved the way to the hypothesis that prognostic information on nodal status deriving from surgery could be obtained with an accurate diagnostic exam. Positron emission tomography/magnetic resonance imaging (PET/MRI) is a relatively new imaging tool and its role in breast cancer patients is still under investigation. We reviewed the available literature on PET/MRI in BC patients. This overview showed that PET/MRI yields a high diagnostic performance for the primary tumor and distant lesions of liver, brain and bone. In particular, the results of PET/MRI in staging the axilla are promising. This provided the rationale for two prospective comparative trials between axillary surgery and PET/MRI that could lead to a further de-escalation of surgical treatment of BC. • SNB vs. PET/MRI 1 trial compares PET/MRI and axillary surgery in staging the axilla of BC patients undergoing primary systemic therapy (PST). • SNB vs. PET/MRI 2 trial compares PET/MRI and sentinel node biopsy (SNB) in staging the axilla of early BC patients who are candidates for upfront surgery. Finally, these ongoing studies will help clarify the role of PET/MRI in BC and establish whether it represents a useful diagnostic tool that could guide, or ideally replace, axillary surgery in the future. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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14 pages, 760 KiB

Open AccessReview

Measuring Quality of Life Using Patient-Reported Outcomes in Real-World Metastatic Breast Cancer Patients: The Need for a Standardized Approach

by Marloes E. Clarijs, Jacob Thurell, Friedrich Kühn, Carin A. Uyl-de Groot, Elham Hedayati, Maria M. Karsten, Agnes Jager and Linetta B. Koppert

Cancers 2021, 13(10), 2308; https://doi.org/10.3390/cancers13102308 - 12 May 2021

Cited by 12 | Viewed by 3360

Abstract

Metastatic breast cancer (MBC) patients are almost always treated to minimize the symptom burden, and to prolong life without a curative intent. Although the prognosis of MBC patients has improved in recent years, the median survival after diagnosis is still only 3 years. [...] Read more.

Metastatic breast cancer (MBC) patients are almost always treated to minimize the symptom burden, and to prolong life without a curative intent. Although the prognosis of MBC patients has improved in recent years, the median survival after diagnosis is still only 3 years. Therefore, the health-related quality of life (HRQoL) should play a leading role in making treatment decisions. Heterogeneity in questionnaires used to evaluate the HRQoL in MBC patients complicates the interpretability and comparability of patient-reported outcomes (PROs) globally. In this review, we aimed to provide an overview of PRO instruments used in real-world MBC patients and to discuss important issues in measuring HRQoL. Routinely collecting symptom information using PROs could enhance treatment evaluation and shared decision-making. Standardizing these measures might help to improve the implementation of PROs, and facilitates collecting and sharing data to establish valid comparisons in research. This is a prerequisite to learn about how they could impact the clinical care pathway. In addition, the prognostic value of intensified PRO collection throughout therapy on survival and disease progression is promising. Future perspectives in the field of PROs and MBC are described. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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27 pages, 4214 KiB

Open AccessEditor’s ChoiceReview

Metronomic Chemotherapy

by Marina Elena Cazzaniga, Nicoletta Cordani, Serena Capici, Viola Cogliati, Francesca Riva and Maria Grazia Cerrito

Cancers 2021, 13(9), 2236; https://doi.org/10.3390/cancers13092236 - 6 May 2021

Cited by 54 | Viewed by 10858

Abstract

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not [...] Read more.

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low –and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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25 pages, 1461 KiB

Open AccessReview

Surgical Management of the Axilla in Clinically Node-Positive Breast Cancer Patients Converting to Clinical Node Negativity through Neoadjuvant Chemotherapy: Current Status, Knowledge Gaps, and Rationale for the EUBREAST-03 AXSANA Study

by Maggie Banys-Paluchowski, Maria Luisa Gasparri, Jana de Boniface, Oreste Gentilini, Elmar Stickeler, Steffi Hartmann, Marc Thill, Isabel T. Rubio, Rosa Di Micco, Eduard-Alexandru Bonci, Laura Niinikoski, Michalis Kontos, Guldeniz Karadeniz Cakmak, Michael Hauptmann, Florentia Peintinger, David Pinto, Zoltan Matrai, Dawid Murawa, Geeta Kadayaprath, Lukas Dostalek, Helidon Nina, Petr Krivorotko, Jean-Marc Classe, Ellen Schlichting, Matilda Appelgren, Peter Paluchowski, Christine Solbach, Jens-Uwe Blohmer, Thorsten Kühn and the AXSANA Study Group Show full author list Hide full author list

Cancers 2021, 13(7), 1565; https://doi.org/10.3390/cancers13071565 - 29 Mar 2021

Cited by 86 | Viewed by 9434

Abstract

In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. [...] Read more.

In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical). Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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Other

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17 pages, 1221 KiB

Open AccessSystematic Review

A Systematic Review of the Use of Circulating Cell-Free DNA Dynamics to Monitor Response to Treatment in Metastatic Breast Cancer Patients

by Elisabeth M. Jongbloed, Teoman Deger, Stefan Sleijfer, John W. M. Martens, Agnes Jager and Saskia M. Wilting

Cancers 2021, 13(8), 1811; https://doi.org/10.3390/cancers13081811 - 10 Apr 2021

Cited by 7 | Viewed by 2652

Abstract

Monitoring treatment response in metastatic breast cancer currently consists mainly of radiological and clinical assessments. These methods have high inter-observer variation, suboptimal sensitivity to determine response to treatment and give little insight into the biological characteristics of the tumor. Assessing circulating tumor DNA [...] Read more.

Monitoring treatment response in metastatic breast cancer currently consists mainly of radiological and clinical assessments. These methods have high inter-observer variation, suboptimal sensitivity to determine response to treatment and give little insight into the biological characteristics of the tumor. Assessing circulating tumor DNA (ctDNA) over time could be employed to address these limitations. Several ways to quantify and characterize ctDNA exist, based on somatic mutations, copy number variations, methylation, and global circulating cell-free DNA (cfDNA) fragment sizes and concentrations. These methods are being explored and technically validated, but to date none of these methods are applied clinically. We systematically reviewed the literature on the use of quantitative ctDNA measurements over time to monitor response to systemic therapy in patients with metastatic breast cancer. Cochrane, Embase, PubMed and Google Scholar databases were searched to find studies focusing on the use of cfDNA to longitudinally monitor treatment response in advanced breast cancer patients until October 2020. This resulted in a total of 33 studies which met the inclusion criteria. These studies were heterogeneous in (pre-)processing procedures, applied techniques and design. An association between ctDNA and treatment response was found in most of the included studies, independent of the applied assay. To implement ctDNA-based response monitoring into daily clinical practice for metastatic breast cancer patients, sample (pre-) processing procedures need to be standardized and large prospectively collected sample cohorts with well annotated clinical follow-up are required to establish its clinical validity. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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