HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial

Llombart-Cussac, Antonio; Cortés, Javier; Paré, Laia; Galván, Patricia; Bermejo, Begoña; Martínez, Noelia; Vidal, María; Pernas, Sònia; López, Rafael; Muñoz, Montserrat; Nuciforo, Paolo; Morales, Serafín; Oliveira, Mafalda; Peña, Lorena de la; Peláez, Alexandra; Prat, Aleix

doi:10.1016/s1470-2045(17)30021-9

Cited by 274 publications

(286 citation statements)

References 41 publications

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“…The PAMELA and TBRC006 trials combined double anti-HER2 blockade with trastuzumab and lapatinib plus ET therapy in the case of HR+ patients. High pCR rates in the breast of 27 and 30%, respectively, were achieved without CT [82,83]. Similarly to data reported from the BERENICE trial combining trastuzumab and pertuzumab, PAMELA demonstrates that HER2-enriched patients according to PAM50 are more likely to achieve a pCR (41%) with double blockade in the absence of CT than other HER2+ intrinsic molecular subtypes (10%).…”

Section: Her2-positive Breast Cancermentioning

confidence: 81%

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

et al. 2018

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For decades, the neoadjuvant setting has provided a useful scenario for research in breast cancer. Historically, neoadjuvant clinical trials, either hormone therapy-based or chemotherapy-based, have tried to recapitulate the results of their counterpart adjuvant studies, but with smaller patient numbers, more rapid outcomes (clinical response and/or pathologic complete response (pCR)), together with additional biologic information. As for neoadjuvant chemotherapy trials, the increase in pCR rates has been recently accepted as an appropriate surrogate marker to accelerate drug approval in high-risk breast cancer patients. In this setting, with the exception of luminal A tumors, pCR has been associated with improved long-term outcomes, particularly when the analysis is based on specific trials for each breast cancer subtype. For luminal tumors receiving neoadjuvant endocrine therapy, Ki67 at 2-4 weeks and the preoperative endocrine prognostic index score are the most accepted intermediate markers of efficacy, which will be validated in ongoing larger trials. In this review, we describe the different neoadjuvant designs: from the classical randomized trials in which treatment is delivered for 6 or more months to short non-therapeutic presurgical studies lasting just 2 or 3 weeks. We also review the main neoadjuvant trials, either ongoing or completed, for luminal, triple-negative, and HER2-positive breast cancer. The translational effort and research of biomarkers conducted in these studies will be particularly addressed.

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Section: Her2-positive Breast Cancermentioning

confidence: 81%

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

et al. 2018

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“…In this regard, methods and defined cutoffs to accurately identify the true HER2-addicted tumors with high HER2 expression and signaling activity are critical. Indeed, recent studies suggest that high HER2 mRNA levels and the PAM50-classfied HER2-enriched subtype are associated with a better response to HER2 therapy both with(17) and without chemotherapy(10). Additionally, the key role of intra-tumor HER2 amplification heterogeneity in HER2-targeted therapy resistance has been recently shown(18), which further emphasizes the need for homogeneous HER2 amplification to achieve an effective response to HER2-targeted therapy.…”

Section: Oncogenic Her2 Addictionmentioning

confidence: 99%

“…With the limitation of cross-study comparison and small patient cohorts, the outcome of patients treated with endocrine therapy compared to no endocrine therapy suggests that adding concomitant endocrine therapy is needed for HER2-positive/HR-positive tumors. Finally, in both the PAMELA trial (after 14 days of dual HER2 blockade without chemotherapy) and the CALGGB 40601 trial (at the completion of single or dual anti-HER2 treatment plus chemotherapy), a substantial percentage of HER2-enriched tumors at baseline switched to the Luminal A subtype, an observation further indicating the reactivation of ER signaling in response to anti-HER2 therapy(10, 17). Together, these data suggest that ER levels and signaling may predict outcome to anti-HER2 therapy and that these two pathways should be concomitantly blocked.…”

Section: Alternative Signaling Pathways: the Role Of Ermentioning

confidence: 99%

“…The promise of a de-escalation approach in reducing the toxicity without affecting patient outcome has been demonstrated in a recent adjuvant trial using only paclitaxel as the chemotherapy backbone with trastuzumab, a low-toxicity regimen, in HER2-positive patients with favorable prognosis(84). Recent neoadjuvant clinical trials TBCRC 006(11), TBCRC 023(85), PAMELA(10), and NeoSphere(9) (Table 1) investigated the efficacy of dual HER2 inhibition without chemotherapy and demonstrated impressive pCR rates (20–30%) in patients. These results suggest that treatment escalation may not always be beneficial or even essential.…”

Section: Conclusion and Future Directions: De-escalation Approaches mentioning

confidence: 99%

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De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

et al. 2017

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Summary Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15–20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.

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“…This has led to the development of multiple commercial and research RNA-based assays for predicting risk of recurrence and need for chemotherapy in hormone receptor-positive, HER2-negative early breast cancer, with two large prospective trials already demonstrating clinical utility of these assays in therapeutic decision-making. (8, 9) Current initiatives include efforts to use gene expression patterns of tumor and immune signatures to prognosticate and tailor treatment in HER2-positive (10–12) and triple negative (13, 14) cancers. The landscape of translational transcriptomics was recently reviewed in a CCR Anniversary commentary.…”

Section: Overview Of This Ccr Focusmentioning

confidence: 99%

Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go?

Partridge

Carey

2017

Clinical Cancer Research

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This CCR Focus highlights areas in breast cancer research with the greatest potential for clinical and therapeutic application. The six articles in the issue address the state of the science in a broad range of areas with a focus on “hot” though sometimes controversial topics, unanswered questions, and unmet need. From mutational signatures, the cancer genomic revolution, and new inroads in immunotherapy for breast cancer, to unique concerns of vulnerable populations as well as national and global health disparities, these works represent much of the promise of breast cancer research as well as the challenges in the coming years. Each review focuses not only on recent discoveries, but also putting the topic in context including limitations to overcome. This overview is designed to further contextualize the highlighted issues within the broader research landscape. We also present new information from a poll of ALLIANCE for Clinical Trials in Oncology Breast Committee members regarding the most needed and viable potential future NCI-supported clinical trials in breast cancer. The great challenge is to translate the potential benefits of greater scientific knowledge reflected in this Focus series into improvements in outcomes for individuals and populations with breast cancer. A unifying theme across the six articles contained in this CCR Focus is the increasingly recognized value and necessity of collaboration across disciplines from bench to bedside to populations. Only continued and iteratively amplified scientific, clinical and governmental commitment to creating, testing, and implementing new knowledge will reduce the global morbidity and mortality of breast cancer.

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HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial

Cited by 274 publications

References 41 publications

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go?

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