Summary Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to ...increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01771458. Findings Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30). Interpretation The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. Funding Institut Curie.
Purpose of Review
The purpose of the review is to summarize the data regarding PD-L1 expression in breast cancer and the results of first clinical trials with PD-1 or PD-L1 inhibitors in patients ...with metastatic breast cancer.
Recent Findings
PD-L1 expression is heterogeneous across primary breast cancers, and is generally associated with the presence of tumor-infiltrating lymphocytes and the presence of poor-prognosis features such as high grade, and aggressive molecular subtypes (triple-negative (TN), basal, HER2-enriched). Early phase clinical trials using PD-1 or PD-L1 inhibitors alone or in combination have shown objective tumor responses and durable long-term disease control, in heavily pre-treated patients, notably in the TN subtype.
Summary
Blockade of PD-1 or PD-L1 shows impressive antitumor activity in some subsets of breast cancer patients. Many clinical trials are ongoing in the metastatic and neoadjuvant setting, alone and in combination with chemotherapy, targeted therapy, radiotherapy, and/or other immune therapy. The identification of biomarkers predictive for a clinical benefit is warranted.
Recently, immune checkpoint inhibitors (ICI) have demonstrated survival benefits in triple-negative breast cancer (TNBC) patients, treated in both the advanced and the early settings.
As monotherapy, ...ICI failed to demonstrate a superiority over chemotherapy in pretreated advanced TNBC. In the first-line setting, ICI in combination with chemotherapy have shown consistent gains in progression-free survival in programmed death-ligand 1-positive TNBC, but only pembrolizumab indisputably demonstrated a significant overall survival benefit. In early-stage TNBC patients treated with neoadjuvant chemotherapy (NAC), ICI may improve the pathological complete response (pCR) rate. In the KEYNOTE-522 trial enrolling stage II to III TNBC patients, pembrolizumab, in combination with a NAC composed of carboplatin-paclitaxel followed by anthracyclines, and continued in the adjuvant phase led to significant increases in both pCR and disease-free survival, a practice-changing result in the field. Importantly, no unexpected safety signal was observed, but the possibility of definitive ICI-related toxicities may be challenging in curable early disease.
Immunotherapy is now an important component in the therapeutic management of TNBC. Unresolved issues include the best chemotherapy partners, additional biomarkers to maximize the clinical benefit, and the possible extension of its use to other breast cancer subtypes.
Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth ...factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations (gBRCA1/2m). In this setting, PARP inhibitors, either as single agent or in combination with platinum-based chemotherapy, significantly increased progression-free survival, as compared to conventional chemotherapy. Accordingly, further therapeutic advances are expected at an earlier stage of the disease. In the neoadjuvant setting, veliparib failed to increase the pathological complete response rate when added to a carboplatin-based regimen, in unselected triple-negative breast cancer patients. Similarly, when administered before anthracycline-cyclophosphamide, the neoadjuvant olaparib-paclitaxel combination was not superior to carboplatin-paclitaxel, in patients with HER2-negative breast cancer and BRCA1/2 mutation, or homologous recombination defect. Yet, neoadjuvant talazoparib, administered as a single-agent in patients with HER2-negative breast cancer and germline BRCA1/2 mutation, achieved an impressive pathological complete response rate of nearly 50%. In the adjuvant setting, the results from the OlympiA phase III study, evaluating adjuvant olaparib in HER2-negative early breast cancer and germline BRCA1/2 mutations, are eagerly awaited. Ongoing trials should clarify whether PARP inhibitors might improve outcome when administered in the adjuvant or neoadjuvant setting in early breast cancer patients with BRCA1/2 mutation or homologous recombination defect.
The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, ...making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main "hotspots". In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.
Summary Background Brain metastases occur in 30–50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy ...(WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. Methods In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m2 , orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov , number NCT00967031. Findings Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2–27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1–79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. Interpretation The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. Funding GlaxoSmithKline-France and UNICANCER.
Breast cancers (BC) associated with germline mutations of
represent 3⁻5% of cases.
-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging ...agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of
-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the
-wild type population, the
ness concept.
Half of HER2-negative breast cancers (BC) show HER2-low expression. The strong efficacy of recent anti-HER2 antibody–drug conjugates (ADC) in HER2-low tumours has risen the interest of HER2-low as a ...proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumours. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumours.
Data were collected from the Institut Paoli-Calmettes database. HER2-low tumours were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0. Clinicopathological characteristics, pCR (defined as ypT0/ypTis and pN0sn or ypN0) and DFS rates were compared between the two cohorts.
From Jan/2005 to Jun/2021, 1111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR)-positive and 37% of HR-negative tumours (p < 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumours (p = 0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p = 0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis. No correlation existed between DFS and HER2-status.
HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients.
•Incidence of HER2-low in “HER2-negative” neoadjuvant patients was 41%.•Including 50% in HR-positive, and 32% in HR-negative patients.•pCR rates of 23% in HER2-low and 30% in HER2-0 tumours.•HER2-status independently impact HR+ patients only.•No correlation between DFS and HER2-status.
Abstract Breast cancer is the first cause of cancer in women worldwide. Recent molecular analyses have shown that it is not a single disease but a mixture of several diseases with different ...biological behaviors, which should lead to treatment customization for each patient. Personalized medicine is based on tumor and/or patient molecular profiles. This new way to think oncology is currently applied at different stages of breast cancer management, including prognosis, prediction of treatment efficacy, and development of new therapies via new kinds of clinical trials. These trials are not only based on tumor site but also on tumor genetic characterization using genomic tools such as gene expression profiling, array-CGH or next-generation sequencing technologies. The aim of personalized medicine is to tailor treatment according to the specificities of a single disease in a given patient. In this review, we present the advances in treatment personalization which are currently used in daily practice as well as the technologies and therapies under investigation in various clinical trials.
Brain metastases (BM) are the most common intracranial neoplasm in adults. Initially considered as an essentially terminal stage of advanced cancer, BM are increasingly being recognized as an ...emerging area of clinical interest. Their epidemiological characteristics have changed significantly, including an increased incidence in tumors frequently associated with BM, such as lung and breast cancer or melanoma, but also a more frequent occurrence with other primary tumor entities such as renal, colorectal and ovarian cancer. BM are more commonly diagnosed in multiple intracerebral sites, but in the context of controlled extracranial disease. Accordingly, progress in the development of systemic treatments, together with the rationalized use of surgical resection, radiosurgery and whole-brain radiotherapy, have led to an increase in the number of long-term survivors and in median survival. The recent emergence of targeted therapies and growing knowledge regarding the specific biology of BM should allow further improvements in prognosis of this devastating disease.
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