K. Punie MD

The current treatment landscape for patients with HER2-low metastatic breast cancer

SUMMARY

HER2 overexpression has been a therapeutic target in breast cancer (BC) for many years and the development of anti-HER2 therapies has markedly improved the outcome of patients exhibiting high levels of HER2 expression. In this, the HER2 status of patients was traditionally defined in a binary fashion, in which patients with high levels of HER2 expression were classified as HER2-positive, while all the rest were denominated as HER2-negative. Despite being classified as HER2-negative; the majority of these BCs do express some level of HER2. Until recently, however, these low levels of HER2 expression did not have any therapeutic implications. This has changed with the publication of the DESTINY-Breast04 (DB-04) study in which trastuzumab deruxtecan (T-DXd) was shown to significantly improve the progression-free (PFS) and overall survival (OS) of patients with HER2-low metastatic BC. These findings require a recalibration of the treatment paradigm for patients with advanced BC. Furthermore, the increased interest in HER2-low BC led to questions on the biology, epidemiology, heterogeneity, and prognostic relevance of HER2-low disease and confronts physicians with the challenge of incorporating the treatment of HER2-low disease in the rapidly evolving treatment landscape for patients with hormone-receptor-positive (HR+) and triple-negative BC (TNBC).

(BELG J MED ONCOL 2024;18(4):141–51)

Belgian clinical practice guidelines for the treatment of patients with HER2-positive advanced breast cancer

SUMMARY

HER2-targeted agents are the central component of HER2-positive metastatic breast cancer (MBC) treatment. The combination of trastuzumab, pertuzumab and a taxane is the preferred first-line regimen in most settings. For patients with disease relapse after adjuvant therapy, treatment decisions in the first-line are influenced by the treatment-free interval and the regimens used in the (neo)adjuvant setting. T-DXd has been recently established as the preferred second-line therapy. T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are reasonable third-line options, although efficacy and safety data of these regimens after prior exposure to T-DXd are lacking. In fourth and later lines, trastuzumab duocarmazine, neratinib plus capecitabine, margetuximab plus chemotherapy, lapatinib-based combinations or the continuation of trastuzumab with different chemotherapy partners are valid alternatives.

(BELG J MED ONCOL 2022;16(6): 287–92)

Current treatment patterns of advanced hormone receptor-positive, HER2-negative breast cancer in Belgium

SUMMARY

Several treatment guidelines exist for hormone receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC), but various factors influence their local implementation. We performed a 3-round Delphi methodbased study in search of a consensus regarding HR+/HER2- aBC management in Belgian practice. Panel questionnaires included questions related to treatment patterns, drug-drug interactions (DDIs) and side-effect management (SEM). A consensus threshold of 75% was applied. The results were evaluated for concordance with the ABC5 guidelines. Treatment patterns in HR+/HER2- aBC reached moderate to high consensus among Belgian oncologists and showed high concordance with ABC5 guidelines. A CDK4/6 inhibitor is the preferred first-line treatment, combined with an aromatase inhibitor or with fulvestrant in the endocrine-sensitive and -resistant setting, respectively. Alpelisib-fulvestrant is the preferred second-line treatment in presence of a PIK3CA-activating mutation. Some practices regarding DDI and SEM needed further discussion before reaching consensus highlighting the need for additional training and incorporation of these topics in guidelines.

(BELG J MED ONCOL 2022;16(4):176–86)

Escalation and de-escalation strategies in early breast cancer

SUMMARY

Early breast cancer is the most frequently diagnosed cancer among women worldwide. Different subtypes have been identified, and with them, new treatment strategies have emerged. In order to elaborate a personalised treatment, clinicians need reliable pathological and molecular disease subtyping, refined assessments of the risk of relapse, and predictive markers to estimate treatment benefit. Combining these elements allows for de-escalation in some patients and, on the contrary, identifies those who should receive more intensive therapy and serve as candidates for escalation strategies in standard practice or clinical trials. This article reviews the de-escalation and escalation strategies currently available and will explore future treatment perspectives in early breast cancer.

(BELG J MED ONCOL 2022;16(3):102–13)

Congress highlights SABCS 2021

SUMMARY

The hybrid SABCS 2021 could only attract a few hundred life attendees, but like every year, several key abstracts were presented. In early stage, a meta-analysis on aromatase inhibitor versus tamoxifen in premenopausal ER+ patients showed lower recurrence with aromatase inhibitors, while the impact on overall survival remains unclear. An EBCTCG meta-analysis showed no benefit for an anthracycline-taxane adjuvant chemotherapy regimen compared to a taxane only regimen, if the taxane was given sequentially after the anthracycline, confirming the role of anthracycline-free chemotherapy regimens in a large proportion of patients with early breast cancer. In ER+ metastatic disease, the new SERD elacestrant was more potent than classical endocrine therapy after progression on first/second line endocrine therapy. Datopotamab deruxtecan is a promising new ADC targeting TROP2 with clear activity in triple negative disease. In HER2 positive disease, T-DXd displayed substantial antitumour effect on brain metastases, and pyrotinib can be added to the list of highly potent HER2 tyrosine kinase inhibitors. In patients with HER2 mutations, neratinib showed clear antitumour activity both in ER positive and triple negative metastatic breast cancer. In the surgery field, black and Hispanic women were shown to be at higher risk for breast cancer related lymphedema after axillary lymph node dissection. The Italian SINODAR-ONE trial built further on the Z0011 trial and confirmed that axillary surgery can be omitted in patients with breast cancer patients and one or two macro metastatic sentinel nodes.

(BELG J MED ONCOL 2022;16(2):79–87)

Genomics of metastatic breast cancer

SUMMARY

The purpose of this review is to highlight the recent knowledge gathered on the genomics of metastatic breast cancer (BC), together with the clinical implications. Through large sequencing efforts, the genomic profile of BC is increasingly being deciphered, with a limited number of those findings having resulted in genomicmatched treatment options. The pace at which new discoveries are made is highest in the early setting, where large samples can easily be accessed through leftover tissue of resection specimens, and smaller diagnostic biopsies are also available. In the metastatic setting however, residual tissue from clinically indicated biopsies or resections are scarce. Some efforts have been undertaken through (inter)national, institutional, clinical trial- or patient-driven initiatives. They have highlighted important differences between the genomic landscape of metastatic versus primary tumour tissues. Especially in hormone receptor positive HER2 negative (HR+/HER2-) disease, driver mutations continue to accumulate after dissemination, most of them in the ESR1 or ERBB2 genes, or in genes involved in transcription regulation, MAPK- or PI3K-signaling pathways. Importantly, the genomic landscape is not homogeneous even within one patient, and significant heterogeneity is seen on an intra-patient, inter-lesion and intra-lesion level. This poses clinical challenges, with different subclones possibly harbouring differential sensitivity to systemic treatments and single biopsies not accurately reflecting the full molecular profile. Finally, through liquid biopsies, a more complete and less invasive insight into the tumour’s characteristic could theoretically be retrieved. However, it is unclear how well these profiles correlate with the actual diversity of the different lesions. Importantly, rapid autopsy programs have been shown to enhance research on the genomics of metastatic BC, and one such program was recently launched at UZ/KU Leuven.

(BELG J MED ONCOL 2022;16(1):18–28)

Highlights in breast cancer

At this year’s annual meeting of the European Society of Medical Oncology (ESMO) experts shared some game-changing data for the treatment of breast cancer (BC). In advanced HER2+ metastatic breast cancer m(BC), the DESTINY-Breast03 trial performed a head-to-head comparison of T-DM1 and trastuzumab deruxtecan (T-Dxd) following initial treatment with trastuzumab and a taxane, showing a major PFS benefit for T-DXd without major toxicity issues, establishing T-DXd as the new standard of care in this setting. In luminal breast cancer, the final analysis of the GIM-4 study supports the use of 7 years instead of 5 years adjuvant endocrine therapy in postmenopausal patients with hormone receptor positive (HR+)/HER2- early BC. For advanced stage HR+/HER2- BC, the MONALEESA-2 study shows >1y OS benefit when adding the CDK4/6 inhibitor ribociclib to letrozole as first-line treatment. Finally, in triple negative breast cancer (TNBC), the phase III BrighTNess study showed that addition of carboplatin to neoadjuvant chemotherapy provides long term EFS benefit. In metastatic TNBC, OS data of KEYNOTE-355 further support the use of first-line pembrolizumab plus chemotherapy in advanced PD-L1+ TNBC.

(BELG J MED ONCOL 2021;15(8):390–7)