K. Punie MD

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)

Highlights in breast cancer

ASCO 2021 featured one crucial, practice-changing trial in early breast cancer: the OlympiA trial showed that one year of adjuvant olaparib improves invasive disease-free survival by 8.8% compared to placebo, when administered to high risk early breast patients (triple negative or hormone sensitive and HER2 negative) with a germline BRCA1 or 2 mutation. Furthermore, ECOG-ACRIN EA1131 failed to show improved outcome in triple negative breast cancer treated without pathological complete response after neoadjuvant chemo-therapy with platinum based chemotherapy compared to the current standard capecitabine. GeparNUEVO for the first time showed long term outcome with anti-PD(L)1 therapy administered with neoadjuvant chemotherapy in triple negative breast cancer. In the advanced setting, interesting overall survival updates of the PALOMA-3 and MONALEESA-3 studies were presented. Furthermore, the SYsucc-002 trial demonstrated that trastuzumab plus endocrine therapy was non-inferior to and had fewer toxicities compared with trastuzumab plus chemotherapy in patients with HR+/HER2- metastatic breast cancer. In addition, this article will touch upon several other studies that are notable.

(BELG J MED ONCOL 2021;15(5):208-17)

A case of HER2-positive breast cancer with rapidly progressing CNS metastases

SUMMARY

A 53-year old woman previously treated for stage IIIc Her2-positive breast cancer presented to the outpatient oncology department with symptoms of holocranial headache irradiating to the neck in combination with morning sickness and vomitus. Brain CT showed multiple cerebellar metastases with signs of tonsillar herniation through the foramen magnum. Since radiotherapy was deemed unsafe given the possibility that transient increase of intracranial pressure could worsen the herniation, urgent treatment with corticosteroids and capecitabine-lapatinib was started. The metastases and peritumoral oedema initially responded well, which allowed subsequent pancranial radiotherapy after three weeks of systemic therapy. We provide a short overview of studies showing that systemic therapy can induce tumour response in brain metastases related to HER2+ positive disease.

BELG J MED ONCOL 2021;15(3):123-7

Systemic treatment landscape and algorithm for hormone-receptor positive, HER2 negative advanced breast cancer

SUMMARY

Hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer accounts for 65% of all metastatic breast cancer (MBC) cases. With the advent of CDK4/6 inhibitors, single-agent endocrine therapy (ET) is no longer the only first-line systemic treatment option for the vast majority of patients presenting without visceral crisis. Other endocrine-based treatment options are emerging in further lines, with the goal to delay the administration of chemotherapy as long as possible. The optimal sequence of treatment is unknown. We here present a review of the available treatments and propose a treatment algorithm taking into account the latest therapeutic developments.

(BELG J MED ONCOL 2021;15(1):20-33)

Immunotherapy for the treatment of triple-negative breast cancer

While immune checkpoint inhibitors (ICIs) demonstrated a convincing efficacy with durable responses in many cancer types, the single agent efficacy of ICIs in patients with advanced triple-negative breast cancer (TNBC) proved to be low. In a successful attempt to boost this clinical activity, ICIs were subsequently combined with chemotherapy in patients with metastatic TNBC. Following the positive results in the metastatic setting, ICIs are now also under evaluation in combination with neoadjuvant chemotherapy in patients with early TNBC. This review provides an overview of the results obtained with ICI in TNBC, from the disappointing results with ICI monotherapy, over the emerging data with ICI-chemotherapy combinations in the neoadjuvant setting to the pivotal, practice-changing results obtained with atezolizumab and atezolizumab in combination with chemotherapy in metastatic TNBC patients.

Highlights in breast cancer

During the 2020 Virtual ESMO meeting, long-awaited results were presented of several important breast cancer studies. For hormone receptor positive (HR+) breast cancer, ESMO 2020 featured conflicting results on the use of CDK4/6 inhibitors in the adjuvant treatment of patients with hormone-receptor positive (HR+) early breast cancer. In HR+ metastatic breast cancer, final overall survival data were presented of the SOLAR-1 trial evaluating alpelisib in PIK3CA mutant patients. In triple negative breast cancer (TNBC), new data on immune therapy were presented. In early-stage TNBC, the addition of atezolizumab to neoadjuvant chemotherapy resulted in a significant increase in the rate of pathological complete responses (pCR). In the metastatic setting, final results of the IMpassion130 trial confirmed the benefit of atezolizumab combined with nab-paclitaxel as first-line treatment for metastatic PD-L1 positive TNBC. Unexpectedly, the IMpassion131 trial evaluating atezolizumab plus paclitaxel in first-line treatment of patients with metastatic TNBC failed to meet its primary endpoint. Finally, the phase III randomized controlled ASCENT trial identified the antibody-drug conjugate (ADC) sacituzumab govitecan as a safe and highly effective treatment option for heavily pre-treated metastatic TNBC patients.