Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer.

Hormone receptor-positive (HR+) breast cancer (BC) accounts for approximately 70% of all breast invasive tumors. Endocrine therapy (ET) represents the standard treatment for HR + BC. Most patients, however, eventually develop resistance to ET, which limits their effectiveness and poses a major challenge for the management of HR + BC. Several mechanisms that contribute to ET resistance have been described. One of the most common mechanisms is the upregulation of alternative signaling pathways that can bypass estrogen dependency, such as activation of the PI3K/Akt/mTOR as well as mitogen-activated protein kinase (MAPK) and the insulin-like growth factor 1 receptor (IGF-1R) pathways. Another common mechanism of endocrine resistance is the acquisition of activating mutations of ESR1, which encodes for the estrogen receptor, that lead to structural changes of the receptor, prevent the binding to anti-estrogen drugs and result in constitutive activation of the receptor, even in the absence of estrogens. Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.

Innovative Therapeutic Approaches for Patients with HER2-Positive Breast Cancer.

Overexpression of human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor, has been described in about 15-20% of breast cancer (BC) and is associated with poor outcomes. Trastuzumab is the first anti-HER2 monoclonal antibody (mAB) that blocks receptor activity but it also activates immune response against cancer cells, thus, revolutionizing the prognosis of patients with HER2-positive BC. Over the years, new therapies have been developed, including other mAbs and tyrosine kinase inhibitors (TKIs) that required multimodal approaches with chemotherapy to optimize their anticancer activity. This chapter gives a comprehensive overview of the last advancements including new approaches and future combinations, which seem to be very promising in overcoming resistance to the traditional anti-HER2 treatments. A modern therapeutic algorithm should include treatment options based on tumour patterns and a patient-centred approach. A proper patient's selection is crucial to derive maximal benefits from a treatment strategy and emerging biomarkers should be integrated along with the HER2 status, which is currently the only validated biomarker in the context of HER2-positive disease. These biomarkers might include molecular features with reported prognostic/predictive significance, such as phosphatidylinositol 3' -kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathways, programmed cell death protein ligand 1 (PD-L1), and tumour-infiltrating lymphocytes (TILs), which all affect prognosis and response to treatments.

Breast Cancer Brain Metastases: Achilles' Heel in Breast Cancer Patients' Care.

Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as a mechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration. Other mechanisms of primary and secondary resistance are still unclear and may vary across the BC subtypes. New small molecules have demonstrated efficacy in BM, in particular for the HER2-positive subtype, with a benefit in survival. A new era has begun in the field of BM, and many trials specifically designed for this population are currently ongoing. The BC research community needs to address this call with the final aim of improving the efficacy of systemic therapy in CNS compartment and ultimately preventing the occurrence of BM.

Postneoadjuvant treatment for triple-negative breast cancer.

PURPOSE OF REVIEW: Triple-negative breast cancer (TNBC) has been conventionally associated with poor prognosis, as a result of limited therapeutic options. In the early setting, prognosis is informed by clinical-pathological factors; for patients receiving neoadjuvant treatments, pathological complete response (pCR) is the strongest factor. In this review, we mapped the landscape of clinical trials in the postneoadjuvant space, and identified three patterns of clinical trial design. RECENT FINDINGS: For patients at higher risk, effective postneoadjuvant treatments are of paramount importance to address a high clinical need. Postneoadjuvant risk-adapted treatments have demonstrated to improve survival in patients at high of recurrence. SUMMARY: Patients at high risk have indication for adjuvant treatment intensification, informed by baseline clinical, pathological or molecular factors (type 1 approach), on the presence, extent and molecular characteristics of the residual disease at the time of surgery (type 2) or on risk factors assessed in the postsurgical setting (type 3), for example, circulating tumour DNA. Most of the past trials were based on type 2 approaches, for example, with capecitabine and Olaparib. Few trials were based on a type 1 approach, notably pembrolizumab for early TNBC. The clinical validity of type 3 approaches is under investigation in several ongoing trials.

Beyond HER2: Targeting the ErbB receptor family in breast cancer.

Targeting the HER2 oncogene represents one of the greatest advances in the treatment of breast cancer. HER2 is one member of the ERBB-receptor family, which includes EGFR (HER1), HER3 and HER4. In the presence or absence of underling genomic aberrations such as mutations or amplification events, intricate interactions between these proteins on the cell membrane lead to downstream signaling that encourages cancer growth and proliferation. In this Review, we contextualize efforts to pharmacologically target the ErbB receptor family beyond HER2, with a focus on EGFR and HER3. Preclinical and clinical efforts are synthesized. We discuss successes and failures of this approach to date, summarize lessons learned, and propose a way forward that invokes new therapeutic modalities such as antibody drug conjugates (ADCs), combination strategies, and patient selection through rational biomarkers.

Accelerating drug development in breast cancer: New frontiers for ER inhibition.

The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field.

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab.

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients' selection.

Loss of HER2 in breast cancer: biological mechanisms and technical pitfalls.

Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers; however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 after neoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequently associated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorly understood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have been suggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behind HER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples. The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of this phenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specifically addressing HER2 loss are warranted.

HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway.

Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.

Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions.

The development of anti-HER2 agents has been one of the most meaningful advancements in the management of metastatic breast cancer, significantly improving survival outcomes. Despite the efficacy of anti-HER2 monoclonal antibodies, concurrent chemotherapy is still needed to maximize response. Antibody-drug conjugates (ADCs) are a class of therapeutics that combines an antigen-specific antibody backbone with a potent cytotoxic payload, resulting in an improved therapeutic index. Two anti-HER2 ADCs have been approved by the FDA with different indications in HER2-positive breast cancer. Ado-trastuzumab emtansine (T-DM1) was the first-in-class HER2-targeting ADC, initially approved in 2013 for metastatic patients who previously received trastuzumab and a taxane, and the label was expanded in 2019 to include adjuvant treatment of high-risk patients with residual disease after neoadjuvant taxane and trastuzumab-based therapy. In 2020, trastuzumab deruxtecan (T-DXd) was the second approved ADC for patients who had received at least 2 lines of anti-HER2-based therapy in the metastatic setting. The success of these two agents has transformed the treatment of HER2-positive breast cancer and has re-energized the field of ADC development. Given their advanced pharmaceutical properties, next-generation HER2-targeted ADCs have the potential to be active beyond traditional HER2-positive breast cancer and may be effective in cells with low expression of HER2 or ERBB2 mutations, opening a spectrum of new possible clinical applications. Ongoing challenges include improving target-specificity, optimizing the toxicity profile, and identifying biomarkers for patient selection. The aim of this review is to summarize the principal molecular, clinical, and safety characteristics of approved and experimental anti-HER2 ADCs, contextualizing the current and future landscape of drug development.

Does preoperative MRI accurately stratify early-stage HER2 + breast cancer patients to upfront surgery vs neoadjuvant chemotherapy?

PURPOSE: HER2 +- amplified breast cancer patients derive benefit from treatment with anti-HER2-targeted therapy. Though adjuvant treatment is based on final pathology, decisions regarding neoadjuvant chemotherapy are made in the preoperative setting with imaging playing a key role in staging. We examined the accuracy of pre-operative imaging in determining pathological tumor size  (pT) in patients undergoing upfront surgery. METHODS: Early (cT1-T2N0) HER2 + breast cancer patients who underwent upfront surgery between 2015 and 2016 were identified from a prospective institutional database. We compared data for both clinical and final pathologic stage. Only those who underwent magnetic resonance imaging (MRI), mammography, and ultrasound in the preoperative setting were included in the analysis. Adjuvant treatment regimens were reviewed. RESULTS: We identified 87 cT1-2N0 patients with invasive HER2 + breast cancer who underwent upfront surgery. Median age was 52 years (IQR 43, 58) and median tumor size was 1.1 cm (IQR 0.5, 1.6). Fifteen patients (17%) were upstaged to stage II/III based on final pathology. Thirty-seven patients were T1cN0 on final pathology; 8 were cT1a-bN0 preop and 12 had pT overestimated by MRI by an average of 1.5 cm (> 0.5-1.5 cm). Compared to both mammography and MRI, the imaging modality most predictive of pT was ultrasound (p = 0.000072 ultrasound vs mammography and 0.000042 ultrasound vs MRI). CONCLUSION: For small HER2 + cN0 tumors undergoing upfront surgery, ultrasound was the imaging modality most predictive of pT. MRI overestimated tumor size in approximately 40% of patients. MRI may not accurately discriminate low-volume tumor burden in the breast and carries the potential of overtreatment in the upfront setting.

Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor-Positive Advanced Breast Cancer (EVERMET).

PURPOSE: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. EXPERIMENTAL DESIGN: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. RESULTS: We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; P = 0.008). CONCLUSIONS: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2- aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2- aBC.

Next Generation Sequencing (NGS): A Revolutionary Technology in Pharmacogenomics and Personalized Medicine in Cancer.

Following the completion of the Human Genome Project in 2003, research in oncology has progressively focused on the sequencing of cancer genomes, with the aim of better understanding the genetic basis of oncogenesis and identifying actionable alterations. The development of next-generation-sequencing (NGS) techniques, commercially available since 2006, allowed for a cost- and time-effective sequencing of tumor DNA, leading to a "genomic era" of cancer research and treatment. NGS provided a significant step forward in Personalized Medicine (PM) by enabling the detection of somatic driver mutations, resistance mechanisms, quantification of mutational burden, germline mutations which settled the foundation of a new approach in cancer care. In this chapter we discuss the history, available techniques and applications of NGS in oncology, with a particular referral to the PM approach and the emerging role of the research field of pharmacogenomics.

Evaluating triptorelin as a treatment option for breast cancer.

Introduction: Triptorelin is a luteinizing hormone-releasing hormone analog (LH-RHa) inducing ovarian function suppression (OFS). It is approved by FDA and EMA in association with tamoxifen or aromatase inhibitor (AI) and with fulvestrant and palbociclib in premenopausal women with hormone receptor (HR)-positive breast cancer. Its potential role to preserve ovarian function during chemotherapy has also been recently clarified. Areas covered: Several studies have investigated the role of adding OFS to tamoxifen and aromatase inhibitors as adjuvant treatment in early breast cancer. The addition of triptorelin is not free from adverse events as the combination with tamoxifen and exemestane resulted in an increase of endocrine-deprivation symptoms. Clinical trials have explored the combination of LH-RHa with chemotherapy in fertility preservation, demonstrating no detrimental effect on patients' oncological outcome. This is all discussed in this evaluation. Expert opinion: Triptorelin represents a standard-of-care in premenopausal women with HR-positive breast cancer and in some cases of male breast cancer. In the adjuvant setting, a personalized approach is required to combine LH-RHa with the right partner considering the risk of recurrence and the toxicity profile. LH-RHa may be offered to breast cancer patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency.

What therapies are on the horizon for HER2 positive breast cancer?

Introduction: Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, HER2-positive metastatic breast cancer remains an almost invariably deadly disease, with primary or acquired resistance to HER2-directed agents developing during treatment. Many efforts are focused on identifying new agents that may more effectively inhibit HER2 signaling and on possible combination strategies. Areas covered: This review summarizes the landscape of drugs under development for HER2-positive metastatic breast cancer, as antibody-drug conjugates, monoclonal anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors. Moreover, available data for possible combination of anti-HER2 drugs and different agents, as immunotherapy, PI3K/mTOR inhibitors, CDK4/6 inhibitors currently under evaluation are reviewed. These strategies may overcome mechanisms of resistance and further improve patient outcomes. Expert opinion: Identification of valuable predictive biomarkers is needed to better inform choice of treatment sequence for the individual patient and limit the financial toxicity of these agents.

The evolving landscape of 'next-generation' immune checkpoint inhibitors: A review.

'First-generation' immune checkpoint inhibitors targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed death-ligand 1 (PD(L)1) have undoubtedly revolutionised the treatment of multiple cancers in the advanced setting. Targeting signalling pathways other than core inhibitory modules may strongly impact the outcome of the antitumour immune response. Drugs targeting these pathways ('next-generation' immune modulators, NGIMs) constitute a major frontier in translational research and have generated unprecedented scientific and financial investment. Here, we systematically reviewed published literature, abstracts from major cancer conferences and pharma pipelines to identify NGIMs that have reached clinical development. We identified 107 molecules targeting 16 pathways, which we classified into 6 groups according to function (inhibitory vs stimulatory) and cell of predominant expression (lymphoid, non-lymphoid and natural killer). We identified all registered past and ongoing clinical trials (n = 428). We summarise the preclinical rationale for these targets, extracting translationally relevant information, and review published and preliminary clinical results. Some targets like indoleamine-2,3-dioxygenase 1, lymphocyte activation gene-3 and IL15 have experienced exceptional growth of interest, measured in terms of activated studies and expected patient enrolment over time. We conclude that in this vast and rapidly changing drug development landscape, novel trial designs and better biomarker identification are necessary to optimise resource allocation.

Homologous recombination deficiency in triple negative breast cancer.

Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. The median overall survival (OS) for patients with metastatic TNBC is around 9-12 months with conventional cytotoxic agents. Considering this suboptimal outcome, which is induced despite of medical treatment, new therapeutic strategies would be urgently needed. The ultimate goal of precision medicine is to identify specific molecular alterations that permit considering effective targeted drug(s). Germline BRCA mutations occur in 10-20% of TNBC patients while somatic mutations occur in 3-5% of them. Alterations in the homologous recombination (HR) system are typical of BRCA mutant tumors, but can also be identified in tumors that do not carry this mutation, defining a subgroup of patients referred to as BRCAness. In this review, we focus on the role of homologous recombination deficiency (HRD) as both predictive and prognostic factor in different settings of TNBC patients treated with DNA damaging drugs and poly ADP ribose polymerase (PARP) inhibitors.

Complexity of genome sequencing and reporting: Next generation sequencing (NGS) technologies and implementation of precision medicine in real life.

The finalization of the Human Genome Project in 2003 paved the way for a deeper understanding of cancer, favouring a faster progression towards "personalized" medicine. Research in oncology has progressively focused on the sequencing of cancer genomes, to better understand the genetic basis of tumorigenesis and identify actionable alterations to guide cancer therapy. Thanks to the development of next-generation-sequencing (NGS) techniques, sequencing of tumoral DNA is today technically easier, faster and cheaper. Commercially available NGS panels enable the detection of single or global genomic alterations, namely gene mutation and mutagenic burden, both on germline and somatic DNA, potentially predicting the response or resistance to cancer treatments. Profiling of tumor DNA is nowadays a standard in cancer research and treatment. In this review we discuss the history, techniques and applications of NGS in cancer care, under a "personalized tailored therapy" perspective.