With more than two million new cases diagnosed in 2018, breast cancer is the most common cancer in women worldwide.[1] The disease represents about 25% of all cancers in women. Incidence rates vary widely across the world, from 27 per 100,000 in Middle Africa and Eastern Asia to 85 per 100,000 in Northern America. Breast cancer is also the fifth most common cause of death from cancer in women globally, with an estimated 522,000 deaths annually

An estimated 90% of all breast cancer is diagnosed at an early stage. [2] And approximately 70% of all breast cancers are HR+, HER2-, the most common subtype of the disease. [3] Even within this subtype, HR+, HER2- breast cancer is a complex disease, and many factors, including cancer which spread to the lymph nodes and the biology of the tumor, can impact the risk of recurrence. Recent data shows that about 30% of people diagnosed with HR+, HER2- early breast cancer are at risk of their cancer returning, potentially leading to incurable metastatic disease.[4]

Metastasized disease
Breast cancer starts when cells in the breast begin to grow out of control. These cells usually form a tumor that can often be seen on an x-ray or felt as a lump. The malignant tumor is getting worse when the cells invade surrounding tissues or metastasize to distant areas of the body. In that case and in ths stage of breast cancer also referred to as ‘stage IV’ breast cancer, spreads or metastasizes beyond the breast and nearby lymph nodes to other parts of the body. In the majority of cases, this includes the bones, lungs, liver, or brain.

Although an advanced disease, most women with metastatic or stage IV breast cancer are treated with systemic therapy. This treatment may include hormone therapy, chemotherapy, targeted therapy, or a combination of these options.

No an end-stage cancer
While some people may refer to metastatic breast cancer as ‘end-stage’ cancer, the disease is NOT hopeless and many people continue to live long, productive lives with breast cancer in this stage.

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In an interview with The Onco’Zine Brief in December 2019, Susan Rafte describes her experience as a 25-year metastatic breast cancer survivor. While challenging, she became a peer-to-peer support volunteer through MD Anderson Cancer Center and has helped many patients with her peer support program. Rafte has also contributed to many research projects and committees as a patient advocate.

Listen to The Onco’Zine Brief: “Susan Rafte: A 25+ Year Survivor of Metastatic Breast Cancer and Patient Advocate”

A growing number of treatment options
And while metastatic breast cancer may be treated in a different way than breast cancer diagnosed at an earlier stage, there is a wide variety of treatment options for metastatic disease.  And investigators are studying new drugs in clinical trials.

Although metastatic breast cancer can be unpredictable, with hopeful times when patients are responding well to treatment and the disease is stable to scary time of progression, the result of ongoing research and development is that more and more patients are given the opportunity of living life to the fullest while, at the same time, being treated for metastatic disease.

Metastatic breast cancer can not be ‘cured.’ But ongoing treatment may control the disease for a number of years. New treatment options may not only help patients live longer, but they can also help in relieving cancer-related symptoms, and improve the patient’s overall Quality of Life (QoL), something doctors describe “keeping [the patient] feeling as good as they can for as long as they can.” And Quality of Life, including issues related to sexual intimacy, is important for the overall health of patients as was demonstrated during a “round table” discussion with patients and physicians during the 2019 San Antonio Breast Cancer Symposium (SABCS).

With a growing number of treatment options, if one option fails, there is usually another option patients can try. For patients diagnosed with a metastatic disease today, there is, as a result, more hope for many years of good Quality of Life compared to patients diagnosed two decades ago. palliative

Listen to The Onco’Zine Brief: “Candid Conversations on Mets, Sex, and Side Effects: a Panel Discussion With Breast Cancer Oncologists, Women’s Health Experts, and Patients.”

Clinical development
Clinical trials are an important step in establishing the safety and efficacy of potential new treatments. Clinical trials also help investigators decide if established side effects – or adverse events – as a result of a particular new treatment option are acceptable when weighed against the benefits of that particular treatment option.

But ongoing research is also instrumental in understanding breast cancer – leading to a better understanding of the biology of the disease – and help physicians to better (or earlier) detect and diagnose the disease.

According to the American Cancer Society, more than 1,000 investigational drugs are studies before just one makes it to clinical trials. And, on average, a new drug for the treatment of breast cancer may take 6 years – and in some cases even longer – before scientists begin are able to test a particular new drug in a clinical trial. And, the clinical trial process itself (from phase I to phase III and market approval) may add another 6 – 10 years to the development process.

Earlier this week, investigators at Oncolytics Biotech® confirmed that they have dosed a first patient in the so-called phase II BRACELET-1 study (BReast cAnCEr with the Oncolytic Reovirus PeLareorEp in CombinaTion with anti- PD-L1 and Paclitaxel; NCT04215146), a clinical trial designed to evaluating Pelareorep-based combination therapies in patients with endocrine-refractory, HR+/HER2- metastatic breast cancer.

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus, a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The investigational compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

In the study, being conducted under a co-development agreement with Merck KGaA and Pfizer, participating patients receive paclitaxel, pelareorep in combination with paclitaxel alone, or pelareorep in combination with paclitaxel and anti-PD-L1 checkpoint inhibitor, avelumab (Bavencio®).

The randomized, open-label, BRACELET-1 study is designed to support the results of a prior successful phase II trial (IND-213) that showed a near doubling of overall survival (OS) with pelareorep treatment, by demonstrating pelareorep’s ability to induce a robust anti-tumor immune response in an identical patient population (patients with HR+/HER2- metastatic breast cancer).

The ability of pelareorep-induced immune responses to enhance anti-PD-L1 therapy will also be evaluated through the inclusion of the paclitaxel-pelareorep-avelumab combination therapy cohort. Importantly, the trial also aims to validate peripheral T-cell clonality as a biomarker of pelareorep response in HR+/HER2- metastatic breast cancerm, which may aid in future registrational trial study design and patient selection.

Another clinical trial, the randomized, open-label, phase III monarchE study, is designed to investigate abemaciclib (Verzenio®; Eli Lilly and Company) in combination with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high-risk, node-positive, early-stage, hormone-receptor-positive, human epidermal receptor 2 negative, breast cancer. The study includes research on acquired genomic alterations in circulating tumor DNA (ctDNA)—an area of particular interest as scientists try to understand how to individualize treatment for people living with HR+, HER2- advanced breast cancer.

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in a reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Investigators at Eli Lilly and Company recently presented data of a study of abemaciclib in combination with standard adjuvant endocrine therapy (ET) and confirmed that study has met the primary endpoint of invasive disease-free survival (IDFS), significantly decreasing the risk of breast cancer recurrence or death compared to standard adjuvant ET alone.

These results are from a pre-planned interim analysis of the phase III monarchE study – making abemaciclib the only CDK4 & 6 inhibitors to demonstrate a statistically significant reduction in the risk of cancer recurrence for people with high-risk hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer. The established safety profile was consistent with that observed in other abemaciclib studies in the MONARCH clinical program.

“When a [patient] is diagnosed with high-risk early-stage breast cancer, they strive to do everything in their power to prevent a recurrence. And as clinicians, we have the same goal,” noted Maura Dickler, M.D., vice president of oncology, late-phase development, Lilly Oncology.

“The monarchE [trial] was intentionally designed for people whose breast cancer is at a high risk of returning. We are incredibly excited by the results of monarchE and that we can potentially offer a new treatment option for patients with high-risk HR+, HER2- early breast cancer. This would not have been possible without the tremendous commitment from the people who participated in this trial.”

Abemaciclib is Lilly’s first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing, a new and advanced type of manufacturing adopted by the pharmaceutical industry.

Continuous production, which is contrasted with batch production, is a flow production method used to manufacture, produce, or process materials without interruption. The production method is called “continuous production” because the raw materials, either dry bulk or fluids that are being processed, are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. One of the benefits of this approach is that it eliminates, or significantly reduces, the “hold times” in-between steps that are typical in batch manufacturing. Lilly was one of the first companies to use this technology on a large scale basis.

Antibody-drug Conjugates
Human epidermal growth factor receptor 2 (HER2) is a gene that can promote cancer progression when mutated or expressed at high levels. High expression levels of HER2 have been observed in different cancer types, including breast cancer. Several HER2-targeted therapies are approved for the treatment of HER2-overexpressing breast cancer.

One of these agents is the HER2-targeted antibody-drug conjugate (ADC), fam-trastuzumab deruxtecan-nxki (Enhertu®; Daiichi Sankyo/AstraZeneca). The FDA-approval of the drug in late 2019, was based on the results of the registrational Phase II trial DESTINY-Breast01 of trastuzumab deruxtecan-nxki (5.4mg/kg) monotherapy in patients with HER2-positive metastatic breast cancer. All patients received prior trastuzumab, trastuzumab emtansine with the majority of patients (66%) receiving prior treatment with pertuzumab (Perjeta®; Genentech/Roche).

The Phase II trial results showed a confirmed objective response rate of 60.3% (n=111, 95% CI 52.9-67.4) including a 4.3% complete response rate (n=8) and a 56.0% partial response rate (n=103). Median duration of response of 14.8 months (95% CI 13.8-16.9) was demonstrated as of 1 August 2019. [5] In addition, a median progression-free survival of 16.4 months (95% CI 12.7-not estimable), based upon a median duration of follow up of 11.1 months, was presented at the 2019 San Antonio Breast Cancer Symposium and published online in The New England Journal of Medicine.[6]

“The approval of trastuzumab deruxtecan underscores that this specifically engineered HER2-directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2-positive metastatic breast cancer,” noted Antoine Yver, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo

“Since the beginning of our clinical trial program four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered Enhertu to patients in the US, as trastuzumab deruxtecan represents one of the fastest-developed biologics in oncology,” Yver added.

In late May 2020, the drug was also approved in Japan.

Triple-negative breast cancer
One of the most difficult to treat forms of breast cancer is (metastatic) triple-negative breast cancer.  Traditional breast cancer treatment options don’t work because cancer cells in (m)TNBC cancer test “negative” for estrogen or progesterone receptors and don’t make too much of the protein called HER2.

This disease, which accounts for about 10-15% of all breast cancers, is more common in women younger than age 40, African-American women, or women who have a BRCA1 mutation and differs from other types of invasive breast cancer in that they grow and spread much faster, have limited treatment options, and overall worse prognosis.[7]

In April 2020 a new treatment option for adult patients diagnosed with (metastatic) triple-negative breast cancer who have received at least two prior therapies for metastatic disease, received accelerated approval in the United States. The drug, sacituzumab govitecan (sacituzumab govitecan-hziy; Trodelvy™) developed by Immunomedics, is a Trop2-directed antibody conjugated to SN-38, the active metabolite of the topoisomerase I inhibitor, irinotecan. Trop2 is a cell-surface receptor that is over-expressed in epithelial cancers, including TNBC. In addition to breast cancer, the uniquely targeting agent is being studied in phase III trials for urothelial cancer, glioblastoma, endometrial cancer, and prostate cancer.

Listen to The Onco’Zine Brief: “Sacituzumab Govitecan, a Novel Treatment for Patients with mTNBC”

The confirmatory multicentre, randomized, phase III ASCENT trial, which compared sacituzumab govitecan versus the physician’s choice of chemotherapy in patients with mTNBC who have failed ≥ 2 prior lines of therapy, was stopped earlier than planned after an independent Data Safety Monitoring Committee confirmed compelling evidence of efficacy in the treatment of patients with mTNBC.

An ongoing phase III study is comparing sacituzumab govitecan with the physician’s choice of chemotherapy in patients with HR-positive/HER2-negative metastatic breast cancer (NCT03901339; TROPiCS-02). In addition, a phase I/II trial (NCT04039230) is investigating the novel antibody-drug conjugates in combination with talazoparib (Talzenna®; Pfizer), a once‑daily oral PARP inhibitor approved for the treatment of gBRCA‑mutated HER2‑negative locally advanced or metastatic breast cancer. In addition, a phase I/II, open-label, multicentre, randomized umbrella study (NCT03424005; Morpheus-TNBC) is evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations, including sacituzumab govitecan, in patients with mTNBC.

Precision oncology
Precision oncology ensures that treatment is specifically designed and targeted to a specific form of cancer using a patient’s individual genetics – the genes that are mutated and cause cancer to grow – to create a personalized treatment protocol based on the genetic mutations. Such an approach may offer far better results with fewer side effects than standard chemotherapy.

Recently, two companies, Invitae Corporation and ArcherDX, confirmed that they entered into a definitive agreement under which Invitae will combine with ArcherDX to create a genetics leader with unrivaled breadth and scale in cancer genetics and precision oncology.

The combined company is expected to help transform care for cancer patients, accelerating the adoption of genetics through the most comprehensive suite of products and services available. Integrating germline testing, tumor profiling, and liquid biopsy technologies and services in a single platform may enable precision approaches from diagnostic testing to therapy optimization and monitoring, expanding access to best-in-class personalized oncology.

Rucaparib and lucitanib
Clovis Oncology, presented four abstracts showcasing non-clinical data from rucaparib and lucitanib development programs during the virtual meeting II of the American Association for Cancer Research (AACR), held June 22 – 24, 2020.

The presented data summarize findings from preclinical studies evaluating the pharmacokinetics (PK)/pharmacodynamics (PD) and anti-tumor activity of rucaparib, an oral, small-molecule PARP inhibitor in orthotopic and intracranial mouse models, and its synergy with CHK1 inhibition in tumor cell lines.

Additional presentations included findings from a study of the PK of lucitanib, an oral, potent inhibitor of tyrosine kinase activity, in a simulated patient population to inform dosing-regimen selection, and from a pre-clinical study evaluating the anti-tumor efficacy and mechanism of action of lucitanib in combination with a mouse ortholog of ALKS 4230, a selective agonist of the intermediate affinity IL-2 receptor, in a mouse colon cancer model. Lucitanib and ALKS 4230 are both development-stage compounds.

“Data from our ongoing non-clinical studies underscore our commitment to pursuing innovative research that advances novel therapies for cancer patients,” noted Patrick J. Mahaffy, President and Chief Executive Officer of Clovis Oncology.

“In particular, we are pleased to present new, non-clinical data exploring the PK/PD of our PARP inhibitor Rubraca, evaluating the synergies of PARP and CHK1 inhibition in combination, as well as important data for lucitanib to understand optimal dosing and use in combination with other anticancer agents to treat solid tumors,” Mahaffy added.

Modulating the effects of cortisol
Corcept Therapeutics, a commercial-stage company developing novel drugs to treat severe metabolic, oncologic, and psychiatric disorders by modulating the effects of cortisol, presented updated genomic data from patients with adrenocortical carcinoma at the 2020 American Association of Cancer Research (AACR) Annual Meeting.

“Excessive cortisol in patients with adrenal cancer causes Cushing’s syndrome and may also blunt the efficacy of immunotherapeutic agents such as checkpoint inhibitors,” said Andreas Grauer, M.D., Corcept’s Chief Medical Officer.

“The data we are presenting informed our Phase Ib trial of our proprietary, selective cortisol modulator relacorilant in combination with the PD-1 checkpoint inhibitor pembrolizumab (Keytruda®; Merck & Co) in patients with metastatic or unresectable adrenocortical cancer. Our trial examines whether relacorilant can, in addition to treating Cushing’s syndrome in these patients, also help immunotherapy achieve its maximum effect, by reducing the immunosuppressive effects of excess cortisol activity,” Graucer concluded.

Clinical Trials
A Study to Assess Overall Response Rate by Inducing an Inflammatory Phenotype in Metastatic BReast cAnCEr With the Oncolytic Reovirus PeLareorEp in CombinaTion With Anti-PD-L1 Avelumab and Paclitaxel – BRACELET-1 Study – NCT04215146
Study of Relacorilant in Combination With Pembrolizumab for Patients With Adrenocortical Carcinoma With Excess Glucocorticoid Production – NCT04373265.
ASCENT-Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer (ASCENT) –

[1] World Health Organization. Breast cancer: prevention and control. Online. Last accessed on June 20, 2020.
[2] Howlader N, et al. SEER Cancer Statistics Review, 1975-2013. Online. Last accessed on June 20, 2020.
[3] Howlader N, Altekruse S, Li C. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5).
[4] Reinert T and Barrios CH. Optimal Management of Hormone receptor-positive Metastatic Breast Cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304-20.
[5] ENHERTU® [fam-trastuzumab deruxtecan-nxki] US prescribing information; 2019.
[6] Modi, S., et. al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. NEJM. December 11, 2019. DOI:10.1056/NEJMoa1914510.
[7] Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

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