Charles E. Geyer, Jr., MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses ongoing challenges in the management of patients with metastatic HER2-positive breast cancer.  

Despite therapeutic advances with monoclonal antibodies, patients are treated indefinitely, says Geyer. When side effects result, they can be difficult to manage. Treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla), though generally well-tolerated, carries a risk of neuropathy, particularly in patients who received trastuzumab (Herceptin) and taxanes.

The treatment of patients with brain metastases remains the greatest challenge in this setting. Although stereotactic radiosurgery techniques have improved, additional systemic therapies are needed. Treatment with small-molecule TKIs have shown response rates of 30% to 45%, Geyer says; however, these responses are not durable.

Going forward, better management strategies in early HER2-positive breast cancer are necessary to combat these challenges, concludes Geyer.

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Charles E. Geyer, Jr, MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses ongoing challenges in the management of patients with metastatic HER2-positive breast cancer.  

Dr. Geyer on Challenges in HER2+ Metastatic Breast Cancer Management

Charles E. Geyer, Jr., MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses the impact of targeted agents in HER2-positive breast cancer.

The emergence of trastuzumab (Herceptin), pertuzumab (Perjeta), and most recently, ado-trastuzumab emtansine (T-DM1; Kadcyla), has provided patients with HER2-positive breast cancer with several new treatment options. Notably, Geyer says, there are even options for patients who do not achieve a pathologic complete response following frontline therapy. In years past, neoadjuvant therapy in this space was merely an option, but now, the treatment paradigm has shifted dramatically.

After results from the KATHERINE study were presented at the 2018 San Antonio Breast Cancer Symposium, researchers now need to determine the role of T-DM1, Geyer notes. Results from the study showed that adjuvant T-DM1 reduced the risk of invasive disease recurrence or death by 50% in this patient population.

Charles E. Geyer, Jr, MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses the impact of targeted agents in HER2-positive breast cancer.

Dr. Geyer on Impact of Targeted Agents in HER2+ Breast Cancer

Charles E. Geyer, Jr, MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses the use of pertuzumab (Perjeta) in HER2-positive breast cancer.

Pertuzumab has established itself as an important addition to the treatment landscape for HER2-positive disease, Geyer says, due in large part to the results of the CLEOPATRA study which focused on the metastatic setting. HER2-targeted antibodies were developed as a way to engage the immune system, but their mechanism of action was not clearly seen until this pivotal trial. Geyer notes that if researchers are seeing such stringent responses in the metastatic setting, then pertuzumab should also have a role in early breast cancer.

In addition to prolonged survival, pertuzumab has been shown to increase pathologic complete response rate, although there has been some skepticism associated with the APHINITY trial. Geyer says that it is important to note that the patient subsets in this study were of a higher-risk disease. The patients who seemed to have the best outcomes were the ones treated with dual antibodies.

Charles E. Geyer, Jr, MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses pertuzumab in HER2-positive breast cancer.

Dr. Geyer Discusses Pertuzumab in HER2+ Breast Cancer

Charles E. Geyer, Jr, MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center, discusses the rationale and results of the phase III KATHERINE trial in HER2-positive breast cancer.

At the 2018 San Antonio Breast Cancer Symposium, Geyer presented the results of the phase III study of ado-trastuzumab emtansine (T-DM1; Kadcyla) versus trastuzumab (Herceptin) as adjuvant therapy. The study was done in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy, including trastuzumab.

Ado-trastuzumab emtansine reduced the risk of invasive disease recurrence by 50% versus trastuzumab. At the interim analysis, the hazard ratio of 0.50 prompted investigators to publish the results in the New England Journal of Medicine. The primary endpoint of the study was invasive disease-free survival (iDFS). Moreover, the 3-year iDFS rate was 88.3% with T-DM1 compared with 77.0% with trastuzumab. Though additional follow-up is needed, the results represent a new standard for patients with early HER2-positive breast cancer and will likely increase the use of neoadjuvant therapy, says Geyer.

Dr. Geyer on the Rationale for the KATHERINE Trial in HER2-Positive Breast Cancer

	Professor, Division of Hematology, Oncology and Palliative Care

 tumor suppressor genes and the recognition that inherited loss of function (deleterious) mutations in one of these important genes places women at high risk for the development of breast, ovarian, and other cancers are major advances in women’s health research.

Efforts are now under way to utilize this knowledge through clinical trials testing olaparib (Lynparza), a poly (ADP-ribose) polymerase (PARP) inhibitor that is the first anticancer therapy approved for patients with tumors that harbor 

 mutations, in individuals with breast cancer.

I am serving as a co-principal investigator on the OlympiA trial, the first major adjuvant study to evaluate a therapy specifically targeting patients with 

 mutation is associated with a 60% to 70% lifetime risk of breast cancer and a 20% to 45% lifetime risk of ovarian cancer. A deleterious 

 mutation is associated with a 40% to 60% lifetime risk of breast cancer and a 10% to 20% lifetime risk of ovarian cancer.

 mutation-associated cancers typically occur at a younger age than similar sporadic cancers in women without these mutations.

Identification of women with deleterious mutations in the 

 genes before they develop cancer provides an opportunity for initiating enhanced early detection programs such as MRI-based breast cancer screening, as well as consideration for risk reduction surgeries such as bilateral salpingooophorectomy and bilateral mastectomies.

 mutations are present in only a small minority of women who develop breast cancer. Approximately 5% of breast cancers are associated with a germline mutation in the 

		Figure. OlympiA Schema for Patients With Triple-Negative Breast Cancer With Germline BRCA Mutations

		gBRCA indicates germline BRCA mutation; MRI, magnetic resonance imaging; pCR, pathologic complete response; TNBC, triple-negative breast cancer.

The majority of cancers that develop in women with 

 mutations are the triple-negative phenotype (70%) while women with mutations in the 

 gene are more likely to develop estrogen receptor—positive breast cancer (70%).

Given the small size of the subpopulation of patients with deleterious 

 mutations in breast cancer, information comparing the outcomes of these patients with the outcomes in the overall breast cancer population is relatively limited. However, the available evidence suggests that once baseline prognostic factors (such as hormone receptor and HER2 status) and treatment are taken into account, patients with 

 mutations have similar outcomes with standard therapies for breast cancer as do women with sporadic breast cancer.

 mutations have been included in clinical trials evaluating new cancer therapies appropriate for the subtype of breast cancer they have developed, so they are treated according to their hormone receptor and HER2 status. Until recently, there have been very few clinical trials evaluating potential new therapies specifically in patients with BRCA mutations.

Women and men who inherit a deleterious mutation in a 

 gene from one parent still have a normal functioning 

 gene from the other parent in the normal cells throughout their body.

 genes code for proteins that play a critical role in the high fidelity, homologous recombination repair of DNA damage in normal cells. Cancer cells also use these proteins to attempt repair of the significant number of mutations present in the cancer cell DNA.

	Olaparib Clinical Trials in Breast Cancer

The amount of DNA damage in the cancer cell is too much to allow complete repair, but enough occurs that the cancer cell can survive. However, in a cancer that developed in a patient with a deleterious mutation in 

, one of the BRCA proteins is absent, so this primary repair mechanism is not available. As a result, the cancer cells must depend on an alternative DNA repair pathway that uses the PARP enzyme for survival. If this enzyme can be inhibited, BRCA-deficient cancer cells may die due to loss of the ability to adequately repair their abnormal DNA, a process referred to as synthetic lethality.

There are several PARP inhibitors in development, and the FDA approved olaparib in December 2014 as monotherapy for patients with advanced ovarian cancer with deleterious germline mutations in 

. Olaparib monotherapy has also shown promise in patients with pretreated metastatic breast cancer with BRCA germline mutations, although the data have not been strong enough to seek approval in this indication from the FDA.

Now, the OlympiAD trial2 is currently enrolling patients with germline 

 mutations and pretreated metastatic breast cancer to receive olaparib versus chemotherapy of investigator’s choice. This study will determine the utility of olaparib in patients with 

A second trial, OlympiA, is a landmark, global collaboration between the National Clinical Trials Network, which is led by NRG Oncology and sponsored by the National Cancer Institute (NCI), and the Breast International Group, which is sponsored by AstraZeneca, the manufacturer of olaparib.

This phase III clinical trial is investigating the efficacy and safety of adjuvant olaparib following completion of standard therapies for high-risk, HER2-negative patients with breast cancers that harbor germline mutations of the 

 gene. Initially launched as a trial limited to patients with triple-negative breast cancer, an amendment is in process to expand eligibility to patients with high-risk hormone receptor (HR)—positive/HER2-negative breast cancer.

This is the first time a major adjuvant study has been launched to evaluate a therapy specifically targeting patients with 

 mutation-associated breast cancer. The study is being led by leading experts in 

-associated breast cancer from around the world, including Andrew Tutt, MBChB, PhD, Judy E. Garber, MD, MPH, and Bella Kaufman, MD. It is my privilege to serve as co-principal investigator on this trial with these outstanding investigators.

OlympiA participants are required to complete all standard treatments including chemotherapy and surgery and, if needed, radiation therapy. Chemotherapy can be administered as neoadjuvant or adjuvant therapy. Participants will be randomized 1:1 to receive either olaparib or a placebo for a year.

Since standard therapy will have been completed by the time patients enter OlympiA, the placebo controlled-design is both appropriate and necessary to understand the benefits and side effects of olaparib in this potentially curative patient population. Patients will be followed for disease recurrence and new cancers for approximately 10 years following randomization to determine the efficacy of adjuvant treatment with olaparib on invasive disease-free survival.

Secondary endpoints include overall survival, distant disease-free survival, and the incidence of new invasive breast primary cancer and/or a new epithelial ovarian cancer. An important secondary aim of the trial is to study how olaparib affects patient quality of life (QoL) by measuring patient-reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale.

 mutations who develop high-risk but potentially curable breast cancer are eligible for OlympiA, timely completion of accrual of the 1500 patients required for the study will be challenging. The trial is being conducted in 23 countries. In North America, the trial is open to all investigators participating in the National Clinical Trials Network, which consists of four academic research bases (NRG Oncology, Alliance, ECOG-ACRIN, and SWOG) and the NCI Community Oncology Research Program (NCORP). The trial is actively recruiting eligible women and men diagnosed with triple-negative breast cancer with an inherited 

 gene mutation, and will soon include those with HR-positive, HER2-negative cancers as well.

On behalf of my co-principal investigators, the members of the Scientific Steering Committee, and the hereditary breast and ovarian community, I want to encourage physician investigators across North America to join this global effort and provide your patients who meet the eligibility criteria the opportunity to participate in OlympiA.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identfier: NCT02032823.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identfier: NCT02000622.

Articles

The identification of the BRCA1 and BRCA2 tumor suppressor genes and the recognition that inherited loss of function (deleterious) mutations in one of these important genes places women at high risk for the development of breast, ovarian, and other cancers are major advances in womenâ€™s health research.


Charles E. Geyer Jr, MD

Articles

Dr. Geyer on Challenges in HER2+ Metastatic Breast Cancer Management

Dr. Geyer on Impact of Targeted Agents in HER2+ Breast Cancer

Dr. Geyer Discusses Pertuzumab in HER2+ Breast Cancer

Dr. Geyer on the Rationale for the KATHERINE Trial in HER2-Positive Breast Cancer

Olaparib Studies Put Focus on BRCA-Positive Breast Cancers