Release Date: April 22, 2020
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Exercise Programs Improve Outcomes for Patients With Breast Cancer
By Brittany Lovely
Special attention to reducing the risk of cardiovascular disease should be a priority for long-term care of patients with breast cancer, according to Jean-Bernard Durand MD, FACC, FACP, FHFSA, FAHA.1
“The mortality for breast cancer continues to go down, but what women are going to be faced with if they do not have a recurrence [is that] their number one cause of death is cardiovascular disease,” Durand, medical director of Cardiomyopathy Services, and director of Cardiovascular Genetics Research and the Cardiology Fellowship Program at The University of Texas MD Anderson Cancer Center in Houston. “We have to do a much better job of managing their modifiable risk factors and comorbid conditions.”
Physical activity and avoidance of weight gain are 2 important factors in reducing recurrence and mortality in patients with breast cancer. At the time of diagnosis, patients with early-stage breast cancer may already be at a heightened risk for developing cardiovascular disease. Adjuvant therapies, surgery, and radiation are associated with adverse effects on the cardiovascular system.
A patient’s cardiovascular reserve could take a hit with treatments and as a result of indirect effects, such as physical inactivity and changes in body composition. Reduced cardiovascular reserve could leave patients more susceptible to further cardiovascular damage and premature mortality.2
Cardiorespiratory Fitness in Patients With Breast Cancer
Cardiorespiratory fitness is an index of functional capacity of the heart and lungs and reflects the efficiency of oxygen uptake, transport, and utilization in the muscles. “It is an excellent surrogate of exercise dose and a reproducible measurement,” said Durand.
In a study of 248 patients with breast cancer, the prognostic significance of cardiopulmonary function was assessed as measured by peak oxygen consumption (Vo2 peak). Patients with breast cancer represented 4 cross-sectional cohorts: (1) before, (2) during, and (3) after adjuvant therapy for nonmetastatic disease; and (4) during therapy in metastatic disease. A cardiopulmonary exercise test (CPET) with expired gas analysis was used to assess Vo2 peak.3
Despite normal cardiac function (defined as resting measurement of left ventricular ejection function ≥50%), women with breast cancer demonstrated marked impairments in cardiopulmonary function. Vo2 peak was, on average, 27% less than that of age-matched sedentary but otherwise healthy women without a history of breast cancer. The impairment in Vo2 peak during primary adjuvant chemotherapy was 31% less than that of healthy sedentary women and 33% less in those patients with metastatic disease.
Improved cardiopulmonary function is possible with the introduction of exercise training programs across the breast cancer continuum. A meta-analysis of 6 studies involving 571 adult patients with cancer examined the effects of supervised exercise training (n = 344) versus nonexercise (n = 227) on measurement of Vo2 peak. Intervention lengths were in the range of 8 to 24 weeks. In all studies, exercise was prescribed 3 times per week, and session duration ranged 14 to 45 minutes. Exercise training was associated with a statistically significant increase in Vo2 peak of 2.90 mL/kg/min (95% CI, 1.16-4.64), translating to an improvement from baseline to postintervention that favored exercise by 15%.4
Introducing Exercise Programs in the Clinic
By providing exercise regimens, clinicians can curb risk factors associated with cardiovascular mortality. Durand noted that the MD Anderson Healthy Heart Program takes a multidisciplinary approach to improve patient outcomes. The team includes physicians, exercise physiologists, health educators, dietitians, and nurses.5
“The Healthy Heart Program helps patients improve their overall fitness and heart health,” said Durand. “Our staff and the cardiologists will provide patients with a personalized exercise boutique, and patients also receive information regarding heart disease and ways to improve heart health over the course of their lives.”
The patient undergoes a preliminary evaluation that includes a screening exam and a treadmill test to determine their maximal oxygen consumption. “This will allow us to assess cardiopulmonary safety and determine the exercise dose, as well as compare their fitness level relative to their age and sex,” Durand explained. Standard of care assessment is also conducted and includes assessing the impact of prior cancer treatment on heart health, cholesterol levels, risk of hypertension or high blood pressure, risk of diabetes, body weight and waist measurements, family history on heart health, and, if needed, smoking cessation.
Developing Prescribed Programs
“One difficulty is trying to explain the metabolic equivalent task [MET] to patients,” Durand noted. “The Harvard School of Public Health does a great job of breaking this down into light, moderate, and vigorous activity. We like to shoot for the [moderate] area of 3 to 6 METs,” he noted.6
In a study by Jones et al that that assessed leisure-time recreational physical activity, patients whose exercise program consisted of 9 or more MET hours per week was associated with a 23% reduction in the risk of cardiovascular events irrespective of age, cardiovascular disease risk factors at diagnosis, menopausal status, and type of anticancer therapy.7
Patient biases also play into difficulties for prescribing exercise programs to patients. “We have biases, and the patient has biases. The patient bias is that you are expecting them to get to a gym, get a personal trainer, and do exercise every single day, and that could not be farther from the truth,” Durand said. “I like to recommend the buddy program, finding a neighbor or friend who will walk with you at a brisk pace, and set up a schedule that you will do this as a team.”
On the importance of personalizing exercise prescriptions, Durand noted that “not everyone of your patients [is] going to be able to do the same thing,” and recommended follow up visits with exercise physiologists and other identified specialists as needed to complete the spectrum of care. “[Clinicians] need to have a team of individuals where you can pick up the phone or you can text them and say, ‘I want to send this patient for an exercise prescription with specific goals.’”
1. Durand JB. Cardiac fitness and optimization for breast cancer therapies. Presented at: 37th Annual Miami Breast Cancer Conference hosted by Physicians’ Education Resource®, LLC (PER®); March 5-8, 2020; Miami Beach, FL.
2. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007;50(15):1435-1441. doi: 10.1016/j.jacc.2007.06.037. 3. Jones LW, Courneya KS, Mackey JR, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol. 2012;30(20):2530-2537. doi: 10.1200/JCO.2011.39.9014.
4. Jones LW, Liang Y, Pituskin EN, et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist. 2011;16(1):112-120. doi: 10.1634/theoncologist.2010-0197.
5. Healthy Heart Program. MD Anderson Cancer Center website. www.mdanderson.org/patients-family/diagnosis-treatment/care-centers-clinics/cancer-prevention-center/clinics-and-programs/healthy-heart-program.html. Accessed March 7, 2020.
6. Examples of Moderate and Vigorous Physical Activity. Harvard T.H. Chan School of Public Health website. www.hsph.harvard.edu/obesity-prevention-source/moderate-and-vigorous-physical-activity/. Accessed March 7, 2020.
7. Jones LW, Habel LA, Weltzien E, et al. Exercise and risk of cardiovascular events in women with nonmetastatic breast cancer. J Clin Oncol. 2016;34(23):2743-2749. doi: 10.1200/JCO.2015.65.6603.
Gene Profiling: An Essential Tool for Treatment Tailoring
By Silas Inman
Gene profiling assays can accurately and reproducibly assist decision making for treating patients with hormone receptor (HR)-positive breast cancer, with the ultimate goal of improving outcomes or avoiding toxicity, according to a presentation by Debu Tripathy, MD.
“In the [past] 10 to 20 years, we’ve gotten more sophisticated tools, such as gene profiling, to further build out the subsets. We’re focusing on the benefits of chemotherapy, and there are many established prognostic factors that we all commonly use,” said Tripathy, professor and chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston.
Tailoring therapy can help avoid many of the short- and long-term adverse events associated with various treatments.1 The main prognostic criteria are tumor size, nodal status, tumor grade, and molecular profile. Several predictive factors also exist, which should be considered for each patient. In addition to HR status and HER2 expression levels, tumor grade and gene expression profiles can be used to determine the appropriateness of chemotherapy.
National Comprehensive Cancer Network (NCCN) treatment recommendations provide guidance on the optimal test to utilize, based on the level of clinical evidence demonstrated in prospective validation, registry, population-based, and clinical trials. Based on findings from the TAILORx and MINDACT trials, respectively, category 1 recommendations are given for Oncotype Dx for node-negative, HR-positive/HER2-negative disease and for MammaPrint for node-negative disease and patients with 1 to 3 positive nodes. Of these 2 tests, Oncotype DX is listed as preferred by the NCCN guidelines and is the only test that provides predictive value.2
TAILORx and Oncotype DX
The TAILORx trial3 included more than 10,000 patients with HR-positive, HER2-negative, axillary node-negative breast cancer. Patients were stratified by risk using the Oncotype DX assay, with 9719 having follow-up information available for analysis. Overall, 69% (n = 6711) had an intermediate recurrence score of 11 to 25; 17% (n = 1619) had a score of 10 or lower; and 14% (n = 1389) had a score of 26 or higher.
Those in the low-risk group received endocrine therapy alone, whereas patients in the high-risk group were treated with the combination of chemotherapy and endocrine therapy. Patients in the intermediate group were randomized to receive either endocrine therapy alone (n = 3399) or chemotherapy plus endocrine therapy (n = 3312). Endocrine therapy most commonly consisted of an aromatase inhibitor for postmenopausal women and tamoxifen alone or with an aromatase inhibitor for premenopausal women.
After a median 7.5 years of follow-up, endocrine therapy alone was noninferior to chemotherapy plus endocrine therapy for invasive disease-free survival (DFS) in the intermediate group (HR, 1.08; 95% CI, 0.94-1.24; P = .26). Moreover, freedom from recurrence at a distant site was similar between the 2 groups (HR, 1.10; 95% CI, 0.85-1.41; P = .48).
For those >50 years of age, there was no additional benefit observed with the addition of chemotherapy for patients with risk scores from 0 to 25. In those 50 years of age or younger, however, there was a benefit for adding chemotherapy in the intermediate-risk group, although the rationale behind this is still unclear, Tripathy noted. Among patients aged 50 years or younger with a recurrence score of 16 to 20, there was a 1.6% difference in 9-year distant recurrence on the combination arm. In the group with a recurrence score of 21 to 25, 6.5% more patients recurred at 9 years in the endocrine-alone arm compared with the chemotherapy plus endocrine arm (86.9% vs 93.4% freedom from recurrence).
“This might be explained by the fact that women in the younger age group can undergo menopause with chemotherapy, and it might be that benefit and not chemotherapy that is helping them,” said Tripathy. “This is still controversial to see whether we should be using chemotherapy or ovarian suppression instead. This is still a dilemma.”
MINDACT and MammaPrint
Findings from the MINDACT trial4 helped establish the 70-gene MammaPrint test as a tool for determining whether chemotherapy could be withheld. For this study, patients were stratified based on their clinical and genetic risk. Those with low risk by both measures (n = 2745) did not receive chemotherapy, whereas those with high risk for both were treated with chemotherapy (n = 1806). A second group with clinical-low but genetic-high (n = 592) risk or clinical-high but genetic-low (n = 1550) risk were randomized to receive chemotherapy or no chemotherapy.
In those with clinical-low/genetic-high risk, the 5-year distant metastasis-free survival (MFS) was similar regardless of treatment type, illustrating the ability of these patients to avoid chemotherapy. In the chemotherapy arm, the 5-year distant MFS rate was 95.8% compared with 95.0% in the chemotherapy-free arm (HR, 1.17; 95% CI, 0.59-2.28; P = .657). For those with clinical-high/genetic-low risk, the 5-year distant MFS was 95.9% in the chemotherapy group versus 94.4% in the chemotherapy-free arm (HR, 0.78; 95% CI, 0.50-1.21; P = .267).
“With this assay, you can really take the higher-risk group, primarily the node-positive ones, and if they have a low recurrence score, you might surmise that based on these data they may not benefit from chemotherapy,” said Tripathy. “This is what is reflected in the ASCO [American Society of Clinical Oncology] guidelines.”
The ASCO guidelines5 note that clinical utility for MammaPrint is only indicated in patients with high clinical risk, for both those with node-negative and node-positive cancers. ASCO also updated its guidelines following the presentation of the TAILORx results. In these guidelines, chemotherapy is listed as having little to no benefit for those aged >50 years with an Oncotype DX score of <26 or those aged ≤50 years with a score of <16.
For the NCCN guidelines, there are 5 gene tests listed for invasive breast cancer, specifically Oncotype DX, MammaPrint, Breast Cancer Index (BCI), Prosigna (PAM 50), and Endopredict.2 Each of these assays examines different molecular characteristics and varying quantities of genes. The Oncotype DX test uses the expression of 21 genes, MammaPrint examines 70 genes, Prosigna is a 50-gene panel, BCI examines 7 key genes and ratios, and EndoPredict is a 12-gene panel. Additional assays continue to be assessed and will be added to the guidelines once they are clinically validated, Tripathy noted.
1. Tripathy D. Refinement of gene profiling for node-negative breast cancer. Presented at: 37th Annual Miami Breast Cancer Conference hosted by Physicians’ Education Resource® (PER®); March 5-8, 2020; Miami Beach, FL.
2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Breast Cancer (version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 6, 2020.
3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710. 4. Cardoso F, van't Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.
5. Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update—integration of results from TAILORx. J Clin Oncol. 2019;37(22):1956-1964. doi: 10.1200/JCO.19.00945.
CDK4/ Breast Cancer Immunotherapy Comes of Age
By Brittany Lovely
Breast cancer has historically been an immunologically cold disease, but new data are carving out space for several immunotherapies in the treatment paradigm. A growing understanding of subtype response to treatment has fueled an exploration of antitumor immune responses in patient subpopulations, especially in those with triple-negative breast cancer (TNBC).
“[It] turned out that, as we understood the biology of breast cancer and these more aggressive subtypes, that actually TNBC and then, next, most frequently, HER2-positive disease, particularly ER-negative/HER2-positive disease, had evidence of an immune response,” said Hope S. Rugo, MD, FASCO, cochair of the 37th Annual Miami Breast Cancer Conference®, said during a presentation
A recent analysis of large trials suggests that, in the metastatic setting, an immune response correlates with better outcomes.
Rugo, a professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, traced the recent progress of immunotherapy trials in breast cancer and identified key focus areas for the future of immune checkpoint inhibition in early-stage disease.
“Responses in patients [with PD-L1–positive disease] in the first-line setting were closer to 25%, so clearly something different was going on here biologically,” said Rugo. “We understood that tumors become less immune-sensitive or immunologically responsive over time, as they garner mutations and have genomic chaos with progression.”
This led investigators to revisit the immunity cycle to find areas where augmentation was possible.
The phase III IMpassion130 trial (NCT02425891) investigated whether the anti–PD-L1 monoclonal antibody atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) would confer a consistent survival advantage for patients with PD-L1–positive, treatment-naïve, metastatic or inoperable locally advanced TNBC.1
Patients were randomly assigned to receive nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of a 28-day cycle with atezolizumab 840 mg (n = 451) or placebo (n = 451) on days 1 and 15. Treatment was given until disease progression or unacceptable toxicity. Patients were assessed using the SP142 assay, which measures PD-L1 in the immune cells surrounding and infiltrating the tumor. There was a 41% of the total population was PD-L1–positive (≥1% expression).
In the primary analysis, atezolizumab plus nab-paclitaxel resulted in a progression-free survival (PFS) benefit in the intention-to-treat population compared with placebo plus nab-paclitaxel (HR, 0.80; 95% CI, 0.69-0.92; P = .0025) and demonstrated a trend toward improved overall survival (OS; HR, 0.84; 95% CI, 0.69-1.02; P = .0840).1
Among patients with PD-L1–positive tumors, the addition of atezolizumab resulted in clinically meaningful improvements in both PFS (HR, 0.62; 95% CI, 0.49-0.78; P <.001) and OS (HR, 0.62; 95% CI, 0.45-0.86). In the patients with PD-L1–negative disease, there was no improvement in PFS (HR, 0.93; 95% CI, 0.77-1.11) or OS (HR, 0.97; 95% CI, 0.78-1.20).
The FDA approved the atezolizumab plus nab-paclitaxel combination in March 2019 based on the primary analysis of IMpassion130 results, which showed that atezolizumab plus nab-paclitaxel reduced the risk for progression or death by 40% compared with nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.2
In a post hoc analysis presented at the 2019 European Society for Medical Oncology, patients with PD-L1–positive tumors continued to show clinically meaningful improvements with the addition of atezolizumab in both PFS (HR, 0.63; 95% CI, 0.50-0.80) and OS (HR, 0.71; 95% CI, 0.54-0.93).3 “With longer follow up, the survival improvement in patients who had IC+ disease was 7 months—very impressive,” said Rugo. “It’s the first treatment to improve survival other than chemotherapy for triple-negative, metastatic breast cancer.”
“We know that our cancers respond less and have shorter duration of response as they progress through metastatic disease,” Rugo said. Several studies have demonstrated a reduction in both expression of PD-L1 and TILs as tumors progress from early- to late-stage disease. Moving therapy forward may lead to improved survival.
The KEYNOTE-522 trial (NCT03036488) examined neoadjuvant pembrolizumab (Keytruda) in early TNBC. In study findings, pembrolizumab plus platinum-containing chemotherapy extended the pathological complete response (pCR) rate by 13.6 percentage points (64.8% vs 51.2%; P = .00055) compared with chemotherapy alone.4
Patients were assigned pembrolizumab 200 mg every 3 weeks (n = 784) or placebo (n = 390). All patients received 4 cycles of carboplatin plus paclitaxel followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. Following surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or unacceptable toxicity.
In the PD-L1–positive group (n = 498), the pCR rate was 68.9% in the experimental arm compared with 54.9% in the placebo arm. In PD-L1–negative patients (n = 97), the pCR rate was 45.3% with pembrolizumab versus 30.3% with placebo.
In a recent exploratory analysis from the phase II SAFIR02-IMMUNO trial, durvalumab (Imfinzi) as maintenance therapy, may improve outcomes compared with chemotherapy.
In patients with TNBC (n = 82) in the SAFIR02 trial, the median OS was 21 months (95% CI, 16.6-27.0) with maintenance durvalumab, compared with 14 months (95% CI, 9.0-16.3) with chemotherapy (HR, 0.54; 95% CI, 0.30-0.97; P = .0377). In those with PD-L1–positive disease across several breast cancer subtypes (n = 44), the median OS was 26 months with durvalumab (95% CI, 15.0–not reached [NR]) compared with 12 months (95% CI, 6.3-NR) with chemotherapy (HR, 0.42; 95% CI, 0.17-1.05; P = .0552).5
“In the group of patients who had triple-negative disease and in the group of patients who had PD-L1–positive breast cancer, most of whom had triple-negative disease, 52% versus 15% non–triple-negative, there seemed to be a marked improvement in overall survival, really quite dramatic,” Rugo said.
Future directions for the field include looking at novel combination strategies that may offer great promise. Explorations into benefit for HER2-positive and estrogen receptor-positive disease are also being explored. “Immunotherapy is a reality now for breast cancer,” Rugo concluded.
1. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615.
2. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA website. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative. Updated March 9, 2019. Accessed March 6, 2020.
3. Rugo H, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry assays in unresectable locally advanced or metastatic triple-negative breast cancer: post hoc analysis of IMpassion130. Presented at: 2019 European Society for Medical Oncology Annual Meeting; September 21-October 1, 2019; Barcelona, Spain.
4. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. doi:10.1056/NEJMoa1910549.
5. Dalenc F, Garberis I, Filleron T, et al. Durvalumab compared to maintenance chemotherapy in patients with metastatic breast cancer: results from phase II randomized trial SAFIR02-IMMUNO. Presented at: 2019 San Antonio.
All Stakeholders Are Responsible for Genetic Testing
By Kristie L. Kahl
Physicians should “get out there and test early and often,” to align with a potential new paradigm for genetic testing that allows anyone on the treatment team to identify and test individuals, with the specialist ultimately providing risk management, according to Kevin S. Hughes, MD, FACS.1
“You should be identifying, you should be testing, you should be organizing the management,” said Hughes, co-director, Avon Comprehensive Breast Evaluation Center, Massachusetts General Hospital; professor of surgery, Harvard Medical School; and medical director, Bermuda Cancer Genetics and Risk Assessment Clinic.
Whole-genome sequencing, has made use of genetic testing has increased exponentially, while also becoming much more affordable. Despite all of this, experts still urge caution. “We’ve got to get over this cautious approach to genetics that’s really holding us back,” Hughes said, adding that the real misconception of genetic testing, causing this caution, is that it is all about counseling. “That’s not the most important thing,” he added.
A recent study, conducted by Pat Whitworth, MD, associate clinical professor of surgery, Vanderbilt University Medical Center, and colleagues, was designed to evaluate Cigna’s implementation of restrictions placed on genetic testing, requiring individuals to visit a genetic counselor first in order for their genetic test to be paid for by the insurance company. The researchers compared the restriction policy with that of other insurance companies, to see how the policy affected denial rates for genetic testing.2
The companies without this policy in place had no change in the denial rates for genetic testing. In the same time period, Cigna’s denial rates increased from 10% to 40% after implementing the restriction policy. Moreover, the approval rate declined from 3.8% to 3.7%, suggesting the policy did not improve outcomes. The company also saw a significant increase in cancellations, rising from 9.5% prior to the policy change to 37.7% afterwards.
“They were denying patients who are the same as the ones that they were accepting, denying them only because a genetic counselor had not seen them,” Hughes explained, adding that more of the cancellations occurred in African American and Latino population. “[This is] a group that we’re trying to get rid of disparities, not create new disparities.”Hughes pointed out that the problem lies in the amount of people missed, who, in fact, need genetic testing.
With this, he noted that there are 3 basic points to genetic testing: How can physicians identify patients who should undergo genetic testing?; How should these patients be tested?; How should physicians manage their risk?
In the old approach to genetic testing, anybody could identify a patient who should undergo genetic testing; however, only a specialist, like a genetic counselor, could test for and manage hereditary risk for cancer. “This model is outdated.” he said. “Thirteen million women in this country need genetic testing. About 2 million genetic tests have been done in the last 24 years and almost all of them need to be redone.” And with such a need, genetic counselors are becoming less and less available.
The proposed new paradigm would shift the onus from the genetic counselor to include more healthcare professionals. “Anybody should be able to ID and test patients and then the management might move on to a specialist,” he explained.
Management should be based on the spectrum of hereditary cancer and the penetrance for each of those diseases. Additionally, it should be personalized on a case-by-case basis, based on the exact gene and its occurrence frequency.
To help with this, Hughes and colleagues have utilized a tool, called ask2me, which is “the all syndromes known to man evaluator,” he said. The site allows physicians to input the genetic mutation, gender, age, prior cancers, and prior surgeries. For each gene, the site identifies the patient’s risk of cancer going forward, compared with the general population.
“We need better tools from computers that can help us manage patients and take care of them,” Hughes concluded. “Absolutely get out there and find patients who need testing. Learn how to test. Just think about what the management is by the gene, by the structure, and by the penetrance.”
Theresa Wicklin Gillespie, PhD, MA, RN, FAAN
Emory University Atlanta, GA
A woman who has a significant family history of breast, ovarian, prostate, or pancreatic cancer, in addition to her personal diagnosis of breast cancer, may be a good candidate for genetic testing and counseling, especially if hereditary cancer mutations have not already been found in the person’s relatives. The most well-known hereditary mutations in breast cancer are BRCA1 and BRCA2. Since these germline mutations may be detected prior to the clinical diagnosis of a cancer, assessment of these mutations may be applied to primary prevention of breast cancer or altering the surveillance approach, in order to detect a cancer at the earliest time possible.
Although the clinical and testing recommendations may differ, breast cancer risk assessment is an important component of breast cancer diagnosis and care. In addition, if an institution or practice takes on genetic testing, they must have resources in place to provide such vital services as pre- and post-testing genetic counseling, which can come from physicians, nurses, genetic counselors, or other professionals with the needed expertise; appropriate referral; support services for families who may be affected; and resources for preventive or surveillance, if the testing demonstrates pathogenic variants. Lastly, not all insurance payers cover the costs of genetic testing; thus, providers should check with the payer to understand what services will or will not be covered.
1. Hughes KS. What’s New in Cancer Genetic Testing. Presented at: 37th Annual Miami Breast Cancer Conference hosted by Physicians’ Education Resource® (PER®); March 5-8, 2020; Miami Beach, FL. .
2. Whitworth P, Beitsch P, Arnell C, et al. Impact of payer constraints on access to genetic testing. J Oncol Pract. 2017;13(1):e47-e56. doi: 10.1200/JOP.2016.013581.
Triple-Negative Breast Cancer
Novel Antibody-Drug Conjugates Show Encouraging Activity in TNBC
By Hannah Slater
Novel antibody-drug conjugates (ADCs) have demonstrated high response rates in patients with heavily pretreated metastatic breast cancer, and ongoing studies targeting actionable cell-surface markers may further expand their clinical utility, according to Aditya Bardia, MD, MPH.
There are several ADCs in development that target cell-surface markers in triple-negative breast cancer (TNBC), namely TROP-2, LIV1, HER2, and HER3. These ADCs consist of a high-affinity antibody linked with a toxic payload. They bind to the target antigen and are internalized by the cell, where the linker is degraded by the lysosome to release the cytotoxic payload within the cancer cell, causing apoptosis.
“The question is how can we further improve the response rates,” explained Bardia, director of Precision Medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic, Massachusetts General Hospital Cancer Center, and assistant professor of medicine, Harvard Medical School. “We saw a response rate of 30% to 40% with these antibody-drug conjugates. Can we improve that to 50%, 60%, 70%, 80% and further improve the outcomes of patients with metastatic breast cancer?”
Sacituzumab govitecan targets TROP-2 to release SN-38, the active metabolite of irinotecan. In a phase I/II single-arm open-label study,1 Bardia along with other researchers found that sacituzumab govitecan showed durable objective responses in pretreated patients with metastatic TNBC, with myelotoxicity being the major adverse effect.
The study included 108 patients with TNBC. A majority of patients had visceral metastases (80%), and the median time from metastatic diagnosis to treatment in the study was 1.5 years. Sacituzumab govitecan 10 mg/kg was administered intravenously (IV) on days 1 and 8 of each 21-day cycle. Overall, 57 patients had moderate (2+) to strong (3+) TROP-2 expression by immunohistochemistry, and 5 had weak or absent staining for the marker. The data were not available for the remaining patients.
In results that were published in the New England Journal of Medicine,1 the objective response rate (ORR) was 33.3% by local assessment (95% CI, 24.6%-43.1%) at a median follow-up of 9.7 months, with a median duration of response (DOR) of 7.7 months (95% CI, 4.9-10.8). The clinical benefit rate (ORR plus stable disease) was 45.4%. By blinded independent central review, the ORR was 34.3% (95% CI, 25.4%-44.0%), and the median DOR was 9.1 months (95% CI, 4.6-11.3).
The median progression-free survival (PFS) was 5.5 months (95% CI, 4.1-6.3). The estimated 6-month PFS rate was 41.9%. By 12 months, the PFS rate with sacituzumab govitecan was estimated at 15.1%. The median overall survival (OS) was 13.0 months (95% CI, 11.2-13.7), with an estimated 6-month OS rate of 78.5% and a 12-month estimate of 51.3%.
Based on these findings, the FDA accepted a biologics license application (BLA) for sacituzumab govitecan in December 2019 as a treatment for patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.
The phase III ASCENT trial (NCT02574455) is currently exploring sacituzumab govitecan in comparison with treatment of physician’s choice for patients with metastatic TNBC. The trial, which has fully accrued 529 patients, is expected to report results in 2020 (NCT02574455). The current BLA for sacituzumab govitecan, if approved, will provide an accelerated approval for the medication. Findings from the ASCENT trial will act as confirmation.
The ADC ladiratuzumab vedotin (SGN-LIV1A) consists of an anti–LIV-1 antibody connected to a microtubule-disrupting agent via a protease-cleavable linker. In phase I findings presented at the 2017 San Antonio Breast Cancer Symposium (SABCS),2 the ORR was 25% (15 of 60 patients). The median PFS was 11.0 weeks (6.1-12.1), and the median duration of response was 13.3 weeks (95% CI, 5.3-19.1).
The drug is being evaluated in an ongoing phase I study in patients with metastatic TNBC who have received 2 or more cytotoxic regimens in the unresectable, locally advanced, or metastatic setting (NCT01969643).
At the 2019 SABCS, findings were presented from a phase Ib/II study investigating the combination of ladiratuzumab vedotin with the PD-1 inhibitor pembrolizumab (Keytruda) in patients with locally advanced or metastatic TNBC.3 According to the abstract, among 26 assessable patients, the ORR was 54% with the combination (95% CI, 33.4%-73.4%). Bardia noted that a majority of patients (>90%) treated with the combination experienced some level of decline in tumor size.
The combination of ladiratuzumab vedotin continues to be assessed in a phase I/II study. The enrollment goal for the study is 97 patients, and the estimated completion date is set for May 2020 (NCT03310957).
Fam-trastuzumab deruxtecan-nxki (Enhertu), is a novel ADC comprising 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivative; and a tetrapeptide-based cleavable linker.
Bardia noted that the novel HER2-targeting agent has been evaluated in multiple studies. In December 2019, the agent was FDA-approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting.
The approval was based on findings from the phase II DESTINY-Breast01 trial (NCT03248492).4 In the study, trastuzumab deruxtecan induced a confirmed ORR of 60.3% per independent central review (95% CI, 52.9%-67.4%), including a 4.3% complete response rate and a 56% partial response rate. ORRs were consistent across subgroups, including those with prior treatment with pertuzumab (Perjeta) and those with 3 or more prior regimens.
Sixty-seven patients had stable disease (36.4%), and 3 developed progressive disease (1.6%). Two patients were not evaluable. Median duration of response (DOR) was 14.8 months (95% CI, 13.8-16.9) with fam-trastuzumab deruxtecan-nxki, and the disease control rate (DCR) was 97.3% (95% CI, 93.8%-99.1%). The median time to response was 1.6 months (95% CI, 1.4-2.6).
After a median follow-up of 11.1 months (range, 0.7-19.9), median PFS was 16.4 months (95% CI, 12.7-not evaluable [NE]). Median PFS in 24 patients with brain metastases at baseline was 18.1 months (95% CI, 6.7-18.1). Median OS was not reached (95% CI, NE-NE).
HER3 overexpression in breast cancer is associated with decreased survival, and there are currently no approved HER3-targeted therapies, making it a target of interest. To that end, Bardia noted that an ongoing phase I/II study (NCT02980341) is exploring the safety and efficacy of the investigational ADC U3-1402 in patients with HER3-overexpressing breast cancer.5
At a median follow-up of 10.5 months for 42 patients, the ORR with U3-1402 was 43% across doses. This included an ORR of 40% for patients treated at a 4.5 mg/kg dose and 60% of those treated at a 6.4 mg/kg dose. The DCR was 91%, which comprised a DCR of 87% at the 4.5 mg/kg dose and 100% at the 6.4 mg/kg dose. Further, the DOR was not reached in any arm, and the median PFS across doses was 8.3 months (range, 1.2-15.8).5 .2
1. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Eng J Med. 2019;380(8):741-751. doi: 10.1056/NEJMoa1814213.
2. Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily pretreated triple-negative metastatic breast cancer. Poster presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Poster PD3-14. .
3. Han H, Diab S, Alemany C, et al. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium. December 10-14, 2019; San Antonio, Texas. Poster PD1-06. .
4. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi: 10.1056/NEJMoa1914510. .
5. Yonemori K, Masuda N, Takahashi S, et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial. Ann Oncol. 2019;30(suppl 3):iii48. doi: 10.1093/annonc/mdz100.002