Deeper understanding of disease biology may improve outcomes in triple-negative breast cancer
The discovery of predictive biomarkers and the subsequent development of effective targeted therapies have dramatically improved breast cancer outcomes over the past decade.
However, one specific subtype remains an area of tremendous unmet need.
Triple-negative breast cancer — so named because it tests negative for ER, PR and HER-2 — often is characterized by younger age and more advanced stage at diagnosis, higher tumor grade, and increased likelihood for locoregional recurrence and metastasis.
Because hormones do not support its growth, this subtype does not respond to hormonal therapy — such as aromatase inhibitors or tamoxifen — or therapies that target HER-2, such as trastuzumab (Herceptin, Genentech) or lapatinib (Tykerb, Novartis).
The aggressive nature of triple-negative disease and the lack of therapeutic options contribute to considerably shorter survival for patients diagnosed with the disease.
However, early-phase studies of novel agents have yielded encouraging results, providing a glimmer of hope that outcomes for this subgroup of patients may improve. Breast cancer specialists are anxiously awaiting data from additional clinical trials later this year.
“There is a lot of ongoing research in the triple-negative breast cancer arena,” Debu Tripathy, MD, chair of the department of breast medical oncology at The University of Texas MD Anderson Cancer Center and a HemOnc Today Editorial Board Member, said in an interview. “I suspect that research will soon identify more targets and more treatment possibilities that we hope will start to change the survival landscape for our patients.”
HemOnc Today spoke with oncologists and investigators about the prevalence and prognosis of triple-negative breast cancer; the potential that treatment strategies under investigation may fill the tremendous unmet need for effective therapies; the realization that triple-negative breast cancer no longer can be considered a single disease; and how the heterogeneity of this subtype is shaping research efforts.
Prevalence and prognosis
Triple-negative breast cancer accounts for approximately 15% to 20% of breast cancer cases.
About 75% of triple-negative breast cancers are basal like, meaning the tumors have cells that appear similar to the inner basal cells that line the mammary ducts.
Age and race appear to influence incidence.
Triple-negative breast cancer is more likely to occur among younger women.
In the United States, black women are twice as likely as white women to develop the disease (24 cases per 100,000 compared with 12 cases per 100,000), according to the American Cancer Society.
Genetic makeup also plays a role.
“Triple-negative disease is commonly diagnosed among those with a BRCA gene mutation — more than 80% are of this subtype,” Tripathy said. “In fact, when we see a patient with triple-negative breast cancer ... who is aged younger than 60 years, even if they do not have a family history, we recommend genetic counseling and testing.”
Outcomes for patients with triple-negative breast cancer historically have been poor.
Dent and colleagues determined the risks for distant recurrence (HR = 2.6; 95% CI, 2-3.5) and death (HR = 3.2; 95% CI, 2.3-4.5) within 5 years of diagnosis are significantly higher among patients with triple-negative disease than those with other subtypes. Over the longer term, however, risks for recurrence seem to attenuate.
Bauer and colleagues used the California Cancer Registry to review data from 51,074 women with breast cancer, including 6,370 women with triple-negative disease.
Results showed approximately 23% of women diagnosed with triple-negative disease died within 5 years, compared with 7% of those with other subtypes. The significant difference in survival — confirmed in several other smaller studies — persisted regardless of disease stage at diagnosis.
“Patients with triple-negative breast cancer certainly have worse prognosis compared with the general breast cancer population, and this is due — in part — to a more aggressive disease biology,” Anees B. Chagpar, MD, MSc, MBA, MA, MPH, FACS, FRCS(C), associate professor of surgery at Yale University School of Medicine and assistant director of global oncology at Yale Comprehensive Cancer Center, told HemOnc Today. “Additionally, triple-negative breast cancer has historically not been affected by certain targeted therapies. We cannot treat these patients with endocrine therapy or HER-2-directed therapy. We are, therefore, left with standard chemotherapy.”
The most common treatment strategies for early-stage triple-negative breast cancer include surgery, radiation and chemotherapy.
Chemotherapy — often administered in the neoadjuvant setting for higher-stage tumors — typically consists of anthracycline- and taxane-containing regimens. Inclusion of platinum with taxane therapy also may be offered.
Sikov and colleagues conducted the randomized phase 2 CALGB/Alliance 40603 trial to assess whether the addition of carboplatin and/or bevacizumab (Avastin, Genentech) to neoadjuvant chemotherapy with weekly paclitaxel followed by doxorubicin/cyclophosphamide increased pathologic complete response (pCR) among 443 patients with stage II or stage III triple-negative breast cancer.
Initial results showed the study met its primary endpoint, as the addition of each agent significantly increased pCR in the breast.
A subsequent analysis — presented at San Antonio Breast Cancer Symposium in 2015 — showed significantly improved EFS among patients who achieved pCR in the breast (HR = 0.33; 95% CI, 0.22-0.5), as well as those who achieved pCR in the breast and axilla (HR = 0.3; 95% CI, 0.19-0.46) compared with patients who had more than minimal residual invasive disease at the time of surgery.
Researchers also reported a statistically significant improvement in OS among patients who achieved pCR in the breast (HR = 0.28; 95% CI, 0.17-0.46), as well as those who achieved pCR in the breast and axilla (HR = 0.2; 95% CI, 0.11-0.36). However, it has not yet been clearly shown that DFS or OS is improved with platinum, and this is being tested in larger trials.
“Increasingly, we are giving chemotherapy before surgery in early-stage triple-negative disease, because we are now able to determine the degree of sensitivity to the chemotherapy,” Angela DeMichele, MD, MSCE, professor of medicine and epidemiology at Perelman School of Medicine at University of Pennsylvania, told HemOnc Today. “[This treatment] typically includes our more aggressive agents. This is the ‘bedrock’ of treatment.”
A key concern in the clinical community relates to the subset of patients with triple-negative breast cancer who develop primary or secondary resistance to treatment.
Resistance likely arises from the genomic instability and diversity, with selection of drug-resistant subclones. Although several oncogenic drivers have been identified, none have been successfully targeted in the clinic, with the exception of recently demonstrated activity with PARP inhibitors in germline BRCA mutation-associated cases. Newer treatment options are urgently needed for patients who have residual disease detected upon surgery.
“These patients do have the opportunity to participate in clinical trials in which they are able to receive novel therapies, which may include immunotherapy, additional chemotherapy, or even a PARP inhibitor for those with BRCA1 or BRCA2 gene mutations,” DeMichele said. “The subset of patients who carry these gene mutations appear to be sensitive to PARP inhibitors. ... These patients are likely to respond to a PARP inhibitor just as well as — if not better than — chemotherapy and appear to have a better overall quality of life. This is becoming the new standard for this subset of patients with triple-negative disease.”
Still, a relatively small subset of patients with triple-negative breast cancer harbor BRCA mutations. Couch and colleagues estimated prevalence at 11.2%.
For patients with triple-negative disease who do not harbor BRCA mutations, standard chemotherapy used for most other breast cancer subtypes remains the backbone of treatment.
“These are the patients [for whom] we are anxious to find clinical trials to help extend their disease control period,” DeMichele said. “This is an area of a major unmet need. Newer, more effective therapies are needed.”
Role of immunotherapy
Triple-negative breast cancer often contains tumor-infiltrating lymphocytes and tends to be more immunogenic than most other subtypes.
Consequently, researchers are exploring the use of immunotherapy for this patient population, and early data appear promising.
“We do see evidence in the advanced setting that there is a subset of patients who have durable response to immunotherapy alone, even after pretreatment with chemotherapy,” Sylvia Adams, MD, director of clinical research for breast cancer at NYU Langone Health’s Perlmutter Cancer Center, told HemOnc Today. “Immunotherapy is potentially beneficial in triple-negative breast cancer, but the numbers are still very small in terms of patients who benefit, and we need newer combination therapies to raise this bar.”
The earlier immunotherapy is used, the more effective it appears to be, DeMichele said.
“We have assessed checkpoint inhibitors for women who had already received several other treatments for metastatic disease, and the response rates were significantly low,” she said. “However, when we tested immunotherapy as first-line treatment for women who first became metastatic, the response rates increased.”
In the phase 2 I-SPY 2 trial, DeMichele and colleagues investigated the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) in combination with standard therapy — paclitaxel, followed by doxorubicin and cyclophosphamide — as neoadjuvant treatment for patients with locally advanced triple-negative breast cancer or hormone receptor-positive, HER-2-negative breast cancer.
The results, presented at last year’s ASCO Annual Meeting, showed checkpoint inhibition in the upfront setting in combination with standard chemotherapy considerably increased the pCR rate among patients with triple-negative disease (60% vs. 20%).
“We tripled the proportion of women who got to surgery and had no evidence of disease in the breast,” DeMichele said. “The outlook is very good at this point, but we do not yet know if this will translate into three times as many patients who will be cured. We need longer-term studies to answer this question, but it certainly is very encouraging to think that we can have a ‘bigger bang for our buck’ by using immunotherapy upfront.”
In cohort A of the KEYNOTE-086 trial, Adams and colleagues assessed the efficacy and safety of pembrolizumab monotherapy for 170 patients with heavily pretreated metastatic triple-negative breast cancer.
In this group, researchers reported a 4.7% overall response rate, with median PFS of 2 months (95% CI, 1.9-2) and median OS of 8.9 months (95% CI, 7.2-11.2). Survival is promising, particularly for patients with complete response, partial response or stable disease. Interestingly, response rate and PFS did not differ by PD-L1 status.
However, data from cohort B — which included 81 previously untreated patients, all of whom were PD-L1 positive — showed an ORR of 23%, with a median duration of response of 10.4 months.
“Although this requires further investigation, the activity seemed greater among patients with less heavily pretreated disease,” Adams said. “PD-L1 was not a predictive factor in the pretreated cohort; therefore, analysis of additional biomarkers, such as tumor-infiltrating lymphocytes, are ongoing.”
CTLA-4 inhibitors — typically associated with more adverse events than newer checkpoint inhibitors — also are being explored in triple-negative disease.
The ability to determine which patients may derive the most benefit from immunotherapy is crucial, given the potential for toxicities. Common adverse events associated with checkpoint inhibitors include rash, diarrhea and effects on endocrine organs, including the thyroid and pituitary gland.
“Based upon what we have seen so far, the response will still outweigh the potential side effects,” Tripathy said. “We have to monitor endocrine function in these patients. “However ... I suspect that, if we do see a clinical benefit, we will see checkpoint inhibitor approvals and these side effects are just going to be things that oncologists have to learn how to monitor, just as they have for other cancer types.”
Researchers also have investigated the role of androgen receptor inhibitors for triple-negative breast cancer.
Traina and colleagues conducted a phase 2 study to evaluate the antitumor activity and safety of enzalutamide (Xtandi; Astellas, Medivation) for patients with locally advanced or metastatic androgen receptor-positive triple-negative disease.
Patients received 160 mg once daily until disease progression. Clinical benefit rate at 16 weeks served as the primary endpoint. Secondary endpoints included clinical benefit rate at 24 weeks, PFS and safety. Investigators assessed endpoints in the intent-to-treat population, as well as in the subgroup of patients with at least 10% androgen receptor expression.
The analysis included 78 evaluable patients.
Results, published this year in Journal of Clinical Oncology, showed clinical benefit rates of 25% (95% CI, 17-33) in the intent-to-treat population and 33% (95% CI, 23-45) in the subgroup, median PFS of 2.9 months (95% CI, 1.9-3.7) in the intent-to-treat population and 3.3 months (95% CI, 1.9-4.1) in the subgroup, and median OS of 12.7 months (95% CI, 8.5-not reached) in the intent-to-treat population and 17.6 months (95% CI, 11.6-not reached) in the subgroup.
Adverse events were consistent with enzalutamide’s known safety profile. Fatigue was the only treatment-related grade 3 or higher adverse event that occurred in more than 2% of patients.
“Enzalutamide demonstrated clinical activity and was well tolerated,” Traina and colleagues wrote. “This study supports additional development of enzalutamide in advanced triple-negative breast cancer.”
Investigators also have assessed KDM4 inhibition.
Metzger and colleagues examined the antitumor properties of QC6352, an investigational, selective KDM4 inhibitor.
Researchers isolated and propagated breast cancer stem-like cells from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy.
Results — published last year in Cancer Research — showed the agent blocked proliferation of breast cancer stem-like cells, and also blocked sphere formation and xenograft tumor formation. Additionally, the agent nullified expression of EGFR, a driver of the growth of therapy-resistant triple-negative breast cancer cells.
“Our findings validate a unique breast cancer stem-like cell culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer,” Metzger and colleagues wrote.
Additional research is evaluating ladiratuzumab vedotin (SGN-LIV1A, Seattle Genetics).
The investigational antibody-drug conjugate — in which an antibody is used as a carrier vehicle to deliver small doses of chemotherapy directly to cancer cells — targets the cell surface protein LIV-1, which is expressed on multiple solid tumors, including breast cancers.
Researchers are combining ladiratuzumab vedotin with pembrolizumab as first-line treatment for locally advanced or metastatic triple-negative breast cancer.
“This class of drugs has shown quite substantial preliminary efficacy in clinical trials,” Adams said, noting significant activity even has been observed among pretreated patients. “The final phase of these studies is expected to be complete within the next year. Hopefully this will widen our therapeutic armamentarium.”
Antibody-drug conjugates may be the next class of agents to receive approval in the triple-negative setting, Tripathy said.
“There are at least two antibody-drug conjugates showing promising early results in phase 2 trials,” he said.
One of them — sacituzumab govitecan (Immu-132, Immunomedics) — appeared associated with compelling response rates in heavily pretreated patients, Tripathy said.
“Randomized studies comparing these agents to standard chemotherapy are ongoing and depending upon the results of these studies, could very well lead to FDA approval,” Tripathy said.
The identification of several subtypes of triple-negative breast cancer has created new challenges for researchers, as well as possible opportunities for more effective treatments.
In a paper published in 2011 in Journal of Clinical Investigation, Lehmann and colleagues described the molecular features of six distinct subtypes of triple-negative disease. The Vanderbilt team also identified chemotherapies to which the different subtypes responded in cultured cells and animal tumor models.
“Knowing the specific subtype could help physicians determine which therapies would work best [among] patients with triple-negative breast cancer, and also inform the discovery and development of new drugs to treat this aggressive form of breast cancer,” the researchers wrote.
Five years later, Jennifer A. Pietenpol, PhD — director of Vanderbilt-Ingram Cancer Center, executive vice president for research at Vanderbilt University Medical Center and chief scientific officer for Susan G. Komen, as well as senior author on the 2011 paper — and colleagues further refined the molecular subtypes to four main categories: hormone receptor negative, androgen receptor positive, immune infiltrate and basal like.
The authors further elucidated the distinct transcriptional subtypes with unique biologies.
“Once we had a view of how heterogeneous triple-negative disease is and how the subtypes have distinct biologies, we came to the realization that we can no longer think of triple-negative breast cancer as one disease that will receive one treatment,” Pietenpol told HemOnc Today. “Each of these four subtypes demonstrate differences in diagnosis, stage, grade, local and distant disease progression, and histology. Two of the subtypes that we had identified before, we are now considering descriptors of the ‘microenvironment’ in which the tumor resides, including immune features.”
Although knowledge of the biology and genomics of triple-negative breast cancer continues to evolve, these insights have not dramatically altered clinical practice, Chagpar said.
“We do not have all the information about the nuances of the various subtypes of triple-negative breast cancer,” Chagpar said. “This is an area of active research and one that we should keep an eye on, but I do not know that this information is making a significant dent in terms of how we treat patients day to day.”
Adams echoed this sentiment.
“Unfortunately, despite the knowledge of the different subtypes of triple-negative breast cancer being around for nearly 5 years now, there have been no approvals based upon these different subtypes,” Adams said. “Clinical trials even lump together the different types of triple-negative disease, which may — in fact — dilute the effect size. The only subgroup of triple-negative breast cancer for which a targeted agent — olaparib [Lynparza, AstraZeneca] — is now approved comprises cancers in BRCA mutation carriers. But, again, this is only a small subset of patients with triple-negative disease.”
Pietenpol, however, said she remains optimistic.
“Any time we make fundamental discoveries that increase our genomic, molecular and biologic knowledge of a disease like triple-negative breast cancer, these discoveries stimulate more hypothesis-driven research,” Pietenpol said. “Also, these discoveries give us new data, much of which are preclinical, and we can then use these preclinical data to inform future clinical trials.”
Pietenpol offered an example of how improved understanding of different biologic subtypes ultimately translated into increased clinical trial participation.
“We know that about 16% of triple-negative breast cancers are androgen receptor positive. Of these, we have determined that approximately 40% have mutations in the PI3K signaling pathway,” Pietenpol said.
This knowledge led to the design of a clinical trial that is ongoing in which women are receiving enzalutamide — an androgen receptor inhibitor — alone or in combination with taselisib (Genentech), an investigational PI 3-kinase inhibitor.
“We would have never designed this trial if we had not discovered that about 16% of women with triple-negative breast cancer expressed androgen receptor in their tumors,” Pietenpol said. “As we conduct more clinical trials that translate more of our bench-based research to investigation in patients, we may be able to help inform the best first-line therapies for the individual patient with triple-negative disease, whether it is localized or metastatic. This is our ultimate goal.”
Moving forward, researchers must intensify their efforts to align existing or novel therapeutic approaches to the identified triple-negative breast cancer subtypes, experts said.
“We are learning more and more about the biological underpinnings of this breast cancer subtype, and we have already seen therapies evolve in this sphere,” Chagpar said. “As we learned more about the immunogenicity of triple-negative breast cancer, studies began to examine immunotherapies in this disease. This is now something that we are beginning to offer our patients on clinical trials. Similarly, as we look at other forms of chemotherapy, we are basing our treatment decisions on the understanding of the biological underpinnings of triple-negative disease.”
The improved biological understanding of triple-negative breast cancer includes growing evidence that tumors have defects in DNA damage repair within cancer cells, Adams said.
“Therefore, by inducing DNA damage, this makes the cancer cells more likely to die,” Adams said. “DNA repair mechanisms are very important. Hopefully, in the near future, we will have more treatments that target the genomic instability of these tumors.”
Despite progress over the past few years, much more work remains to be done, Pietenpol said.
“Fundamental and translational research is critical for driving advances,” she said. “This is an exciting time given all that we have discovered — relatively recently — in terms of leveraging genomic technologies. ...
“Now, with the advent of some immune-based approaches to treatment, the outlook is even more promising,” she added. “However, it also is a time in which research is more important than ever.” – by Jennifer Southall
Click here to read the , “Should neoadjuvant carboplatin be used for triple-negative breast cancer?”
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For more information:
Sylvia Adams, MD, MSCI, can be reached at Perlmutter Cancer Center, 160 E. 34th St., New York, NY 10016; email: firstname.lastname@example.org.
Anees B. Chagpar, MD, MSc, MBA, MA, MPH, FACS, FRCS(C), can be reached at The Breast Center-Smilow Cancer Hospital at Yale-New Haven, 20 York St., New Haven, CT 06510; email: email@example.com.
Angela DeMichele, MD, MSCE, can be reached at University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: firstname.lastname@example.org.
Jennifer A. Pietenpol, PhD, can be reached at Vanderbilt University Medical Center, 652 Preston Research Building, Nashville, TN 37232-0146; email: email@example.com.
Debu Tripathy, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030; email: firstname.lastname@example.org.
Disclosures: Adams, Chagpar, DeMichele, Pietenpol and Tripathy report no relevant financial disclosures.