Mateusz Opyrchal, MD, PhD, associate professor, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, discusses the current state of biomarkers in triple-negative breast cancer (TNBC).

Identifying actionable biomarkers in breast cancer and other solid malignancies remains an ongoing challenge, Opyrchal says. In TNBC, PD-L1 expression has shown correlation with improved likelihood of response; however, some clinical trials have not corroborated this evidence.

Despite the inconclusive findings from clinical trials, the checkpoint inhibitor atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) is approved for patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 as determined by an FDA-approved test. 

Identifying additional biomarkers that can target chemotherapy-resistant TNBC in the neoadjuvant setting may have a significant effect on how to sensitize patients with immunotherapy in the future, concludes Opyrchal.

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Mateusz Opyrchal, MD, PhD, discusses the current state of biomarkers in triple-negative breast cancer.  



Dr. Opyrchal on the Current State of Biomarkers in TNBC 

Associate Director of the Early Phase Clinical Trials Program

Co-leader of the Adoptive Cellular Therapy Program

Co-leader of the Breast Disease Specific Research Group at Roswell Park Comprehensive Cancer Center, Buffalo, New York 

Despite considerable advances and promising developments in recent years, metastatic breast cancer (mBC) continues to be a deadly disease. Although the first immune agonist was recently approved for patients with locally advanced or metastatic triple-negative breast cancer (mTNBC), the effectiveness of immunotherapy strategies in the treatment of mBC remains a work in progress.

Several strategies with a strong scientific basis are now under investigation, including many clinical trials under way at Roswell Park Comprehensive Cancer Center in Buffalo, New York. These secondgeneration immunooncology studies hold great promise for breaking through the known barriers highlighted by earlier research against this intractable disease.

Anti-PD-1 antibodies work by blocking the inhibitory signal from the tumor cells to CD8-positive T cells, preventing interaction of the PD-1 receptor and its ligands, PD-L1 and PD-L2.

 Although these drugs have seen spectacular successes in the treatment of melanoma and are approved for multiple other cancers, the results in breast cancer studies have been disappointing.

In clinical trials using these agents as part of treatment for mTNBC, responses have been seen in 5% to 10% of patients, a statistic that highlights the difficulty of these approaches in this malignancy. Despite such low response rates, the patients who do respond often experience prolonged control of the disease, which shows the promise of immunotherapy approaches.

In March, the FDA approved the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) as a first-line treatment for patients with mTNBC expressing PD-L1 on tumor-infiltrating immune cells covering ≥1% of the tumor area. The approval is based on findings from the IMpassion 130 trial.

Schmid et al reported that patients with PD-L1—positive mTNBC achieved median progression-free survival of 7.5 months with the atezolizumab combination compared with 5.0 months with nab-paclitaxel plus placebo (HR, 0.62; 95% CI, 0.49-0.78; 

 <.001). Median overall survival was 25.0 months versus 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86).

However, early analysis of the data has not provided any evidence of long-term responses; the median duration of response in patients with PD-L1—positive tumors, after 12.9 months of median follow-up, was 9.2 months (95% CI, 7.5-11.9) with the atezolizumab combination versus 6.2 months (95% CI, 5.5-8.8) for chemotherapy alone.

One of the main obstacles identified as a resistance mechanism to immunotherapy is the lack of breast cancer tumor infiltration by the PD1-expressing CD8-positive T cells that must be activated by PD-1 blockade to attack the cancer cells, resulting in the phenomenon of “cold” tumors. This is an area of intense research, with multiple approaches in active investigation to improve efficacy.

Our research team, which includes my Roswell Park Comprehensive Cancer Center colleagues Pawel Kalinski, MD, PhD, and Shipra Gandhi, MD, is attempting to address this by targeting abnormal signaling in the breast cancer microenvironment—specifically, mechanisms that attract immunosuppressive cells instead of antitumor immune cells.

This approach, which is based on Kalinski’s preclinical work, attempts to change the mTNBC microenvironment from cold to hot so that these tumors will be subsequently responsive to anti-PD1 therapy.

 This research led to a novel clinical trial (NCT03599453) that includes pretreatment with a regimen designed to change the breast cancer microenvironment signaling to allow CD8-positive T-cell infiltration so that these patients will respond well to subsequent pembrolizumab (Keytruda).

Adoptive cell strategies including chimeric antigen receptor T-cell therapies have gained acceptance in the wider clinical world following the FDA approvals of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) for the treatment of patients with leukemia and lymphoma. Solid tumors, including mBC, present a new set of challenges because of their high antigenic heterogeneity and microenvironmental barriers to infiltration with adoptively transferred cells.

Manipulating dendritic cells is one strategy for overcoming both of these barriers. The goal with this area of immunotherapy is to generate effective antitumor CD8-positive T cells. Our team is working on using dendritic cell vaccines to allow for an effective immune response against mBC. Clinical trials are being prepared in collaboration with Moffitt Cancer Center in Tampa, Florida.

Using adoptive T-cell strategies is another approach that focuses on designing active T cells against specific targets present in cancer cells. We are focusing on T-cell—receptor T-cellbased adoptive cell therapies because they target a wider range of proteins. In collaboration with our colleagues from Roswell Park’s Center for Immunotherapy, led by Kunle Odunsi, MD, PhD, and Richard Koya, MD, PhD, we are in the process of developing a breast cancer–specific protocol targeting the NY-ESO-1 protein. We are awaiting completion of the ongoing phase I trial to assess safety of the treatment in locally advanced or stage IV solid tumors that express NY-ESO-1 (NCT02650986).

Together, these investigational approaches represent exciting prospects for finally breaking through the challenges that mBC has posed to date. Because this is an area of such dire clinical need in one of the most common cancer types in women, we greet the coming years with excitement and eagerly look forward to seeing the results from our own trials and many others from our colleagues around the globe.

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Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. 

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Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. 

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Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. 

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Articles

Second-generation immuno-oncology studies hold great promise for breaking through the known barriers highlighted by earlier research against metastatic breast cancer.

Roswell Park Metastatic Breast Cancer Studies Focus on New Immunotherapies

	Providing medical care to patients in the hospital setting has become increasingly complicated. Large amounts of clinical data need to be processed, and new rules governing resident and fellow hours have resulted in fragmented care. There have been many initiatives to improve hospital care, and it is a process that needs continuous reevaluation and updating.

	Communication between physicians has been identified as an area in which many mistakes happen. These can lead to potentially negative outcomes for our patients, such as prolonged hospital stay or death.

 In 2003, the Accreditation Council for Graduate Medical Education instituted limits on the number of hours that residents can work in the hospital per 24-hour period. Although the goal was to improve patient safety by decreasing fatigue among residents, it had unintended consequences. The rules led to the increased need for multiple handoffs of patient care among residents, fellows, and attending physicians in the inpatient setting. Unfortunately, these communications are often not standardized and may lead to disastrous results.

	The change of physician on duty can be a perilous time for the patients, because the majority of medical errors resulting in liability have been traced to miscommunications.

 The errors resulting from poor handoffs can include incomplete or incorrect lists of medications, incorrect code statuses, and inaccurate laboratory results. But the most serious mistakes are errors of omission, when the events of the last 12 to 24 hours are not relayed and the new physician does not have an accurate picture of the patient’s health.

	In the studies that examined liability claims, 26% to 31% of events were due to errors in communication.

There are not many data that directly evaluate physician-to-physician communication at the time of patient-care handoff. Specifically, there is a lack of data about teams caring for patients on internal medicine hospital services, although a few studies report an alarmingly high rate of errors and omissions during change-of-care times.

	Over the past 5 years, the Joint Commission has made standardized communications a priority among physicians performing patient- care handoffs. However, there is no concerted effort to evaluate and recommend the most efficient and reliable methods. Individual institutions have designed their own solutions, although there are no high-quality data on which approaches lead to better outcomes in patient care and safety. Most institutions now use some form of electronic board that can be updated by various members of the team.

	Unfortunately, there is great variation among different institutions and their approach to patient-care handoffs.

 Some of the differences stem from the fact that there are many solutions to the resident-hour rules, ranging from the night-float system to residents staying overnight in the hospital and leaving early in the morning. It is disturbing to learn that the process was not standardized across institutions nor within specific programs.

 These observations call attention to the lack of high-quality data needed to help institutions implement solutions that would assure patient safety, and to the lack of education for physicians and residents on how to efficiently and thoroughly communicate patient information to other physicians.

	The uniform standardization of patient handoffs across all institutions might not be possible or even desirable due to the differences between academic institutions and private institutions. Also, hospital services caring for certain patient populations have their own requirements and points of emphasis specific to their specialties. Internal medicine services and especially hematology and oncology inpatient services have increasingly complex patients with multiple medical problems. It is imperative that physicians caring for these patients have up-to-date and accurate information.

	Several existing studies offer recommendations to make the process safer. Face-to-face interactions between the 2 parties is essential in limiting errors.

 This allows the physicians to ask questions and clarify information, resulting in more accurate patient data being transferred. Interruption- free time was also important in ensuring an error-free transfer of care. Computerized systems that automatically pull information from patients’ charts help to reduce errors and make the process more efficient.

	It is clear that the process of patient-care handoffs must be made safer and more efficient. The increasing implementation of sophisticated software programs will most likely improve the accuracy of the information as well as the efficiency of the process. Unfortunately, these ancillary products will not be able to replace a physician’s necessary clinical acumen. One of the most important parts of the change of care is anticipation of potential problems and designing appropriate responses. All doctors do this to some degree while caring for their patients—often subconsciously. The challenge lies in communicating this information to others. No software program will be able to replace this interaction. Medical schools and residency programs will need to introduce or expand existing programs in teaching physicians the necessary methods to effectively and concisely hand off the care of their patients to new care teams. Likewise, institutions must continually reevaluate the process to decrease the number of poor patient-care handoffs, leading directly to improved patient safety.

1. Pham JG, Aswani MS, Rosen M, et al. Reducing medical errors and adverse events [published online ahead of print January 26, 2011]. 

2. White AA, Pichert JW, Bledsoe SH, Irwin C, Entman SS. Cause and effect analysis of closed claims in obstetrics and gynecology. 

3. White AA, Wright SW, Blanco R, et al. Cause-and-effect analysis of risk management files to assess patient care in the emergency department. 

4. Sehgal NL, Auerbach AA. Communication failures and a call for new systems to promote patient safety: comment on “structured interdisciplinary rounds in a medical teaching unit.” 

5. Kannry J, Moore C. MediSign: using a Web-based signout system to improve provider identification. 

6. Horwitz LI, Krumholz HM, Green ML, Huot SJ. Transfers of patient care between house staff on internal medicine wards: a national survey. 

7. Alvarado K, Lee R, Christoffersen E, et al. Transfer of accountability: transforming shift handover to enhance patient safety. 

8. Petersen LA, Orav EJ, Teich JM, O’Neil AC, Brennan TA. Using a computerized sign-out program to improve continuity of inpatient care and prevent adverse events. 

Providing medical care to patients in the hospital setting has become increasingly complicated. Large amounts of clinical data need to be processed, and new rules governing resident and fellow hours have resulted in fragmented care. 

Mateusz Opyrchal, MD, PhD

Articles

Dr. Opyrchal on the Current State of Biomarkers in TNBC

Roswell Park Metastatic Breast Cancer Studies Focus on New Immunotherapies

Reducing Errors During Patient-Care Handoffs