A preplanned secondary analysis of the BRE12-158 randomized clinical trial found that the presence of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in patients with early-stage triple negative breast cancer (TNBC) after neoadjuvant chemotherapy are critical indicators for the prediction of disease recurrence and disease-free survival.

Researchers indicated that this research, published in 

,supports the routine use of this technology for proper risk stratification across clinical trials in the curative setting.

“This is an important step forward in the treatment of women with triple negative breast cancer, who have not had much scientific evidence to point to—until now—for treatment of their disease,” Bryan Schneider, MD, researcher at the Indiana University School of Medicine and Bren Simon Comprehensive Cancer Center, said in a press release.

 “We are going to use these findings and continue on until we find a treatment that works for each individual woman. This effort not only involves finding the best way to kill cancer, but to minimize side effects.”

The multicenter, randomized phase 2, trial included 196 female patients randomized to receive either postneoadjuvant genomically directed therapy or physician’s choice of treatment. Participants had blood samples collected for ctDNA and CTCs at time of their treatment assignment. Overall, ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).

The primary outcome measures were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS).

Among the total cohort, detection of ctDNA was significantly associated with inferior DDFS (median, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; 

 = 0.006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Similarly, detection of ctDNA was associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; 

 = 0.009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; 

Importantly though, the combination of ctDNA and CTCs afforded additional information with regard to increased sensitivity and discriminatory capacity.

Patients who were found to be ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; 

 = 0.009). At 24 months, DDFS probability was 52% for those who were ctDNA positive and CTC positive compared with 89% for patients who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; 

 = 0.04) and OS (HR, 8.60; 95% CI, 1.78-41.47; 

“Our findings now support using [minimal residual disease; MRD] as a major stratification variable in all clinical trials to be conducted in this setting,” the authors wrote. “In addition, the ability to sequence ctDNA broadly for important gene variations affords the possibility of not only uncovering an ultra-high-risk population for relapse but also revealing drug targets.”

“Perhaps equally important, if the results from the group of patients who are ctDNA negative and CTC negative hold, this may be a subgroup in which the patients do not benefit from additional therapy, and this may be an ideal place to study novel de-escalation strategies,” the authors continued. “At the present time, we would discourage the use of MRD as a marker for relapse or to guide therapy in routine clinical practice because there is no evidence that early detection improves outcomes.”

Moving forward, researchers suggested that future trials should determine if genomically guided therapeutic interventions in patients who have molecular MRD can improve outcomes. Specifically, the planned successor trial to BRE12-158, the PERSEVERE trial, will focus on this concept. Patients with TNBC and ctDNA positivity after surgery will be included in the trial and assigned to receive a targeted agent matched to the patients’ plasma sequencing results.

1. Radovich M, Jiang G, Hancock BA, et al. Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer. 

2. IU School of Medicine findings set new standard for use of blood-based biomarkers in clinical trials for prediction of cancer recurrence [news release]. Indianapolis. Published July 9, 2020. medicine.iu.edu/news/2020/07/iu-school-of-medicine-findings-set-new-standard-for-use-of-blood-based-biomarkers-in-clinical-trials-for-prediction-of-cancer-recurrence. Accessed July 29, 2020.

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Researchers suggested that these findings support using minimal residual disease as a major stratification variable in all clinical trials to be conducted in patients with triple negative breast cancer.

Study Supports Using MRD as a Stratification Variable for Patients with TNBC

Journal of the American College of Surgeons

 indicated that a longer time from diagnosis to surgical treatment does not lower the overall survival (OS) of women with early-stage breast cancer who had to delay operations due to the coronavirus disease 2019 (COVID-19) pandemic.

In addition, researchers found no survival decrease with operative delays in women with estrogen receptor (ER)-positive early-stage breast cancer who received neoadjuvant endocrine therapy. Typically, this patient population receives anti-estrogen therapy following surgical removal of the tumor or breast; however, according to lead study author Christina Minami, MD, MS, an associate surgeon at Brigham and Women's Hospital in Boston, endocrine therapy was recommended nationwide as the initial treatment of ER-positive breast cancer due to pandemic-related surgical delays.

"Usually we take these patients with very small tumors directly to surgery, so it is a big change in practice to first put those patients on tamoxifen or an aromatase inhibitor," Minami explained in a press release. "What we can say from our findings is that despite the delay in surgical therapy, because you were on neoadjuvant endocrine therapy, we do not think that your survival will at all be impacted."

To better understand the impact of COVID-19 related surgical delay tactics, researchers utilized data from 378,839 patients included in the National Cancer Database with either ductal carcinoma in situ (DCIS) or ER-positive cT1-2N0 breast cancer treated from 2010 to 2016. Time to surgery (TTS) was then recorded and analyses were stratified by disease stage and initial treatment strategy.

Overall, increased TTS was associated with increased odds of pathological upstaging in patients with DCIS breast cancer, though women with ER-positive DCIS had a slightly increased odds of pathologic upstaging with a surgical delay surpassing 60 days (OR, 1.15; 95% CI, 1.08-1.22). Patients whose DCIS was ER-negative had a higher risk of upstaging only if they underwent an operation more than 120 days after diagnosis (OR, 1.36; 95% CI, 1.01-1.82).

“We can tell our patients they can still expect an excellent prognosis from their early-stage hormone receptor-positive cancer and that their excellent prognosis is not negatively impacted by this delay they have experienced,” senior study author Elizabeth Mittendorf, MD, PhD, FACS, professor of surgery at Brigham and Women's Hospital, explained in the release.

Notably, the applicability of these study findings is limited given that the populations experiencing delays in surgical therapy who were selected for neoadjuvant endocrine therapy in this retrospective analysis were more select then the patients who have experienced a surgery delay during the pandemic. Study participants who received neoadjuvant endocrine therapy from 2010 to 2016 did so for specific reasons according to researchers, such as older age and coexisting illnesses. However, the investigators also indicated that these data are the best currently available to study the possible outcomes of oncologic surgical delays.

“While the applicability of these data to the patients experiencing surgical delays during the COVID-19 pandemic is limited, surgeons and patients may find some reassurance in these findings, as these two groups represent patients significantly affected by the surgical triage recommendations of the COVID-19 Pandemic Breast Cancer Consortium,” the authors wrote. “Future study of outcomes of patients treated during this time will be required to determine the actual impact of COVID-related surgical delays and delay strategies.”

1. Minami CA, Kantor O, Weiss A, Nakhlis F, King TA, Mittendorf EA. Association between Time to Operation and Pathological Stage in Ductal Carcinoma in Situ and Early-Stage Hormone Receptor-Positive Breast Cancer. 

 (2020). doi: 10.1016/j.jamcollsurg.2020.06.021.

2. Delay in breast cancer operations due to COVID-19 pandemic appears to be non-life-threatening for women with early-stage disease [news release]. Chicago. Published August 6, 2020. Accessed August 11, 2020. https://www.facs.org/media/press-releases/2020/breast-080620

These study results suggested that a longer time to surgery does not lower overall survival for women with early-stage breast cancer who had to delay operations due to the COVID-19 pandemic.

Study Finds Impact of Surgical Delay on Women with Breast Cancer Due to COVID-19

With new challenges presented by the coronavirus disease 2019 (COVID-19) pandemic, survivorship care planning has become even more essential for patients with cancer. 

To discuss this topic further and discover how other industry experts are handling survivorship in the midst of the pandemic, join 

on Twitter this Friday, August 14th, at 1 PM EST for a tweet chat on survivorship. To participate, just follow the directions below. 

CancerNetwork® will be hosting a tweet chat on survivorship this Friday, August 14th, at 1 PM EST. 

Join CancerNetwork's Survivorship Tweet Chat

The American Society of Hematology (ASH) recently released new guidelines to aid older patients who are newly diagnosed with acute myeloid leukemia (AML), as well as their health care providers in making care decisions.

The guidelines, developed in partnership with the McMaster GRADE Centre, are based on systematic reviews of all available evidence. The recommendations were developed on the basis that throughout a patient’s disease course, optimal care includes ongoing discussions between clinicians and their patients, continuously examining goals of care, and the corresponding risk-benefit balance of treatment.

“These guidelines take providers through the conversations they have with newly diagnosed patients, almost in real-time,” Mikkael Sekeres, MD, chair of the ASH AML guideline panel and director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute, said in a press release.

 “A discussion between patient and physician is instrumental to creating a personalized treatment plan, and these guidelines are unique in that they keep a patient’s goals and wishes front and center in that conversation.”

Overall, the guidelines consist of 6 overarching recommendations, including:

For older adults with newly diagnosed AML who are candidates for cancer therapy, ASH recommends offering antileukemic therapy over best supportive care.

Thereafter, for those who are considered candidates for antileukemic therapy, ASH suggests the use of intensive antileukemic therapy over less intensive antileukemic therapy.

For those who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and who have achieved remission after at least a single cycle of intensive antileukemic therapy, ASH suggests postremission therapy over no additional therapy.

Should patients be considered appropriate for antileukemic therapy but not for intensive antileukemic therapy, ASH suggests the use of monotherapy with hypomethylating agents (azacytidine and decitabine) or low-dose cytarabine over a combination of 1 of these drugs with other agents.

Among patients who achieve a response after receiving less-intensive therapy, ASH suggests continuing therapy indefinitely until progression or unacceptable toxicity over stopping therapy altogether.

For those no longer receiving antileukemic therapy, ASH suggests having red blood cell transfusions available over not having transfusions available; however, there may also be rare instances where platelet transfusions may be of benefit in the event of bleeding, though there is less data to support this practice.

“We recognize the serious issues that patients face, including the side effects and risks of chemotherapy and time in the hospital,” Sekeres explained in the release. “Weighing these issues against possible benefits, including remission and extended life, patients can decide what treatment is consistent with their goals.”

With regard to the last recommendation, the organization highlighted the need for comparative studies addressing the effectiveness of transfusions. According to researchers, the optimal study design to inform this recommendation question would be a randomized clinical trial comparing the options of interest and measuring the outcomes that are important to patients, such as health-related quality of life, symptom burden, survival, and the quality of end-of-life care provided.

“Absent higher-quality data that answer these important clinical questions about the benefits and burdens of palliative blood product transfusions among patients with AML no longer receiving antileukemic therapy, clinicians will continue to provide care on an ‘n of 1’ basis, doing what they think is best for the patient, in accordance with their personal values and wishes,” the authors of the guidelines wrote.

1. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. 

. Submitted March 25, 2020; accepted May 8, 2020; published online August 6, 2020. Doi: 10.1182/bloodadvances.2020001920.

2. ASH Releases New Clinical Practice Guidelines on Acute Myeloid Leukemia in Older Adults [news release]. Washington. Published August 6, 2020. Accessed August 10, 2020. https://www.hematology.org/newsroom/press-releases/2020/ash-releases-new-clinical-practice-guidelines-on-acute-myeloid-leukemia-in-older-adults

The American Society of Hematology released guidelines that “take providers through the conversations they have with newly diagnosed patients, almost in real-time.”

ASH Releases New Guidelines on Treating Newly Diagnosed AML in Older Adults

, Aline Bobato Lara Gongora, MD, medical oncologist and preceptor of the Medical Oncology Fellowship at Hospital Sírio-Libanês in São Paulo, Brazil; Deni Leonardo Fontes Jardim, MD, PhD, medical oncologist at Hospital Sírio-Libanês; and Diogo A. Bastos, MD, genitourinary oncologist at Hospital Sírio-Libanês and Instituto do Cancer do Estado de São Paulo, discussed policies which should be implemented to the current clinical trials system as a result of the coronavirus disease 2019 (COVID-19).

Based on observations made throughout the pandemic thus far, the team recommended the oncology research community implement formal policies based on the guidance given from regulatory agencies, with the goal of minimizing the risks of COVID-19 infection while maintaining appropriate oncologic treatments for patients during this pandemic.

“Regulatory agencies have formalized recommendations to help guide the research community,” the authors wrote. “Research institutions ultimately should write their own guidance materials, considering their site’s COVID-19 epidemiology and access of staff and patients to technologies, and discussions with their trials’ sponsors and their IRB/IEC should be ongoing.”

, Mehmet Sitki Copur, MD, a medical oncologist/hematologist at Morrison Cancer Center of Mary Lanning Healthcare and a professor at the University of Nebraska Medical Center, explained the inadequacies of the current clinical trials system highlighted by the COVID-19 pandemic.

Speaking further about these challenges in an interview with 

, Copur specifically discussed difficulties surrounding enrollment and protocol adherence difficulties, needing to reduce patient visits, staffing constraints, and limited availability of ancillary services.

This segment comes from the CancerNetwork® portion of the MJH Life Sciences Medical World News, airing daily on all MJH Life Sciences channels.

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The expert oncologist/hematologist spoke with CancerNetwork® about the challenges brought to light by the current pandemic.

 Mehmet Sitki Copur, MD, on Inadequacies of the Clinical Trials System Highlighted by COVID-19

Equillium announced positive interim data from the first 2 cohorts of the open label, dose escalation, phase 1b portion of the EQUATE study of itolizumab (Alzumab) in acute graft-versus-host disease (aGVHD).

The EQUATE study is evaluating itolizumab in patients with severe aGVHD as a first-line treatment concomitant with standard of care, which is typically comprised of high dose corticosteroids. Currently, there are no other therapeutics approved for this indication.

“We are very encouraged by the early response rates observed in the first 2 cohorts of aGVHD patients dosed with itolizumab, particularly since the individuals enrolled in the EQUATE study had grade III or IV disease, representing the most gravely ill patients,” Krishna Polu, MD, chief medical officer of Equillium, said in a press release. “Achieving clinical activity in a majority of these initial patients treated with itolizumab, with a time to the initial response within 15 days, is promising given the rapid progression and high acuity of aGVHD, where the time to an effective response may be critical.”

In the first 2 dose cohorts of the phase 1b open-label portion of the study, 71% of patients achieved a complete response (CR) by day 29. Specifically, in the first cohort, 2 of 4 patients achieved a CR at a dose of 0.4 mg/kg, which resulted in a CR and overall response (OR) rate of 50%. In the second cohort at a dose of 0.8 mg/kg, all 3 patients achieved a CR, resulting in a CR and OR rate of 100%. Importantly, these CRs were observed early during the itolizumab treatment course, with all patients achieving a CR within the first 15 days of treatment.

Thus far, itolizumab has been generally well tolerated and adverse events (AEs) have been consistent with those anticipated in this severely ill aGVHD patient population. Based on a thorough review of the available safety data across both cohorts, the independent data safety monitoring committee has recommended to proceed with the planned dose escalation of 1.6 mg/kg in the third cohort of the EQUATE study.

“These early response data are very promising as patients with severe aGVHD typically have a lower response to steroids,” principal investigator of the EQUATE study, John Koreth, MBBS DPhil, director of translational research and stem cell transplantation at Dana-Farber Cancer Institute, said in the release. “I am optimistic about the future of itolizumab as a potential treatment for aGVHD patients in need of effective and well-tolerated therapies. With the increase in the number of stem cell transplants to address aggressive/advanced hematologic malignancies, there continues to be significant need for new treatment options for GVHD, particularly for the patients at highest risk of mortality.”

In July 2020, Equillium indicated that its partner, Biocon Limited, conducted a randomized, controlled, open label clinical trial in India demonstrating that itolizumab significantly reduced mortality over 1 month as compared to placebo in patients hospitalized with COVID-19. In addition, it was reported that the Drugs Controller General of India granted emergency use of itolizumab for the treatment of cytokine release syndrome in patients with COVID-19 with moderate to severe acute respiratory distress syndrome in India.

Given these results, Equillium has submitted a request to the FDA for a pre-investigational new drug meeting to review a proposal to initiate a global randomized controlled clinical trial to evaluate itolizumab in hospitalized patients with COVID-19.

“We believe these data, along with the encouraging results reported by Biocon from its recent COVID-19 study, continue to support the hypothesis that itolizumab’s novel immune-modulating mechanism may have promise in addressing a range of severe immuno-inflammatory disorders,” Polu continued. “We look forward to continuing to advance our development programs as rapidly as possible.”

Equillium Announces Positive Interim Data with Itolizumab in Acute GVHD Study [news release]. La Jolla, California. Published August 10, 2020. Accessed August 11, 2020. https://www.globenewswire.com/news-release/2020/08/10/2075965/0/en/Equillium-Announces-Positive-Interim-Data-with-Itolizumab-in-Acute-GVHD-Study.html#:~:text=(Nasdaq%3A%20EQ)%2C%20a,graft%2Dversus%2Dhost%20disease%20(

The study is evaluating itolizumab in patients with severe acute graft-versus-host disease as a first-line treatment concomitant with standard of care.