“Smarter screening” strategies may play a crucial role in helping Latina and Black women survive breast cancer at the same rates as their White counterparts, according to a presenter at the 

 School of Nursing Oncology virtual conference.

During her presentation, Olufunmilayo I. Olopade, MD, FACP, OON, American Cancer Society clinical research professor at the University of Chicago’s Center for Clinical Cancer Genetics & Global Health, stressed the need to better understand how breast cancer affects Latina and Black women to improve their survival outcomes following treatment.

“We want to make sure we can provide the right treatment for the right patient at the right time,” explained Olopade. “Then, we can keep our families healthy…what we're looking for in preventive oncology, we can do in the clinic and we can also do it in the population. [We] identify individuals who have already had cancer as a way for us to reach their family members.”

Olopade told the attendees that screening has been an effective tool at reducing breast cancer deaths. However, in her research, Black women in and around the Chicago, Illinois area get screened at rates higher than the national average, yet still have poorer outcomes than White women — even though patients achieve pathologic complete responses at similar rates.

Over time, she said she has learned from genomic assays that breast cancer is not simply one disease but is made up of several different ones. Furthermore, she noted how she has learned that screening for early detection of breast cancer should no longer be age based.

“What we learned from Chicago is that Black and Brown women, and in fact, all young women who get breast cancer under the age of 14, are the ones that are having the worst disparity. In all other cancers, older women tend to do worse,” she said. “We suddenly say, ‘Everyone starts screening at 40,’ [but] there are some women who would have had breast cancer that would have the potential to kill them before they ever get that first mammogram.

“So that’s why we're going away from talking about age-based screening to begin to say, ‘Let us personalize screening.’ Let us all figure out what exactly we are at risk for. Are we at risk for a ‘cheetah’ type of cancer? Or are we at risk for a ‘snail’ type of cancer that grows very slowly?”

Patterns of Inherited Breast Cancer in Black Women

Olopade has studied patterns of inherited breast cancer women in Nigeria, Cameroon, Uganda, Brazil, and among Black women in the United States. Those data, along with findings from the CARRIERS study which included 32,247 women with breast cancer and 32,544 controls, show that 

 are the most important genes for assessing breast cancer risk in this patient population. Black women who harbor these genes develop cancer are almost 15 years younger at diagnosis on average compared with White women who carry the same pathogenic variants.

“These are women who get breast cancer at a very young age. So that’s why we cannot use a one-size-fits-all [approach], and then say, ‘Oh, but you know, 

 are not important.’ They are important. It all depends on your population. When you test 1000 cases and 1000 controls in Nigeria and you have almost 12% of them showing up with a mutation in

, you’re going to focus on that as an intervention for cancer control.”

Determining a patient’s individual risk is challenging, in part because Black women tend to be underrepresented in clinical trials in the United States and abroad. Genomic testing for precision risk assessment will transform cancer care, Olopade said.

“We can’t just take what is being shown in White women and then expect it to work for Indian women, expect it to work for Asian women, expect it to work for women from Africa,” she added. “So, what is the heterogeneity? What is it that we need to do for Black and Brown women?”

This is where investigators need to go beyond race and ethnicity, she said. Physicians can use data from genome-wide association studies (GWAS) to develop a polygenic risk score (PRS), which is calculated for an individual based on the presence or absence of risk variants identified in large GWAS studies. PRS can provide better insight than traditional risk models, especially in these populations. The model can estimate risk for a Black or Brown woman based on the proportion of African ancestry in her DNA.

“We can now identify women who are in the top percentile, [representing] 5% of women who have a risk that is actionable before the age of 50. If we can find those women before the age of 50, or even if we can…can really track them [and] counsel them, and then we can put them on a screening, that is going to be different because they are at risk for [estrogen receptor]-negative breast cancer, [and] I think that will really help the field. We’re talking about deescalating—not just using more and more treatment. We have to deescalate in what we're doing for early detection. We have to use innovations.”

Olopade OI. Retooling precision oncology for true equity of cancer care. Presented at: 5th Annual School of Oncology Nursing; August 6-7, 2021; virtual.

Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. 

. 2021;384(5):440-451. doi:10.1056/NEJMoa2005936

This article was originally published on OncLive as, “

Smarter Screening, Risk Assessments Are Key to Eliminating Racial Disparities in Breast Cancer Outcomes

Articles

“We want to make sure we can provide the right treatment for the right patient at the right time,” says Olufunmilayo I. Olopade, MD, FACP, OON. 

 Personalized Screenings are Needed to Address Racial Disparities in Breast Cancer Outcomes 

Oral cancer therapies can be appealing to patients, particularly during the COVID-19 era, because they can be taken at home. However, at-home medication can also pose a threat to adherence. Oncology nurses therefore need to remain diligent in educating their patients and monitoring their adherence.

“You avoid intravenous infusions; I’m all about that. And patients feel empowered [taking their medication at home], but we have to give them the tools to succeed,” said Patricia Jakel, MN, RN, AOCN, a clinical nurse specialist in the Solid Tumor Program at UCLA Medical Center, at the 5th Annual School of Oncology Nursing Annual Meeting.

Patients may be burdened with complicated medication schedules, that could include taking 1 drug to ensure that another works properly, as well as adverse event management. Add chemotherapy-related cognitive impairments – commonly referred to as “chemo brain” – and clinicians may be surprised to see how many patients are struggling with their medications. Jakel admitted she has struggled with chemo brain.

“I’m a breast cancer patient [who was] on treatment for the last 4 years. Oral adherence was not the best for me, so I have personal experience with it,” Jakel said. She joked, “I used to be smart. I used to be really smart, and chemo brain has really affected me. It doesn’t matter if you’re taking oral agents, IV agents, or anti-estrogen agents. [Chemo brain] is really real to patients.”

Cancer treatments can affect memory, executive functioning, and a patient’s ability to organize their thoughts. Their ability to pay attention or processing speed may be affected, too. Jakel said that cognitive training, which could be as simple as doing puzzles or keeping up to date on the latest news in an area of interest, can help curb the effects of chemo brain, as can complementary treatment methods such as acupuncture.

“Poor adherence decreases clinical benefits and overall effectiveness of the healthcare system,” she said. “It not only affects the patient, but these patients who are non-adherence actually end up back in the hospital and end up with other complications.”

Strikingly, 20%-30% of medication prescriptions are never filled. And according to Jakel, there are factors besides chemo brain that contribute to non-adherence.

In her experience, Jakel has seen patients stop taking their medications once they start to feel better or that the drug is working. Others may be experiencing cost barriers or psychosocial issues that prevent them from taking their medication as prescribed. “Make sure you talk to your patients about … the reasons why they’re not taking [their medication.]”

There are steps that clinicians can take to help their patients improve medication adherence. Some are simple, like calling and checking in on them, asking them to keep a drug diary, or conducting pill counts. Doctors can also encourage patients to use apps or alarms on their phone that reminds them to take their drugs.

When discussing medication adherence, clinicians should be careful of their word choice, Jakel said.

“What I say [to patients] is ‘Tell me how you’re taking your medication.’ I don’t say ‘Are you taking it?’” Jakel said. “I think that’s very important to have them talk to you.”

Additionally, caregivers should be educated on proper drug handling, scheduling, and potential drug-drug interactions.

“Make sure that education is done for the family and the caregiver,” Jakel said. “Hopefully the patient has a caregiver or a friend or family member helping them, because that’s critical for adherence.”

Ultimately, when patients do not take their cancer drugs properly, it can lead to a barrage of other complications that will have negative consequences both for the individual with cancer and the healthcare system.

Jakel P. Breast Cancer Supportive Care in 2021. Presented at: 5th Annual School of Nursing Oncology. August 6-7, 2021. Virtual.

With a newfound abundance of available oral cancer therapies, it has become necessary for oncology nurses to ensure that their patients are adhering to treatment. 



Oncology Nurses Must Stress Importance of Medication Adherence 

CDK4/6 inhibitors have demonstrated promise in treating patients with estrogen receptor (ER)–positive, HER2-negative breast cancer in both a neoadjuvant and adjuvant setting. However, according to Joyce A. O’Shaughnessy, MD, investigators still need to confirm the durable benefit in the adjuvant setting before they can be incorporated into routine clinical practice. O’Shaughnessy spoke on the topic at the 20th Annual International Congress on the Future of Breast Cancer® West, a virtual program hosted by Physicians’ Education Resource®, LLC.

O’Shaughnessy is the chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care® in Community Outreach.

In the neoadjuvant setting, the phase 2 NeoPalAna trial (NCT01723774) enrolled pre- and postmenopausal patients with stage II and III ER-positive, HER2-negative breast cancer. Patients received 4 weeks of anastrozole followed by 16 weeks of anastrozole plus palbociclib (Ibrance) followed by a 3- to 5-week treatment-free interval before surgery.1

The results showed that the complete cell cycle arrest (CCAC; Ki-67 <2.7%) rate increased from 28% after 4 weeks of anastrozole to 87% after 2 weeks of treatment with the combination. However, Ki-67 rebounded at the time of surgery, except in patients who stayed on palbociclib, suggesting that continuous treatment with palbociclib is necessary to maintain the response.

In the phase 2 FELINE trial (NCT02712723), patients were randomized to placebo plus letrozole, intermittent letrozole plus ribociclib (Kisqali), or continuous letrozole plus ribociclib. There was no difference in the preoperative endocrine prognostic index 0 score. However, the rate of patients with a Ki-67 of 2.7% or less at surgery was 71.4% with the addition of ribociclib vs 63.3% with letrozole alone (

 = .4225). Moreover, the addition of ribociclib led to a higher rate of node negativity vs letrozole alone, at 46.5% vs 35.5%, respectively (

However, as in the NeoPalAna trial, during the period of being off ribociclib prior to surgery, the Ki-67 rebounded in a subset of patients.

“There was a group [whose Ki-67 remained] very suppressed, so it’s just a proportion of the patients that are having a rebound in their Ki-67,” said O’Shaughnessy. “This really raises the question of how long we need to keep the preoperative or adjuvant therapy going in order to continue the [Ki-67] suppression,” said O’Shaughnessy.

The phase 2 NeoMONARCH trial (NCT02441946) enrolled postmenopausal patients with stage I, II, IIIA, or IIIB, hormone receptor (HR)–positive, HER2-negative breast cancer. Patients were randomized to anastrozole, anastrozole plus abemaciclib (Verzenio), or abemaciclib alone.3

The results demonstrated that the percent changes in Ki-67 from baseline to week 2 were 92.86%, 90.52%, and 62.78% in the abemaciclib/anastrozole, abemaciclib alone, and anastrozole alone arms, respectively.

Moreover, the rates of CCCA, which O’Shaughnessy termed a “very good end point,” were 67.8%, 57.7%, and 14.3%, respectively.

“Clearly, we’re getting much greater suppression of proliferation with the preoperative CDK4/6 inhibitors, regardless of which [agent you use],” said O’Shaughnessy.

The final neoadjuvant study O’Shaughnessy highlighted, the phase 2 CORALLEEN trial (NCT03248427), randomized postmenopausal patients with stage I to IIIA, HR-positive, HER2-negative disease with luminal B biology to doxorubicin and cyclophosphamide plus paclitaxel or letrozole plus ribociclib for 6 months.4

The study, which adopted the Prosigna risk of recurrence (ROR) score as the primary end point, showed no absolute difference in the ROR score between arms from baseline to surgery.

“The CDK4/6 inhibitor doesn’t look any worse than chemotherapy, but we can’t really say it’s any better,” said O’Shaughnessy.

“Are we ready to use [these agents] preoperatively? I would say probably not yet because we don’t know the duration the CDK4/6 inhibitor [should be given]. We really need the adjuvant data to know whether we [should] give them preoperatively,” said O’Shaughnessy.

In the adjuvant setting, O’Shaughnessy called attention to 3 trials. The first, the phase 3 PALLAS trial (NCT02513394), randomized patients with stage II to III, HR-positive, HER2-negative breast cancer to 2 years of palbociclib plus endocrine therapy or endocrine therapy alone.5

At a median follow-up of 23.7 months, the 3-year invasive disease-free survival (IDFS) rate was 88.2% with palbociclib/endocrine therapy vs 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; 

 = .51).4 The 3-year distant relapse-free survival (DRFS) rate was 89.3% and 90.7%, respectively (HR, 1.00; 95% CI, 0.79-1.27; 

“There was no benefit from the palbociclib. It’s a bit of a mystery why that is,” said O’Shaughnessy.

In the phase 3 monarchE trial (NCT031559970), patients with node-positive, high-risk, early HR-positive, HER2-negative breast cancer were randomized to 2 years of abemaciclib plus standard endocrine therapy or endocrine therapy alone.

“[monarchE] enrolled the highest-risk patients. The [trial investigators] really selected patients who were going to recur within 2 or 3 years,” said O’Shaughnessy.

The primary results indicated that at a median follow-up of 19.1 months, abemaciclib/endocrine therapy reduced the risk of invasive disease by 25.3% vs endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided 

 = .0096). The 2-year IDFS rates were 92.2% in the abemaciclib/endocrine therapy arm vs 88.7% in the endocrine-alone arm.6

Additional results demonstrated that the addition of abemaciclib to endocrine therapy had a significant impact on DRFS across all prespecified subgroups, reducing the risk of distant recurrence by 28.3% (HR, 0.717; 95% CI, 0.559-0.920; 

 = .0085). The 2-year DRFS rates were 93.6% with abemaciclib/endocrine therapy vs 90.3% with endocrine therapy alone.

Updated findings from monarchE demonstrated that the risk of developing an IDFS event was reduced by 28.7% with abemaciclib/endocrine therapy (HR, 0.713; 95% CI, 0.583-0.871; 

 = .0009).7 The 2-year IDFS rates were 92.3% in the abemaciclib/endocrine therapy arm vs 89.3% in the endocrine-alone arm. Moreover, the risk of distant recurrence was reduced by 31.3% with abemaciclib/endocrine therapy (HR, 0.687; 95% CI, 0.551-0.858; 

 = .0009). The 2-year DRFS rates were 93.8% with abemaciclib/endocrine therapy vs 90.8% with endocrine therapy alone.

Moreover, in a prespecified subgroup analysis that was presented at the 2021 ASCO Annual Meeting, patients who had received neoadjuvant chemotherapy experienced an absolute improvement in 2-year IDFS and 2-year DRFS of approximately 6% with abemaciclib.8

“The curves are clearly pulling apart. We hope they’ll continue to pull apart, but it’s too soon to tell,” said O’Shaughnessy.

The final phase 3 trial, PENELOPE-B (NCT01864746), randomized patients with HR-positive, HER2-negative disease who did not achieve a pathologic complete response to neoadjuvant chemotherapy to 1 year of palbociclib or placebo.

Results showed that at a median follow-up of 42.8 months, the number of IDFS events in the palbociclib/endocrine therapy arm was 152 vs 156 in the placebo/endocrine therapy arm (stratified HR, 0.93; 95% CI, 0.74-1.17; 

 = .525).9 At 2 years, the estimated IDFS rates were 88.3% and 84.0%, respectively. Moreover, the estimated 3-year IDFS rates were 81.2% with palbociclib vs 77.7% with placebo, while the 4-year IDFS rates were 73.0% vs 72.4%, respectively.

“We need to see additional data at 3 and 4 years in order to really know whether those curves can continue to pull apart,” said O’Shaughnessy.

Ongoing trials to keep an eye on include the phase 2 CARABELA (NCT04293393) and phase 3 ADAPTlate (NCT04565054), eMonarcHER (NCT04752332), NATALEE (NCT03701334), and POETIC-A (NCT04584853) trials, concluded O’Shaughnessy.

Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 Inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. 

. 2017;23(15):4055-4065. doi:10.1158/1078-0432.CCR-16-3206

Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). 

. 2020;38(suppl 15):505. doi:10.1200/JCO.2020.38.15_suppl.505

Hurvitz SA, Martin M, Press MF, et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR +/HER2 - breast cancer. 

. 2020;26(3):566-580. doi:10.1158/1078-0432.CCR-19-1425

Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. 

. 2020;21(1):33-43. doi:10.1016/S1470-2045(19)30786-7

Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. 

. 2021;22(2):212-222. doi:10.1016/S1470-2045(20)30642-2

Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). 

. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514

O’Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. 

. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS1-01

Martin M, Hegg R, Kim SB, et al. Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC). 

. 2021;39(suppl 15):517. doi:10.1200/JCO.2021.39.15_suppl.517

Loibl S, Marme F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the Penelope-B trial. 

 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639

This article was originally published on OncLive as 

“CDK4/6 Inhibitors Continue to Build Traction in Early-Stage ER+/HER2- Breast Cancer”

CDK4/6 inhibitors have demonstrated promise in treating patients with estrogen receptor (ER)–positive, HER2-negative breast cancer in both a neoadjuvant and adjuvant setting.



CDK4/6 Inhibitors Gain Momentum in Early-Stage Breast Cancer, But More Research is Still Needed

The FDA approved pembrolizumab (Keytruda) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, to be continued as an adjuvant monotherapy after surgery.

The approval was based off findings from the randomized, multicenter, double-blind, placebo-controlled KEYNOTE-522 trial (NCT03036488). Data from this study indicated that the use of pembrolizumab as a neoadjuvant therapy with chemotherapy significantly increased the pathologic clinical response. The findings showed a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; 

In addition, adjuvant pembrolizumab following surgery displayed a favorable trend in event-free survival (EFS): 16% vs 24%, respectively (HR, 0.63; 95% CI, 0.48-0.82).

The study reported that adverse events (AEs) were consistent with the preexisting safety profiles of each agent. The median duration of exposure to pembrolizumab was 13.3 months. Fatal reactions from pembrolizumab treatment occurred in 0.9 % of patients. Serious AEs occurred in a little less than half (44%) of patients and included febrile neutropenia, pyrexia, anemia, and neutropenia. The most common AEs resulting in the permanent discontinuation of pembrolizumab were increased alanine aminotransferase, increased aspartate aminotransferase, and rash.

“Even when TNBC is diagnosed early, 30% to 40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Joyce O’Shaughnessy, MD, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas, Texas, in a press release. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”

The study evaluated patients who were previously untreated, non-metastatic, and had been diagnosed with centrally confirmed TNBC. Participants were randomized 2:1 to receive either 200 mg of pembrolizumab or preoperative placebo paired with 4 cycles of carboplatin and paclitaxel, continued with 4 cycles of doxorubicin or epirubicin and cyclophosphamide. Following surgery, the 2 groups were then treated with either pembrolizumab or placebo as a monotherapy for either 9 cycles or until unacceptable toxicity was reached. Patients were separated by nodal status, tumor size, and carboplatin schedule.

End points included pathologic complete response and EFS. pCR was defined as an absence of invasive cancer in the breast and lymphs (ypT0/Tis or ypNO) while EFS was measured from the time of randomization to the first occurrence of disease progression. Secondary end points included partial complete response where pCR was defined as ypT0 ypN0 and ypT0/Tis, overall survival and efficacy in the pD-L1 L1þ population.

The age of participants ranged from 22 to 80 years and the mean age was 49. Ninety-nine percent of the participants were female, and 64% were white.

“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the U.S. in younger women and in Black women,” expressed Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with KEYTRUDA is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”

This KEYTRUDA combination is the first immunotherapy regimen approved for high-risk early-stage triple-negative breast cancer (TNBC). News release. MERCK. July 27, 2021. Accessed July 27, 2021. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/


The FDA has approved the first immunotherapy, pembrolizumab (Keytruda), to treat patients with high-risk early-stage triple-negative breast cancer.


FDA Approves Pembrolizumab for High-Risk Early-Stage TNBC

Plinabulin, an investigational, first-in-class, selective immunomodulating microtube binding agent (SIMBA), has demonstrated a potential capability to prevent chemotherapy-induced neutropenia (CIN) as well as serve as an anticancer agent in treating non-small cell lung cancer (NSCLC). 

 The drug’s status as a potential preventative and active drug is based on its highly differentiated mechanism of action.

Plinabulin binds to the vicinity of the colchicine binding domain of the ß-tubulin in αβ-tubulin heterodimers. The binding occurs at a site and with kinetics that is unique from other tubulin targeting agents.

Moreover, by binding to tubulin, GEF-H1, an immune defense protein, is released by plinabulin. This activates a signaling transduction pathway that leads to dendritic cell (DC) maturation. In turn, DC maturation elicits innate and adaptive immune activity. DC maturation also results in increased antigen presentation and T-cell activation, which appears to contribute to plinabulin’s anticancer activity.

On June 1, 2021, the FDA granted a priority review designation to a new drug application for plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of CIN.2 The regulatory designation is based on findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), as well as 5 supportive trials that enrolled over 1200 patients.

In PROTECTIVE-2, the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN vs pegfilgrastim alone in patients with early-stage or stage III breast cancer receiving high–febrile neutropenia risk chemotherapy (n = 221).

The final results of the study, which were presented during the 2021 ASCO Annual Meeting, confirmed that the combination elicited superior CIN protection compared with pegfilgrastim alone.5 The addition of plinabulin also reduced adverse clinical sequalae, did not add toxicity, reduced the severity of grade 4 treatment-emergent adverse effects (AEs), and significantly reduced bone pain (

“We think that the combination protects [patients] throughout the chemotherapy cycle. We know from a long experience that there is a vulnerability or lack of protection within the first week after chemotherapy with pegfilgrastim. Adding plinabulin to pegfilgrastim seems to mitigate that vulnerability or increase the protection in the first week after chemotherapy,” said lead study author of the PROTECTIVE-2 study Douglas W. Blayney, MD, a medical oncologist at Stanford Health Care and a professor of medicine at Stanford Medicine, in an interview during an episode of 

“This will help oncologists and their patients receive more chemotherapy during both weeks of the chemotherapy cycle before the bone marrow recovers normally,” Blayney added.

Plinabulin’s activity has also been evaluated in lung cancer. The agent is currently being evaluated in combination with docetaxel for patients with advanced NSCLC who have measurable lung lesions in the phase 3 DUBLIN-3 trial (Study 103; NCT02504489).

The anticancer results for overall survival are expected in the final quarter of 2021, according to Blayney.

Plinabulin is also being evaluated in combination with the PD-1 inhibitor nivolumab (Opdivo) with the rationale that adding the agent will elicit synergistic immune-enhancing effects.1 Historically, cumulative toxicity has been a concern with nivolumab in combination with other checkpoint inhibitors; however, it is thought that plinabulin/nivolumab may demonstrate improved antitumor activity vs nivolumab alone without significantly increased toxicity. An ongoing phase 1/2 study (NCT02812667) is evaluating the combination in patients with metastatic NSCLC.

Triplet combinations are also under study with plinabulin.

 The combination of plinabulin, nivolumab, and ipilimumab (Yervoy) is being evaluated in a phase 1/2 study (NCT03575793) in patients with recurrent small cell lung cancer to determine whether plinabulin will be synergistic with nivolumab and ipilimumab while limiting immune-related AEs associated with the agents.

Finally, research is ongoing to test the potential benefits of adding plinabulin to PD-1 inhibitors and radiation therapy.

“Given the high incidence of progression with PD-1/PD-L1 antibody therapies in the majority of cancers, we believe this novel triplet approach will restore or enable the immune targeting of cancer in patients that have progressed on checkpoint [inhibitor] therapy,” according to BeyondSpring Pharmaceuticals.

Plinabulin. BeyondSpring Pharmaceuticals. 2021. Accessed July 14, 2021. https://bit.ly/3rjFXPu.

BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring. June 1, 2021. Accessed July 14, 2021. https://bit.ly/2SQVl8U.

Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PS13-53-01.

BeyondSpring announces new positive PROTECTIVE-2 phase 3 registrational trial results at the 2020 San Antonio Breast Cancer Symposium. News release. BeyondSpring. December 10, 2020. Accessed July 14, 2021. 

Blayney DW, Shi Y, Adamchuk H, et al. Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention. 

. 2021;39(suppl 15):533. doi:10.1200/JCO.2021.39.15_suppl.533

Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC. ClinicalTrials.gov. Updated May 21, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02504489

Nivolumab in combination with plinabulin in patients with metastatic non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02812667

A phase I/II study of nivolumab, ipilimumab and plinabulin in patients with recurrent small cell lung cancer. ClinicalTrials.gov. Updated May 28, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03575793

This article was originally published on OncLive as “

Unique Mechanism of Action Positions Plinabulin as a Preventive and Active Therapy in Breast Cancer, NSCLC”


Study results have posited plinabulin as a potentially effective preventative and active therapy due to its unique mechanism of action.


Distinct Mechanism of Action Makes Plinabulin a Potentially Powerful Therapy in Treating Breast Cancer

The phase 3 MINDACT trial (NCT00433589) demonstrated that patients with early-stage breast cancer who have ultralow risk disease indicated by a 70-gene signature show superior survival outcomes.

At a median follow-up of 8.7 years, the 8-year distant metastasis-free interval (DMFI) rate in patients with ultralow-risk disease was 97.0% (95% CI, 95.8%-98.1%) vs 94.5% (95% CI, 93.6%-95.3%) in low-risk patients and 89.2% (95% CI, 87.9%-90.5%) in high-risk patients. The risk of distant metastases or death was significantly lower in ultralow-risk patients vs low-risk patients (Hazard ratio [HR], 0.65; 95% C, 0.45-0.94). Similarly, the risk was lower for low-risk patients, compared with high-risk patients (HR, 2.17; 95% CI, 1.68-2.80). Moreover, the 8-year breast cancer–specific survival (BCSS) rate was 99.6% (95% CI, 99.1%-100%) in patients with ultralow-risk disease, 98.2% (95% CI, 97.7%-98.7%) in those with low-risk disease, and 93.7% (95% CI, 92.6%-94.7%) in those with high-risk disease.

“Our results confirm previously published results of excellent survival in ultralow-risk patients in the largest cohort to date,” presenting author Josephine Lopes Cardozo, MD, a PhD candidate at the Netherlands Cancer Institute and medical fellow at the European Organization for Research and Treatment of Cancer, said during an oral presentation of the data. “As we know, especially in low-risk breast cancers, recurrences occur very late. Longer follow-up will reveal whether the excellent prognosis of ultralow-risk patients continues, as seen in other studies on ultralow-risk [disease].”

Since the 1990s, there has been an increase in the incidence of breast cancer, with a large increase in the incidence of small tumors, and almost no decrease in the incidence of large tumors, according to Lopes Cardozo. However, there has also been an increase in 10-year survival for patients with all stages of breast cancer, with the exception of stage IV disease. This increase in survival rates can be attributed to developments in adjuvant systemic treatment, mammographic screening, and improvements in local and regional treatments.

The 70-gene signature has demonstrated level 1 clinical utility in identifying patients with a preserved outcome when treated with adjuvant endocrine therapy and no chemotherapy, Lopes Cardozo said. Moreover, the 70-gene signature is able to identify patients who are at a low- or high-risk of distant recurrence within 5 years of breast cancer diagnosis. In 2017, a threshold for ultralow-risk disease was defined as a 100% BCSS rate at 15 years in independent validation cohorts of the 70-gene signature, she explained.

Two studies have demonstrated that tumors with a low- and ultralow-risk biology, according to the 70-gene signature, are overrepresented in cancers detected through screening. In one study, a cohort of patients were examined prior to the introduction of widespread screening (1984 to 1992) and compared with another cohort of patients who were examined after widespread screening was adopted (2004-2006). Results indicated that there was a significantly higher proportions of patients with low- and ultralow-risk tumors in the screened cohort vs the prior to the widespread introduction of screening cohort.

Similarly, in Dutch patients who were assessed on the MINDACT trial, a significantly higher rate of low- and ultralow-risk tumors were observed in patients with cancers detected through screening (69%; n = 754) compared with patients whose tumors were found in the intervals between 2 screening rounds (52%; n = 348).

Historically, patients with ultralow-risk tumors, as assessed by the 70-gene signature, have had excellent survival outcomes. In validation cohorts that were used to set the threshold for ultralow-risk tumors, 98% of patients received no adjuvant systemic treatment. Moreover, the 15-year BCSS was 100% for patients with ultralow-risk disease.

Additionally, another prior study analyzed a cohort from the historic STO-3 trial, which examined patients with lymph node–negative breast cancer smaller than 3 cm. Patients were randomized to receive either tamoxifen or no adjuvant systemic treatment. Among patients for whom a 70-gene signature could be performed, 339 received tamoxifen, while 313 received no adjuvant systemic treatment. Results indicated that patients in the cohort with ultralow risk tumors had excellent 20-year BCSS outcomes, with rates of 97% in those who received tamoxifen and 94% in those who received no adjuvant systemic treatment. However, the number of patients with ultralow-risk disease examined on both studies was notably small.

As such, investigators sought to assess survival outcomes in patients with an ultralow-risk tumor biology who were included in the MINDACT trial, as well as examine if the identification of an ultralow-risk patient subgroup by 70-gene signature could help to avoid overtreatment in early-stage breast cancer.

The MINDACT trial enrolled women aged 18 to 70 years old with operable invasive breast cancer and whose tumor size was a maximum of 5 cm. Additionally, patients enrolled on the study could have 0 to 3 positive lymph nodes. Patients with distant metastases were excluded from the trial.

Patients were stratified based on clinical risk by clinical-pathological characteristics and genomic risk based on the 70-gene signature.9 On the study, patients with concordant low-risk stratification received no adjuvant chemotherapy, while those with concordant high-risk stratification did receive chemotherapy. Additionally, the 2 study groups with discordant risk stratification were randomized to follow either the clinical or genomic risk stratification to receive chemotherapy or not, Lopes Cardozo added.

In total, 6693 patients were enrolled on the MINDACT trial. Of those patients, profiling revealed ultralow risk by 70-gene signature in 15% (n = 1000) of patients and 49% (n = 3295) of patients were clinically low risk. Among these patients, approximately 95% presented with hormone receptor (HR)–positive, HER2-negative disease vs 57% of high-risk patients (36%; n = 2398). Additionally, 76% to 85% of patients with low- or ultralow-risk disease received endocrine therapy only or no adjuvant systemic treatment, while 83% of high-risk patients received chemotherapy.

Among the subgroup of patients with ultralow-risk disease, the majority were older than 50 years of age (67%), lymph node-negative (80%), had tumors sized 2 cm or smaller (81%), had grade 1 or 2 disease (96%), and had HR-positive/HER2-negative subtyping (97%). Additionally, 16% of ultralow-risk patients received no adjuvant systemic treatment, 69% received endocrine therapy, and 14% received chemotherapy. Moreover, in terms of clinical risk, 741 of the ultralow risk patients had clinically low-risk tumors, while 259 had clinically high-risk tumors, defined as being larger in size, having a higher grade, and being lymph node positive.

In an assessment of DMFI in genomic ultralow-risk patients by clinical risk, those with clinically low-risk tumors had a slightly higher 8-year DMFI rate of 97.6% (95% CI, 96.4%-98.8%), vs 95.0% (95% CI, 92.3%-97.8%) in those with clinically high-risk tumors.

No statistically significant difference in 8-year BCSS rate was noted among genomic ultralow-risk patients, with the clinically low-risk group achieving a rate of 99.7% (95% CI, 99.3%-100%) and 99.2% (95% CI, 98.0%-100%) in the clinically high-risk group.

Additionally, in patients with ultralow-risk disease who received no adjuvant systemic treatment (n = 157), the 8-year DMFI rate was 97.8% (95% CI, 95.3%-100%), while it was 97.4% (95% CI, 96.1%-98.7%) in those who received endocrine therapy only (n = 685). Lastly, a rate of 94.9% (95% CI, 94.4%-98.7%) was reported in those who received chemotherapy with or without endocrine therapy (n = 144). Notably, 92% of patients who received chemotherapy had clinically high-risk disease.

“The clinical implications of this research are that we can confirm that the 70 gene signature can identify patients with an ultralow risk of recurrence, and that these patients could be candidates for further de-escalation of treatment, thus further reducing overtreatment, and the risk of [adverse] effects,” Lopes Cardozo concluded.

Cardozo J, Drukker C, Schmidt M, et al. Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. 

. 2021;39(15):500-500. doi:10.1200/JCO.2021.39.15_suppl.500

Autier P, Boniol M, Koechlin A, et al. Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. 

Piccart M, Veer L, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. 

. 2021;22(4):476-488. doi:10.1016/S1470-2045(21)00007-3

Veer L, Dai H, Vijver M, et al. Gene expression profiling predicts clinical outcome of breast cancer. 

. 2002;415(6871):530-6. doi:10.1038/415530a.

Delahaye L, Drukker C, Dreezen C, et al. A breast cancer gene signature for indolent disease. Breast Cancer Res Treat. 2017;164(2):461–466. doi:10.1007/s10549-017-4262-0

Esserman L, Shieh Y, Rutgers E, et al. Impact of mammographic screening on the detection of good and poor prognosis breast cancers. 

. 2011;130(3):725-34. doi:10.1007/s10549-011-1748-z

Drukker C, Tinteren H, Schmidt M, et al. Long-term impact of the 70-gene signature on breast cancer outcome. 

. 2014;143(3):587-92. doi:10.1007/s10549-013-2831-4

Esserman L, Yau C, Thompson C, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. 

. 2017;3(11):1503-1510. doi:10.1001/jamaoncol.2017.1261

Cardoso F, Veer L, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. 

. 2016; 375:717-729. doi:10.1056/NEJMoa1602253

“Ultralow Risk 70 gene Signature is Indicative of Excellent Survival Outcomes in Early Stage Breast Cancer.”


Regardless of clinical risk, the survival prognosis of patients with early-stage breast cancer is high amongst those who have ultralow risk disease indicated by a 70-gene signature. 



Ultralow Risk 70-Gene Promises Superior Survival Outcomes in Patients with Early-Stage Breast Cancer

Sacituzumab govitecan, an antibody drug conjugate, maintained progression-free survival (PFS), overall survival (OS), and response benefits over chemotherapy regimens, regardless of the agents used, according to data from a subanalysis of the phase 3 ASCENT trial (NCT02574455), presented during the 2021 ASCO Annual Meeting.

Sacituzumab govitecan resulted in a longer median PFS compared with any of the physician’s choice chemotherapy options, which included eribulin, vinorelbine, capecitabine, or gemcitabine (HR, 0.41; 95% CI, 0.32-0.52; 

 <.001). The median PFS, by blinded independent central review, was 5.6 months (95% CI, 4.3-6.3) with the ADC, 2.1 months (95% CI, 1.5-2.8) with eribulin, 1.6 months (95% CI, 1.4-2.7) with vinorelbine, 1.6 months (95% CI, 1.4-2.4) with capecitabine, and 2.7 months (95% CI, 1.6-4.8) with gemcitabine.

The ADC also prolonged the median OS over eribulin, vinorelbine, capecitabine, or gemcitabine, at 12.1 months (95% CI, 10.7-14.0) vs 6.9 months (95% CI, 5.8-7.8), 5.9 months (95% CI, 4.5-6.7), 5.2 months (95% CI, 3.5-8.6), and 8.4 months (95% CI, 5.0-9.6), respectively (HR, 0.48; 95% CI, 0.38-0.59; 

 <.001). Sacituzumab govitecan elicited an ORR of 35% vs 5%, 4%, 6%, and 3% with eribulin, vinorelbine, capecitabine, or gemcitabine, respectively.

“The efficacy benefit for median PFS, median OS, and ORR with sacituzumab govitecan vs single-agent chemotherapy in the second-line or greater metastatic TNBC setting in ASCENT was retained when evaluating each chemotherapy agent individually,” Joyce A. O’Shaughnessy, MD, lead study author, cochair of Breast Cancer Research and chair of breast cancer prevention research at Baylor-Sammons Cancer Center of Texas Oncology, said in a poster presentation on the data. “These results confirm that sacituzumab govitecan should be considered as a new standard of care in this patient population.”

For patients with previously treated TNBC, standard treatment has comprised single-agent chemotherapy; however, this approach has been linked with responses rates of under 20% and a short PFS ranging from just 2 to 3 months. Eribulin is a frequently used agent in this population, but median PFS continues to be poor, at less than 3 months.

Sacituzumab govitecan is comprised of a Trop-2 antibody that is paired with SN-38 through a proprietary hydrolysable linker. The agent is unique from other available ADCs in that the antibody is highly specific for Trop-2 and it has a high drug-to-antibody ratio of 7:6:1. Moreover, internalization and enzymatic cleavage by tumor cell is not needed to free SN-38 from the antibody. Notably, the ADC also has a bystander effect because hydrolysis of the linker releases SN-38 extracellularly in the tumor microenvironment.

In April 2021, the FDA granted a full approval to sacituzumab govitecan for the treatment of patients with unresectable locally advanced or metastatic TNBC who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease. The regulatory decision was based on earlier data from ASCENT, which showed that the agent significantly improved survival over physician’s choice of single-agent chemotherapy in patients with metastatic TNBC who were receiving treatment in the second- or later-line setting.

Earlier data from the trial showed that the median PFS with the ADC was 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6) with chemotherapy (HR, 0.41; 95% CI, 0.32-0.52; 

 <.001). Moreover, the median OS in the investigative and control arms was 12.1 months (95% CI, 10.7-14.0) and 6.7 months (95% CI, 5.8-7.7), respectively (HR, 0.48; 95% CI, 0.38-0.59; 

In the subanalysis presented during the meeting, investigators evaluated the safety and efficacy of sacituzumab govitecan vs each chemotherapy agent to determine how each drug performed individually.

Of the 529 patients enrolled to the phase 3 study, 235 patients in the ADC arm were negative from brain metastases, as were 233 patients in the chemotherapy arm. In the control arm, eribulin was noted to be the most frequently selected agent (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29).

At the time of data cutoff, 6% (n = 15) of those on the sacituzumab govitecan arm remained on treatment vs 0% of those on the chemotherapy arm. The most frequently reported reasons for study discontinuation included disease progression and withdrawn consent.

Across the arms, the majority of patients were female, and the median age ranged from 50 years to 56 years. The majority of patients were White, had an ECOG performance status of 1, and received more than 3 prior lines of chemotherapy. The median number of prior anticancer regimens received ranged from 3 to 5 lines.

Additional data showed that of those who responded to treatment with sacituzumab govitecan, the complete response (CR) rate was 4% and the partial response (PR) rate was 31%. The clinical benefit rate achieved with the ADC was 45% vs 8% with eribulin, 6% with vinorelbine, 10% with capecitabine, and 14% with gemcitabine. The median duration of response across these subsets was 6.3 months (95% CI, 5.5-9.0), 3.6 months (95% CI, 2.9-4.2), 2.8 months (not evaluable [NE]), NE, and 2.9 months (NE), respectively.

Regarding safety, key treatment-related adverse effects (TRAEs) that were grade 3 or higher in severity experienced with the ADC vs eribulin comprised neutropenia (51% vs 31%), leukopenia (10% vs 5%), diarrhea (10% vs 0%), anemia (8% vs 2%), febrile neutropenia (6% vs 2%), fatigue (3% vs 5%), and peripheral neuropathy (0% vs 2%).

Important grade 3 or higher TRAEs reported with sacituzumab govitecan vs vinorelbine, capecitabine, and gemcitabine combined included neutropenia (51% vs 36%), leukopenia (10% vs 6%), diarrhea (10% vs 1%), anemia (8% vs 8%), febrile neutropenia (6% vs 2%), and fatigue (3% vs 6%).

Additionally, treatment-emergent AEs resulted in discontinuation in 5% of those who received sacituzumab govitecan, 2% of those given eribulin, 10% of those who received vinorelbine, 7% of those given capecitabine, and 9% of those who were administered gemcitabine. Only 1 treatment-related death was reported in the chemotherapy arm; this patient received eribulin and had died from neutropenia sepsis. Notably, no treatment-related deaths occurred with the ADC.

Sacituzumab govitecan, an antibody drug conjugate, maintained survival and response benefits over chemotherapy regimens.

Breast Cancer

Personalized Screenings are Needed to Address Racial Disparities in Breast Cancer Outcomes

Oncology Nurses Must Stress Importance of Medication Adherence

CDK4/6 Inhibitors Gain Momentum in Early-Stage Breast Cancer, But More Research is Still Needed

FDA Approves Pembrolizumab for High-Risk Early-Stage TNBC

Distinct Mechanism of Action Makes Plinabulin a Potentially Powerful Therapy in Treating Breast Cancer

Ultralow Risk 70-Gene Promises Superior Survival Outcomes in Patients with Early-Stage Breast Cancer

Sacituzumab Govitecan Beats All Chemo Regimens in TNBC Treatment

Olaparib Is Beneficial 1 Year After Standard of Care Therapies in BRCA, High-Risk, Early HER2- Breast Cancer

Routine Cancer Screening Declined During the COVID-19 Pandemic

Shorter Adjuvant Trastuzumab Has Long-Term Benefits for HER2+ Breast Cancer