Intravenous (IV) cetirizine (Quzyttir) showed comparable efficacy to IV diphenhydramine for the prevention of infusion reactions (IRs) in patients with cancer who are undergoing treatment with an anti-CD20 antibody or paclitaxel, according to results from a prospective, phase 2 trial (NCT04189588) that were presented during the 

Findings showed that the IR rate in patients who received IV cetirizine was 11.8% (n = 2/17) compared with 17.6% (n = 3/17) in those who received IV diphenhydramine. One of 3 patients with breast cancer experienced an IR.

“This was the first prospective, randomized, controlled trial evaluating IV antihistamine pretreatment for the prevention of IRs,” Jarrod P. Holmes, MD, FACP, medical oncology at St. Joseph Health Medical Group, and coinvestigators noted in the poster presented at the meeting. “IV cetirizine was associated with less sedation, less time in the treatment center, and fewer treatment-related [adverse effects (AEs)] than IV diphenhydramine.”

Pretreatment with antihistamine for drug-induced hypersensitivity is recommended to be used with other chemotherapies, including paclitaxel, for patients with breast cancer. IV cetirizine is a second-generation IV antihistamine and has been shown to treat patients with acute urticaria with outcomes comparable to that of IV diphenhydramine but with fewer toxicities. The study authors suggested that IV cetirizine may also show promise as a pretreatment of IRs.

In the prospective, double-blind, randomized, controlled, phase 2 trial, investigators sought to compare the incidence of IRs to treatment with an anti-CD20 antibody, such as rituximab (Rituxan), or paclitaxel, following pretreatment with IV cetirizine (n = 17) or IV diphenhydramine (n = 17) during infusion.

IRs were defined as flushing, itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking, chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, syncope, or dizziness.

Pretreatment was given with a single IV dose of 10-mg cetirizine or IV diphenhydramine at 50 mg in 34 patients who were being treated with paclitaxel, rituximab or a rituximab biosimilar, or obinutuzumab (Gazyva) at the first cycle or retreatment after 6 months or in patients with persistent IRs while on maintenance or retreatment.

To be eligible for enrollment, patients had to be 18 years or older, could be male or female, and required treatment premedication with an antihistamine for hypersensitivity IRs linked with rituximab or paclitaxel. Those who had a high risk of developing tumor lysis syndrome, may have contraindications with an antihistamine, had received any antihistamine within 24 hours prior to receiving the study drug regardless of the administration route, and who had received an H2 antagonist in the prior 4 hours before receiving study drug, were excluded.

The primary end point of the trial was the incidence of IRs following pretreatment; the key secondary end point was sedation score due to IV antihistamines. Sedation was assessed by health care providers as well as patients on a scale of 0 to 4 (0 = none; 4 = extremely severe/asleep). Time to readiness for discharge served as another efficacy end point, the investigators noted in the poster.

The patient population comprised those with both hematologic and solid tumors, including breast cancer, and were enrolled between March 25, 2020 and November 23, 2020. An addition of patients receiving paclitaxel was added to the protocol in amendment 2 on August 10, 2020. Twenty-five patients had received an anti-CD20 agent and 9 had been given paclitaxel; those who had received the anti-CD20 drug had hematologic malignancies or immune disorders, while those who had paclitaxel had solid tumors, 3 of whom had breast cancer.

The median age of the participants was 66.0 years (range, 36-87), 35.3% were female, and most were White (76.5%) and not Hispanic or Latino (82.4%).

Additional data showed that the mean sedation scores in the IV cetirizine arm was 0.5 (0.72), 0.6 (0.61), and 0.1 (0.33) vs 1.3 (1.26), 0.9 (1.14), and 0.4 (0.71) in the IV diphenhydramine arm at 1 hour, 2 hours, and at discharge, respectively, as rated by the patients enrolled on the trial. Moreover, these data were similar with the health care provider­–rated sedation scores.

The median time for readiness for discharge was 24 minutes less with IV cetirizine compared with IV diphenhydramine, at 4 hours and 18 minutes and 4 hours and 42 minutes, respectively.

Regarding safety, fewer patients experienced treatment-related AEs with IV cetirizine (n = 2) vs IV diphenhydramine (n = 4). Treatment-emergent AEs (TEAEs) occurred in 8 and 9 patients, respectively. In the IV cetirizine arm, these TEAEs were mild in 2 patients, moderate in 4, severe in 1, and life-threatening in 1; none were fatal. In the IV diphenhydramine arm, 3 cases were mild, 5 were moderate, and 1 was fatal; no severe or life-threatening TEAEs were reported.

Overall, 2 and 4 TEAEs were possibly related to study treatment; there were 0 AEs that led to discontinuation of study treatment in either arm.

The TRAEs in the IV cetirizine arm included insomnia, dyspepsia, and malaise; in the IV diphenhydramine arm, these effects were diarrhea, injection site pain, headache, somnolence, dizziness, and lightheadedness.

In the poster, investigators noted that study limitations include the small sample size without formal statistics.

“However, the results of key secondary end points of sedation score, time to discharge, and safety profile are consistent with the results from the studies with IV cetirizine in acute urticaria,” the authors stated.

Holmes JP, Dasanu CA, Peguero J, et al. Aphase 2 exploratory study of intravenous cetirizine versus intravenous diphenhydramine in the prevention of hypersensitivity infusion reactions in patients with breast cancer and other malignancies. Presented at: 

 Miami Breast Cancer Conference; March 4-7, 2021; Virtual.

This article was originally published on OncLive as, "

Intravenous Cetirizine Prevents Infusion Reactions From Paclitaxel in Breast Cancer, Other Tumors.

Articles

Intravenous cetirizine showed comparable efficacy to IV diphenhydramine for the prevention of infusion reactions in patients with cancer who are undergoing treatment with an anti-CD20 antibody or paclitaxel.

Preventing Paclitaxel-Related Infusion Reactions

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer (TNBC) as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm, explained William J. Gradishar, MD, in a presentation during the NCCN 2021 Virtual Annual Conference.

“In early-stage disease, anthracycline/taxane therapy—the sequence not so critical—remains foundational,” Gradishar said. “The addition of […] checkpoint inhibitors can increase the [pathologic complete response] rate, but the data in the adjuvant setting are still awaited. We need event-free survival to determine the overall impact.”

Moreover, for patients with residual disease following neoadjuvant therapy, capecitabine is an appropriate treatment, said Gradishar, professor of medicine of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

However, in the metastatic setting, immunotherapy has improved progression-free and overall survival (OS) in a subset of patients with TNBC, and the antibody-drug conjugates (ADCs) have provided another option for those who have progressed on prior treatment.

All these advances with evidence-backed data led to updates in the latest version of the National Comprehensive Cancer Network® Guidelines Version 2.2021 in Invasive Breast Cancer.

The updated guidelines list the following as preferred preoperative/adjuvant therapy regimens—as category 2A recommendations —in HER2-negative breast cancer:

Dose-dense doxorubicin/cyclophosphamide followed by paclitaxel every 2 weeks

Dose-dense doxorubicin/cyclophosphamide followed by weekly paclitaxel

Capecitabine for patients with TNBC and residual disease after preoperative treatment with taxane-, alkylator-, and anthracycline-based chemotherapy

In the metastatic setting, the following regimens are noted as category 1 recommendations in HER2-negative metastatic breast cancer:

Atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) as a preferred frontline therapy for patients with PD-L1 expression with 1% or greater tumor-infiltration immune cells (ICs)

Pembrolizumab (Keytruda) plus chemotherapy (either nab-paclitaxel, paclitaxel, or gemcitabine and carboplatin) as a preferred frontline therapy for PD-L1–positive patients with a combined positive score (CPS) of 10 or higher

Carboplatin and cisplatin for TNBC and germline 

Sacituzumab govitecan (Trodelvy) is also considered a recommended regimen in recurrent or stage IV HER2-negative breast cancer. A number of chemotherapy regimens also remain as preferred options in the NCCN guidelines for use in the metastatic setting.

In his presentation on the evidence behind the guideline updates, Gradishar touched upon selecting optimal localized therapy for patients with locally advanced TNBC, recognizing key patient factors to influence systemic treatment selection for metastatic disease, and optimally managing common adverse effects (AEs) linked with new agents used to manage this malignancy.

Gradishar homed in on the summary of neoadjuvant platinum-based therapy in TNBC, adding that carboplatin augments pathologic complete response (pCR) in TNBC. For example, when carboplatin was added to chemotherapy regimens for patients with TNBC in the GeparSixto, CALGB 40603, and BrighTNess studies, the pCR rates increased to 53.2%, 54%, 58% and 53% (both BrighTNess), respectively.

However, there has been controversy with using platinum agents concomitantly with chemotherapy, which was seen in GeparSixto. Also, in CALGB 40603, the addition of carboplatin resulted in markedly higher toxicity, which led to significantly fewer patients (less than 65%) receiving 11 to 12 doses of paclitaxel vs the control group (more than 85%).

A meta-analysis of 9 randomized trials evaluated the role of platinum-based therapy as neoadjuvant therapy for TNBC (n = 2109). Data showed that platinum therapy significantly improved pCR from 37.0% to 52.1% (odds ratio [OR], 1.96; 95% CI, 1.46-2.62; 

 <.001), even when restricting the analysis to 3 studies with standard chemotherapy regimens (n = 611; OR, 2.53; 95% CI, 1.37-4.66; 

However, no improvement was observed in a subset of patients with germline 

 mutations (OR, 1.17; 95% CI, 0.51-2.67; 

 = .711). There was also a significantly higher risk of grade 3/4 hematologic adverse events (AEs).

The guidelines state that, “Several studies have shown improved pCR rates with the incorporation of platinum. However, long-term outcomes remain unknown. The routine use of platinum agents as part of neoadjuvant therapy for TNBC is not recommended for most patients (including 

 mutation carriers), but it may be considered in select patients, such as those for whom achieving better local control is necessary.”

Citing the updated guidelines, Gradishar noted that the inclusion of platinum agents in the neoadjuvant setting remains controversial.

“For most patients, this would not be viewed as standard, but it could be used in individual patients,” he added.

Capecitabine has also been noted in the guidelines as an option for patients with residual disease following neoadjuvant therapy. In the CREATE-X trial, which had 887 evaluable patients with stage I to IIIB, HER2-negative breast cancer, who did not have a pCR and/or were node positive after surgery and neoadjuvant chemotherapy, patients received capecitabine at 2500 mg/m2 daily on days 1 to 14, repeated every 3 weeks for 8 cycles, plus standard therapy or standard therapy alone.

Thirty-two percent of patients had TNBC, 95% were treated with anthracyclines and taxanes, and 41% were node positive.6 Results showed that the real impact of capecitabine was seen in the TNBC subset, in regard to disease-free survival (DFS; HR, 0.58; 95% CI, 0.39-0.87) and overall survival (OS; HR, 0.52; 95% CI, 0.30-0.90).

“The use of capecitabine can be justified in such patients with residual triple-negative disease following preoperative therapy,” said Gradishar, citing the ongoing ECOG-ACRIN EA1131 (NCT02445391) and SWOG 1418 (NCT02954874) trials as efforts to evaluate adjuvant capecitabine in basal-like residual TNBC and adjuvant pembrolizumab (Keytruda) in TNBC, respectively.

Immunotherapy for PD-L1–Positive Disease

Checkpoint blockade has been evaluated in both the neoadjuvant and metastatic settings. In his presentation, Gradishar focused on the IMpassion031 trial of neoadjuvant atezolizumab with nab-paclitaxel, which showed a pCR rate of 58% compared with 41% with chemotherapy alone (

KEYNOTE-522, a phase 3 trial of pembrolizumab and carboplatin/paclitaxel vs carboplatin/paclitaxel and placebo in previously untreated patients with stage II or III TNBC, garnered attention in 2020 and 2021 this year. At an interim analysis with a median follow-up of 15.5 months, data showed that pembrolizumab improved event-free survival (EFS) over chemotherapy alone (HR, 0.63; 95% CI, 0.43-0.93).

“pCR rates that go up are great, but does it translate into an improvement in EFS, and hopefully, downstream even further [with] overall survival?” asked Gradishar. “If you ask the question: Who are the patients who are gaining the greatest benefit? For the most part, [it is] in the patients with PD-L1–positive disease.”

Data from KEYNOTE-522 were further extrapolated at an FDA Oncology Drugs Advisory Board Meeting (ODAC) on February 8, 2021. Although the pembrolizumab arm did have an improved pCR rate versus placebo with neoadjuvant chemotherapy, the ODAC committee voted 10 to 0 against an approval of pembrolizumab in this setting, adding that a regulatory decision should be deferred until further data from KEYNOTE-522 become available.

“The biggest reason is not because the pCR rate was questioned, but rather, the pCR rate over time, was actually starting to decrease,” Gradishar shared. “Most importantly, there were insufficient data at that point to say [whether this] affected EFS. This does not stick a dagger in the idea of checkpoint inhibitors preoperatively, but rather, it requires further follow-up to see whether the impact is going to have an outcome measure on the overall outcome of patients.”

The current role for immunotherapy in the metastatic setting of TNBC is based upon the IMpassion130, IMpassion131, and KEYNOTE-355 studies, Gradishar emphasized.

In the phase 3 IMpassion130 trial, atezolizumab plus nab-paclitaxel compared with nab-paclitaxel and placebo was evaluated in the first-line treatment of patients with metastatic or unresectable locally advanced TNBC (n = 902). Patients had to be treatment naïve in the metastatic setting and have an ECOG performance status of 0 or 1. The co-primary end points were progression-free survival (PFS) and OS in both the intent-to-treat (ITT) and PD-L1–positive population.

PD-L1 IC status was assessed via the SP142 assay. In the PD-L1–positive population, the median PFS was 7.5 months compared with 5.3 months for the atezolizumab and placebo arms, respectively (HR, 0.63; 95% CI, 0.50-0.80; 

 <.0001).10 A similar trend was seen in this subset for OS at 25.0 and 18.0 months, respectively (HR, 0.71; 95% CI, 0.54-0.93). No benefit was observed with atezolizumab in the PD-L1–negative groups for PFS (HR, 0.93) nor OS (HR, 0.97).

Most recently, at the ESMO 2020 Virtual Congress, findings of the final OS analysis showed that the median OS with atezolizumab was 25.4 months vs 17.9 months for placebo/nab-paclitaxel (HR, 0.67; 95% CI, 0.53-0.86) in the PD-L1–positive population.11 The 3-year OS rates were 36% and 22% in this subgroup, respectively.

Similarly, in the phase 3 KEYNOTE-355 study, patients with previously untreated locally recurrent inoperable or metastatic TNBC, with no active central nervous system metastases or active autoimmune disease, were randomized 2:1 to receive pembrolizumab/chemotherapy or placebo/chemotherapy until disease progression or cessation of study treatment. Chemotherapy regimens consisted of nab-paclitaxel, paclitaxel, and gemcitabine and carboplatin.

Data showed that, in the ITT population, PFS was favored in the pembrolizumab/chemotherapy arm vs placebo/chemotherapy at 7.5 months and 5.6 months, respectively (HR, 0.82; 95% CI, 0.69-0.97), but was higher in those with PD-L1 combined positive score (CPS) of 1 or greater (HR, 0.74; 

 value boundary of .00111 was not met.12 This benefit was even higher in patients with a PD-L1 CPS of 10 or greater (HR, 0.65; 

 = .0012). In the ITT population, statistical significance was not tested due to the prespecified hierarchical testing strategy.

“In this dataset, we don’t yet have a survival advantage that has been demonstrated or reported,” explained Gradishar. “We simply don’t have enough events yet to report OS.”

However, it was the double-blind, placebo-controlled, randomized, phase 3 IMpassion131 study that Gradishar coined as a “fly in the ointment.”

Here, atezolizumab was combined with paclitaxel compared with paclitaxel/placebo in a similar patient population. At a primary analysis of the PD-L1–positive population, the median PFS was 6.0 months with the atezolizumab arm and 5.7 months with placebo/paclitaxel, demonstrating a stratified HR of 0.82 (95% CI, 0.60-1.12; log-rank 

 = .20).13 Updated OS findings, at a data cutoff date of August 19, 2020, showed that the median OS was 22.1 months and 28.3 months with atezolizumab/paclitaxel and paclitaxel/placebo (HR, 1.12; 95% CI, 0.76-1.65). The benefit was similar in the ITT population (HR, 1.11; 95% CI, 0.87-1.42).

Some key reasons for the discordant results between this trial and IMpassion130, Gradishar noted, could be that IMpassion131 utilized corticosteroids, and also utilized paclitaxel vs nab-paclitaxel in IMpassion130.

Safety has also been an area of investigation with checkpoint blockade in metastatic TNBC, specially with organ-specific immune-related AEs, such as pneumonitis, pruritis, rash, anemia, and colitis, among others.

“If you look at severe or high-grade AEs, they are relatively uncommon and can be managed for most patients, but certainly as these agents go into the earlier-stage settings, these become more of an issue,” Gradishar noted.

The ADC sacituzumab govitecan was granted an accelerated approval in April 2020 for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease, based on phase 1/2 findings.14

Moreover, the confirmatory phase 3 ASCENT study showed further benefit with the agent in this setting. The median PFS by blinded independent central review was 5.6 months (95% CI, 4.3-6.3) in the sacituzumab govitecan arm compared with 1.7 months (95% CI, 1.5-2.6) with physician’s choice of single-agent chemotherapy in patients with previously treated metastatic TNBC (HR, 0.41; 95% CI, 0.32-0.52; 

Additional data presented at the 2020 San Antonio Breast Cancer Symposium showed that the benefit with sacituzumab govitecan is seen independent of the level of Trop-2 expression or 

“Sacituzumab govitecan is the newest kid on the block, and this is a drug that has utility in patients with triple-negative disease who have progressed through other therapies,” said Gradishar.

Two phase 3 trials in advanced breast cancer highlight the significance of PARP inhibition and therefore have had an impact on the latest guidelines: OympiAD and EMBRACA.

-mutated, HER2-negative metastatic breast cancer, who had received at least 2 prior lines of chemotherapy, were randomized 2:1 to receive olaparib or physician’s choice of treatment. Olaparib was linked with a significant reduction in the risk of death in patients who received it as a frontline treatment versus chemotherapy (HR, 0.51; 95% CI, 0.29-0.90; 

 = .02), but not in those who had received prior chemotherapy (HR, 1.13; 95% CI, 0.79-1.64; 

The EMBRACA trial enrolled patients with germline 

-mutated, HER2-negative locally advanced or advanced breast cancer who had received at least 3 prior lines of chemotherapy. Here, the median PFS was 8.6 months (95% CI, 7.2-9.3) with talazoparib and 5

6 months (95% CI, 4.2-6.7) with chemotherapy (HR, 0.54; 95% CI, 0.41-0.71; 

One-year PFS rates were 37% and 20%, respectively.

Gradishar noted that talazoparib and olaparib both improve PFS in patients with germline 

-mutated metastatic breast cancer compared with chemotherapy, and that talazoparib is also promising as a single-agent neoadjuvant therapy in germline 

 mutation and have high PD-L1 expression, Gradishar suggested using a checkpoint inhibitor with chemotherapy first before going onto a PARP inhibitor.

NCCN Guidelines update: triple-negative breast cancer. Presented at: NCCN 2021 Virtual Annual Conference; March 18-20; 2021; Virtual.

von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. 

. 2014;15(7):747-756. doi:10.1016/S1470-2045(14)70160-3

Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). 

. 2015;33(1):13-21. doi:10.1200/JCO.2014.57.0572

Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. 

. 2018;19(4):497-509. doi: 10.1016/S1470-2045(18)30111-6

Poggio F, Bruzzone M, Ceppi M, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. 

. 2018;29(7):1497-1508. doi: 10.1093/annonc/mdy127

Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. 

. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645

Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. 

. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X

Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer

. 2020;382(9):810-821.doi:10.1056/NEJMoa1910549

Merck announces outcome of Oncologic Drugs Advisory Committee (ODAC) for Keytruda (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC). Merck. News release. Published February 9, 2021. Accessed March 19, 2021. 

Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2020;21(1):44-59. doi:10.1016/S1470-2045(19)30689-8.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

Cortes Jm Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. 

. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9

Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). 

Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. 

. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). 

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Hurvitz SA, Tolaney SM, Punie K, et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual.

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This article was originally published on OncLive as, "

Chemo Reigns Control in Early-Stage TNBC, But Immunotherapy, ADCs Gain Ground in Metastatic Setting

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm.

Immunotherapy and ADCs Make Headway in Metastatic TNBC

One in 7 Caribbean-born individuals with either breast or ovarian cancer had hereditary disease with an actionable pathogenic variant, which provides the opportunity for the utilization of targeted therapeutics and precise prevention strategies, according to results from a study recently published in 

Results from the research indicated that of 1018 patients, 98.1% (n = 999) had breast cancer, while 2.1% (n = 21) had ovarian cancer. Moreover, of the 1015 patients for whom data were available, 14.2% (n = 144) were found to have a pathogenic or likely pathogenic variant in a gene associated with hereditary breast cancer and ovarian cancer syndrome. Notably, 64% of patients who had these variants had them in 

Patients in the Bahamas were noted to have the highest proportion of hereditary breast and ovarian cancers at 23%; this was followed by Barbados (17.9%), Trinidad (12%), Dominica (8.8%), Haiti (6.7%), Cayman Islands (6.3%), and Jamaica (4.9%).

“This genetic association study was a large, unique, and multinational study of breast and ovarian cancer in the Caribbean population. Pathogenic variants in the breast cancer genes of 

 are common causes of breast cancer in Caribbean women,” Sophia George, PhD, research assistant professor at Sylvester Comprehensive Cancer Center of the University of Miami Health System, and colleagues, wrote. “People of African descent are understudied and undertested in both the breast and gynecologic cancer settings. Targeted genetic testing of only 

 is insufficient in Caribbean women, and panel multigene testing should be recommended.”

Approximately 40 million individuals reside in the Caribbean and most patients are of African descent with genetic admixture of Indigenous, Asian, Indian, European, and Middle Eastern immigrants. Importantly, breast cancer is a leading cause of cancer-associated deaths in these women; in fact, in some countries, young women are disproportionately affected by this.

In light of the high rates of breast and ovarian cancer that have been observed in the Caribbean, and the relatively young age of patients at the time of presentation, investigators set out to identify the rate of inherited breast and ovarian cancers in select countries within the Caribbean as a way to derive a better understanding of different disease variants region wide.

To do this, investigators planned to consider the odds of harboring a pathogenic or likely pathogenic variant when individuals are diagnosed with these diseases at an early age. They also performed multigene testing for hereditary breast and ovarian cancer genes in individuals who resided in 7 Caribbean countries: the Bahamas, the Cayman Islands, Barbados, Dominica, Haiti, Jamaica, and Trinidad and Tobago.

The cross-sectional Caribbean Women’s Cancer Study was conducted between June 2010 and June 2018 in 1018 patients with invasive breast cancer and/or ovarian cancer who resided in the Caribbean. Individuals were identified by the following: treating physicians, local cancer societies, hospital and pathology records, and outpatient oncology clinical records of the individual islands. Investigators also recruited participants through the use of different media outlets.

To be eligible for enrollment, patients had to have a pathologic diagnosis of breast cancer and/or ovarian cancer, at least 1 grandparent born in 1 of the 7 selected countries, and they had to be able to provide consent, as well as a saliva sample.

All samples collected from patients underwent next-generation sequencing (NGS) and multiplex ligation–dependent probe amplification to allow for the identification of all classes of variants. All individuals were initially screened for 

 variants in the phase 1 portion of the research. 

In phase 2, those residing in the Barbados, Cayman Islands, Dominica, and Haiti received full NGS of 30 genes. Those residing in Jamaica and Trinidad who had a family history of either cancer, were less than 40 years of age, and tested negative for the variants examined in phase 1, were re-examined using a multipaneled test.

Following these test results, participants were identified to be have pathogenic variants, or those that directly contribute to disease development; to have likely pathogenic variants, or those with greater than 90% certainty that the variant will cause disease; or to have a variant of unknown significance (VUS).

Of the 1018 participants enrolled to the study, the majority (n = 996) were women, 21 female individuals had ovarian cancer and 3 men had breast cancer. Notably, 86% of patients with breast cancer had a self-detected mass and sought medical attention, underscoring the fact that disease detection via mammogram was uncommon.

More than half of the women who were diagnosed with breast cancer (63%) were premenopausal, and the mean age at the time of diagnosis was 46.6 years. The mean age in those diagnosed with ovarian cancer was 47.6 years. Discrepancies of age and population-based cancer registries in Trinidad and Tobago and the Barbados were noted.

Of 607 patients with a documented disease stage at diagnosis, 33.4% had stage III disease and 5.9% had stage IV disease. Those residing in Haiti had the highest percentage of advanced-stage disease, at 64.7%, while the lowest percentage was noted in Cayman Island residents, at 11%.

A total of 144 variant carriers was identified in the study cohort. Among the carriers for breast cancer, the mean age was 40.7 years; these individuals were significantly younger than those who did not have germline variants, according to the study investigators (

 = .03). Approximately 44% (n = 29/66) of carriers were diagnosed with triple-negative breast cancer (TNBC) vs 21.1% of noncarriers (

Moreover, 50.5% of participants were found to have a family history of either a first- or second-degree relative with breast cancer, while 11.3% had relatives with ovarian cancer. Approximately half of those with VUS had a family history of breast cancer, while 8.5% had a history of ovarian cancer. Any family history of breast cancer was linked with a 

 variant (odds ratio [OR], 4.87; 95% CI, 2.82-8.42; 

Specifically, of the individuals born in the Caribbean who had breast cancer, having a first- or second-degree family member with the disease was linked with having any 

 germline variant (OR, 1.58; 95% CI, 1.24-2.01; 

 variant was found to be more strongly associated with TNBC vs a 

“These data may be useful in screening, increasing awareness of cancer risk, and encouraging risk reduction strategies in people of Caribbean origin and their unaffected family members,” the study authors concluded. “Awareness of the heightened risks among these patients may help minimize morbidity and maximize care in a group already overburdened with well-described cancer health disparities.”

George SHL, Donenberg T, Alexis C, et al. Gene sequencing for pathogenic variants among adults with breast and ovarian cancer in the Caribbean. 

. 2021;4(3):210307. doi:10.1001/jamanetworkopen.2021.0307

1 in 7 Caribbean Adults With Breast or Ovarian Cancers Have Actionable Pathogenic Variants

One in 7 Caribbean-born individuals with either breast or ovarian cancer had hereditary disease with an actionable pathogenic variant, which provides the opportunity for the utilization of targeted therapeutics and precise prevention strategies.

Study Explores Actionable Pathologic Variants in Caribbean Women With Breast or Ovarian Cancer

Treatment strategies for patients with breast cancer, especially the combination of anthracyclines and HER2-targeted therapies, come with an increased risk of heart failure and cardiac toxicity.

 To prevent patients with breast cancer from also becoming patients with heart disease, primary prevention and cardiovascular surveillance strategies must be in place over the course of treatment, according to Mandar Aras, MD, PhD, assistant professor of medicine and cardiology at the University of California, San Francisco.

“Patients who have existing cardiovascular issues are most at risk, including those with cardiovascular risk due to uncontrolled blood pressure, uncontrolled cholesterol, or uncontrolled diabetes. If we can manage these risks before they start chemotherapy, that can be very helpful,” he said.

However, even those without preexisting cardiac conditions may experience cardiomyopathy with or without overt heart failure, which is associated with risks treatments for breast cancer. “Anthracyclines and the targeted therapies against the HER2 pathway, such as trastuzumab [Herceptin], have a well-documented and well-established risk of causing cardiomyopathy.”

Risk assessment prior to initiating therapy can help build treatment strategies to reduce the occurrence of severe or fatal cardiac adverse events. These strategies can include a combination of preventive measures, cardiac surveillance while on treatment, and drug interventions such as the use of β-blockers or angiotensin-converting enzyme (ACE) inhibitors. 

Anticipating Cardiovascular Toxicities of Therapy

As it stands, the evaluation of left ventricular ejection fraction (LVEF) has played a substantial role in identifying those at risk for and minimizing the occurrence of posttreatment heart failure. Although LVEF decline is observed after myocardial deformation has begun, timely treatment with β-blockers or ACE inhibitors and/or a reduction in cancer therapy has led to improved outcomes for patients.

 Guidelines differ on the timing for the evaluation of LVEF; the National Comprehensive Cancer Network guidelines recommend the evaluation of LVEF before and during treatment, with 12-month follow-up for patients who receive anthracyclines who have elevated cardiovascular risk.

 Further, the FDA recommends that clinicians use trastuzumab, pertuzumab (Perjeta)

, and ado-trastuzumab emtansine (T-DM1; Kadcyla)

 in patients whose LVEF is above 50% and delay or discontinue their use in patients whose LVEF declines during treatment.

Results of studies examining the correlation between breast cancer treatment and cardiac toxicity have begun to show that, with management, patients with breast cancer at high risk for cardiac events can be treated safely. For example, in 2021 investigators of the SAFE-HEaRt trial (NCT01904903) published long-term follow-up results showing that it is possible to administer targeted therapy to patients with HER2-positive breast cancer and reduced LVEF.

In SAFE-HEaRt, 15 patients were treated with trastuzumab, 14 patients were treated with trastuzumab and pertuzumab, and 2 were treated with T-DM1. Patients had stage I to IV breast cancer and were receiving or planned to receive 1 of the 3 treatment regimens in the neoadjuvant or metastatic setting. Patients with LVEF 40% to 49% prior to study participation were eligible.

Mean LVEF was 44.9% at baseline and improved to 52.1%. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Of the 23 patients evaluated for follow-up, 1 patient developed symptomatic heart failure with no change in LVEF. One patient withdrew from the study for reasons unrelated to the trial, and thus was not included in the analysis. There were no cardiac deaths during the study period.

All patients received serial echocardiograms, β-blockers, and ACE inhibitors. The primary end point was completion of the therapy without developing either a cardiac event (defined as heart failure, myocardial infarction, arrhythmia, or cardiac death) or significant asymptomatic worsening of LVEF. The study was considered successful if the planned oncology therapy completion rate was at least 30%.

Twenty-one patients met the primary end point of the trial. Fifteen of these patients had LVEF recovery to at least 50%, and at the time of analysis, 9 patients were on cardiac medication and 6 were off medication; 5 patients with stable LVEF (40%-49%) were asymptomatic on cardiac medication; and 1 patient with suggestive symptoms of heart failure but stable LVEF had not sought medical care.

“This is very exciting and very informative because we would be excluding these patients from the therapy that they needed for their breast cancer if we shied away from it because of the low [ejection fraction],” Aras said. “This was an important study and an important first step in helping us understand the risks.”

Earlier study results on the primary prevention of cardiovascular adverse effects demonstrated some signals that cardiac events may be managed with the use of β-blockers or ACE inhibitors. However, investigators reported a mixed bag of efficacy findings with these pharmacologic agents in patients treated with anthracyclines or trastuzumab, resulting in an unanswered clinical question for an evidence-based recommendation for their use.

For example, investigators of the PRADA trial (NCT01434134) evaluated women with early breast cancer who were being treated with either adjuvant anthracycline chemotherapy with or without or trastuzumab. These patients also received the angiotensin receptor blocker, candesartan cilexetil (Atacand; n = 32), or the β-blocker metoprolol (n = 30), the combination of the 2 agents (n = 28), or a placebo (n = 30).7

Published in June 2016, findings showed that candesartan reduced the decline in LVEF that occurs during adjuvant therapy. The overall decline from baseline to the end of study was 0.8 (95% CI, –0.4-1.9) percentage points in the candesartan group and 2.6 (95% CI, 1.5-3.8) percentage points in the placebo group in the intention-to-treat analysis (

 = .026). No patient developed symptomatic heart failure during the study period.

In another study, MANTICORE (NCT01016886), patients with HER2-positive early breast cancer were randomly assigned to receive treatment with the ACE inhibitor perindopril, the β-blocker bisoprolol, or placebo during trastuzumab adjuvant therapy.8 Investigators found that perindopril and bisoprolol were well tolerated and protected against declines in LVEF related to cancer therapy, but the primary end point— prevention of trastuzumab-mediated left ventricular remodeling—was not met.

Further, findings from the CECCY trial (NCT01724450) suggested that the use of the β-blocker carvedilol protected against myocardial injury but did not result in significant change in LVEF. The study assessed patients with HER2-negative breast cancer being treated with anthracycline chemotherapy. Patients were randomized to either carvedilol (n = 96) or placebo (n = 96) during chemotherapy treatment. The primary end point of prevention of 10% or greater reduction in LVEF at 6 months was achieved in 14.5% of patients in the carvedilol arm and 13.5% in the placebo arm (

 Investigators reported a lower incidence of diastolic dysfunction in the carvedilol group compared with the placebo group (

Aras recommended close communication between oncologists and cardiologists. “Screening and monitoring these patients is the best strategy. Patients who have existing cardiovascular issues are most at risk for cardiotoxicities related to cancer treatment. Managing these cardiac risk factors before starting chemotherapy is the best way to prevent these cardiotoxicities.”

He predicted more partnerships between oncology and cardiology in the future. “My role in the care of the cancer patient is to work with the oncologist once a patient has been identified as being high risk or if they have some toxicity that affects their heart. A lot of centers are going to have a cardiologist embedded in their cancer center to help address many of these issues. A cardiologist can also play a role in survivorship,” Aras said.

Other treatment strategies for patients with breast cancer are also under evaluation for cardiac toxicity, including immune checkpoint inhibitors. Although some patients with breast cancer who have been treated with immunotherapies have experienced cardiac toxicities, the data are not well fleshed out, Aras said. “Immunotherapies are super exciting, and they have revolutionized cancer treatment. There are reports of cardiac toxicity, even fatal cardiac toxicity, with the use of combination checkpoint inhibitors. This [adverse event] was seen in other cancer types such as melanoma and lung cancer.”

One review found that cardio toxicities related to immunotherapy are not common but can be severe and include fulminant heart failure, hemodynamic instability, and cardiac arrest.

Cardinale D, Caruso V, Cipolla CM. The breast cancer patient in the cardioncology unit. 

. 2018;10(suppl 35):S4306-S4322. doi:10.21037/ jtd.2018.10.06

NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2021. Accessed February 22, 2021. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

Perjeta. Prescribing information. Genentech Inc; 2020. Accessed February 22, 2021. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2020/125409s124lbl.pdf

Kadcyla. Prescribing information. Genentech Inc; 2020. Accessed February 22, 2021. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2020/125427s108lbl.pdf

Khoury K, Lynce F, Barac A, et al. Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function. 

 Published online January 3, 2021. doi:10.1007/ s10549-020-06053-y

Khoury K, Barac A, Lynce F, et al. Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function. 

. 2020;38(suppl 15):12069. doi:10.1200/JCO.2020.38.15_suppl.12069

Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. 

 2016;37(21):1671-1680. doi:10.1093/eurheartj/ehw022

Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE-101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. 

 2017;35(8):870-877. doi:10.1200/JCO.2016.68.7830

Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial. 

. 2018;71(20):2281-2290. doi:10.1016/j. jacc.2018.02.049

Zarifa A, Salih M, Lopez-Mattei J, et al. Cardiotoxicity of FDA-approved immune checkpoint inhibitors: a rare but serious adverse event. 

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