Updates in Triple-Negative Breast Cancer Treatment

Mikel Ross, MSN, RN, AGPCNP-BC, OCN, CBCN

For years, standard care for triple-negative breast cancer (TNBC) was limited to chemotherapy. Recurrence was common, and prognoses was poor.¹ However, that paradigm has shifted with results from clinical trials expanding options and allowing a more tailored approach.

We recently spoke with Mikel Ross, MSN, RN, AGPCNP-BC, OCN, CBCN, who is a nurse practitioner in the Breast Medicine service at Memorial Sloan Kettering Cancer Center, in New York, New York. Ross discussed updates in the treatment of patients with TNBC and their significance for patients and providers.

Treatment Tools

“Within the past 5 years, the addition of PARP inhibitors, immunotherapy, and anti­body-drug conjugate[s] has expanded the tools for treating TNBC,” Ross told Oncology Nursing News^®. “We still use chemotherapy, but it is no longer the only choice.”

Such PARP inhibitors as olaparib (Lynparza) and talazoparib (Talzenna) have demonstrated efficacy in reducing the rate of recurrence in patients with BRCA-mutant metastatic disease in both the early stage setting to reduce recurrence, and also in metastatic setting to achieve disease control.² Immunotherapy like pembroli­zumab (Keytruda) has been shown to extend survival in patients with early-stage, high-risk disease when given as neoadjuvant therapy.³ And sacituzumab govitecan-hziy (Trodelvy), an antibody-drug conjugate (ADC), has improved both progression-free survival (PFS) and overall survival (OS) in patients with relapsed or refractory metastatic TNBC compared with single-agent chemotherapy.⁴ Fam-trastuzumab-deruxtecan-nxki (Enhertu), another ADC, is a new option for patients with low expression of HER2 (Immunohistochemistry (IHC) 1+ or 2+ but negative by Fluorescence in situ hybridization (FISH).⁵

Ross noted that although TNBC may be a more challenging subtype to manage in terms of prognosis, adverse effects (AEs), and the number of available treatment agents, cancers tend to be individual in terms of extent of disease burden and length of progression. “We generally have long periods of disease control with metastatic hormone sensitive and HER2-positive breast cancers, but that may now be a distinction without a difference as we have more options for meta­static triple negative disease,” he said.

Neoadjuvant/Adjuvant Pembrolizumab

KEYNOTE-522 (NCT03036488; Table³)was a phase 3, randomized, double-blind, placebo-controlled trial for patients with newly diagnosed and previously untreated nonmeta­static TNBC. Neoadjuvant pembroli­zumab 200 mg intravenous (IV) infusion or placebo was adminis­tered every 3 weeks for 4 cycles plus chemotherapy (paclitaxel or carboplatin), followed by 4 cycles of pembrolizumab or placebo plus doxorubicin-cyclophospha­mide or epirubicin-cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to 9 cycles.³

Clinical Trial Updates in TNBC

The number of patients who experienced an event or died was 123 (15.7%) with pembrolizumab and chemotherapy (n = 784) and 93 (23.8%) with placebo (n = 390; HR, 0.63; 95% CI, 0.48-0.82; P < .001). The estimated event-free survival (EFS) at 36 months was 84.5% (95% CI, 81.7%- 86.9%) with the immunotherapy combination and 76.8% (95% CI, 72.2-80.7) with placebo. The median EFS was not reached in either group. Moreover, OS data were immature at 36 months; however, the estimated OS in each group was 89.7% (95% CI, 87.3%- 91.7%%) and 86.9% (95% CI, 83.0%-89.9%), respectively.³ In the safety population, treatment-related AEs grade 3 or higher occurred in 71.1% of the pembrolizumab/ chemotherapy group (n = 783) and in 73.3% of the placebo/chemotherapy group (n = 389). Most common events were neutro­penia and anemia. Serious treatment-related AEs occurred in 34.1% of patients in the pembrolizumab/chemotherapy group and in 20.1% of the placebo/chemotherapy group. Two patients in the pembrolizumab group died from immune-mediated AEs. Most AEs occurred during neoadjuvant treatment.³

“KEYNOTE-522 [was] an intensive regimen,” Ross said. “You’re giving a lot of chemotherapy, but now with an overlay of immune therapy. After that, it’s off to surgery, then pembrolizumab continues for another 6 months.”

Patient education about pembrolizumab included information about the AEs of classic cytotoxic chemotherapy, when to call the provider (ie, after fever, vomiting, consti­pation, rash), and how to watch for signs of neuropathy, limit nausea, and manage muco­sitis.⁷ “You have all that and then you add on an entirely different, sometimes overlap­ping, set of toxicities, with immune-related AEs,” Ross explained. Immune-related AEs are numerous and nuanced; the National Comprehensive Cancer Network has a full set of clinical guidelines for their management.⁶ For example, monitoring thyroid function is necessary to differentiate between fatigue from thyroiditis and from chemotherapy.

With immunotherapy, clinicians must teach patients about all the “itis” reactions, including uveitis, myocarditis, pneumonitis, dermatitis, arthritis, hepatitis, colitis, pancre­atitis, and nephritis. “You take symptoms [like] diarrhea much more seriously in a patient on immunotherapy [because] it could be the beginnings of a colitis,” Ross said. He suggested giving patients markers for when to call their provider, emphasizing that reactions can occur months after completion of therapy.

To drive home the point, he shared the story of a patient who had completed immunotherapy 6 months before devel­oping achiness in the chest wall and wrists that progressed to multiple joints and knee effusion over a 2-to 3-week period. The patient went to a local emergency department and was treated for rheuma­tology with pain management and effu­sion drainage. However, what the patient needed was a course of steroids to settle the immune system.

“The context around the agents we use is critical management for an acute problem,” Ross said, who concludes every patient education session with 2 messages: “If it bothers you, it bothers me; and small things early stay small, [but] small things later [are not] not quite so small.” He reminds patients that if something is out of the ordinary, not easily managed, is new, persistent, or progressing, the physician needs to know.

Sacituzumab Govitecan

The ASCENT trial (NCT02574455) (Table⁴) was an international phase 3, open-label, randomized trial that compared the efficacy and safety of sacituzumab govitecan with those of single-agent chemotherapy of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients with metastatic relapsed or refractory TNBC who had received at least 2 systemic therapies, including 1 for metastatic disease, were assigned to receive sacituzumab govitecan 10 mg/kg IV infusion on days 1 and 8 of a 21-day cycle or single-agent chemotherapy. The primary end point was median progression- free survival (PFS) among patients without brain metastases. The secondary end point was median overall survival (OS) for all patients.⁴

The median PFS in the sacituzumab govitecan group was 5.6 months (95% CI, 4.3-6.3) compared with 1.7 months (95% CI, 1.5-2.6) in the chemotherapy group (HR, 0.41; 95% CI, 0.32-0.52; P < .001). The median OS was 12.1 months with sacituzumab govitecan (95% CI, 10.7-14.0) and 6.7 months (95% CI, 5.8-7.7) with chemotherapy (HR, 0.48; 95% CI, 0.38-0.59; P < .001), both end points represented statistically significant improvements.⁴

Sacituzumab govitecan is administered via IV infusion only. Infusion time for the first dose is 3 hours and subsequently 1 to 2 hours per dose, if well-tolerated. Treatment cycles continue for 1 week on, 1 week off until disease progression or unacceptable toxicity. AEs of the smaller chemotherapy payload are more tolerable for patients, as the drug is delivered directly to the cancer cells rather than body-wide. Most common AEs are fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite.

Premedication is recommended for prevention of chemotherapy-induced nausea, vomiting, and other reactions. Patients should be monitored during treatment and for at least 30 minutes after infusion. To manage adverse reactions, treatment should be adjusted or interrupted or the dose reduced if necessary.⁸

Severe or life-threatening neutropenia and severe diarrhea may occur. Granulocyte colony-stimulating factor should be considered to help prevent infection and anti-infective treatment in cases of febrile neutropenia. Patients with diarrhea should be monitored and given supportive care as needed in addition to fluids/electrolytes. The dose should be reduced, delayed, or discontinued if need be due to diarrhea or neutropenia. Anaphylactic reactions are possible. Patients with reduced uridine-diphosphate glucuronosyltransferase 1A1 activity have an increased risk for neutropenia.⁸

Patient education includes instructions to call their provider immediately if they have signs or symptoms of infection, diarrhea, black or bloody stools, or dehydration. Clinicians should also teach patients about allergic and infusion-related reactions. Uncontrolled nausea and vomiting should be reported immediately.⁸

Future Directions in TNBC

When asked where the treatment of TNBC is headed, Ross said that he anticipates the addition of more classes of drugs, more immunotherapy, and more antibody-drug conjugates. Genetic targets in the tumor itself (somatic) may lead to actionable targets. “More tools and more choices within classes of available drugs will help provide care that is more patient-centered. We will see longer and better survival.”

It is no longer appropriate, he stressed, to think of TNBC merely as a difficult-to-treat disease with limited options and a poor prognosis. “That is really no longer the case,” he noted. “We now have multiple agents, classes of drugs, and AE profiles that are more tolerable than in the past. We can be more optimistic in terms of what we can offer these patients. We have more opportunities to provide high quality of life with durable treatments that allow [individuals] to live longer.”

Ellen Rice Tichich, MFA, MSN, RN, NPD-BC is a clinical/medical editor, freelance health writer, and certified nursing professional development specialist.

References

1. Triple-negative breast cancer. American Cancer Society. Updated March 2022. Accessed January 11, 2022. https://www.cancer.org/
2. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. FDA. March 11, 2022. Accessed January 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Schmid P, Cortes R, Dent J, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
4. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
5. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed January 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/
6. NCCN. Clinical Practice Guidelines in Oncology. Management of immune checkpoint inhibitor-related toxicities, version 1.2022. Accessed January 11, 2022. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf.
7. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2022. Accessed January 11, 2022. https://www.merck.com/product/
8. Trodelvy. Prescribing information. Gilead Sciences, Inc; 2022. Accessed January 11, 2022. https://www.gilead.com/-/media/files/pdfs/