Managing Brain Metastases in a Patient With HER+ Breast Cancer

Suppose you are caring for a patient receiving fam-trastuzumab deruxtecan-nxki (Enhertu).

Previously, she had undergone neoadjuvant TCHP (Docetaxel, carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]), followed by lumpectomy, to treat a 4.3 cm breast mass and clinically concerning lymph nodes. A biopsy showed that she had a grade 3 invasive ductal carcinoma that was estrogen receptor-negative, progesterone receptor-negative, HER2-positive (3+)—with a Ki67 of 55%, and axillary lymph node involvement.

Following her lumpectomy, she proceeded to receive adjuvant ado-trastuzumab emtansine (Kadcyla) with radiation.

When she came to clinic complaining of a persistent cough, a CT scan of her chest, abdomen, and pelvis (CT C/A/P) showed numerous enlarged, abnormal lymph nodes and 4 pulmonary nodules. A biopsy confirmed that this was a recurrent carcinoma consistent with breast cancer. She began THP but had to stop the docetaxel after 9 cycles because of neuropathy, and CT scans showed the lung metastases were progressing.

Because of this, you recommended trastuzumab deruxtecan. Now, she has been on this therapy for 22 months when a CT scan of her chest, abdomen, and pelvis, detects disease progression in her lungs, with 2 new nodules, each 1 cm.

This patient tells you that she has been taking acetaminophen more frequently for her headaches and asks if that is OK to do given her other medications. Concerned, you ordered magnetic resonance imaging, which shows 4 brain metastases, which are 0.6 cm, 0.7 cm, 1.4 cm, and 1.8 cm in size, respectively.

What is the next treatment step?

In a presentation on improving outcomes for patients with metastatic HER2-positive breast cancer, Stephanie L. Graff, MD, FACP; Christine McGinn, MSN, APRN, ACNP-BC; and Jeanine Showalter, MSN, APRN, FNP-BC, AOCNP, addressed this question for an audience of advanced practice providers.¹

After presenting this scenario, they presented their audience with 4 potential next steps: whole brain radiation (WBRT); stereotactic radiosurgery (SRS); changing their systemic treatment regimen to tucatinib, trastuzumab, and capecitabine; or continuing with trastuzumab deruxtecan.

Weighing Radiation Approaches

According to the panelists, SRS, which is a targeted form of radiation therapy, would be the ideal choice in this setting over WBRT, based on the lesion size.²

Christine McGinn, MSN, APRN, ACNP-BC

“I would say for this patient, I would favor SRS because the lesions are small,” McGinn, who is a practitioner at Lifespan Cancer Institute, said, noting that “We know there is really no overall survival benefit with whole brain radiation versus SRS and there is more cognitive decline with that approach.”

Showalter, who is a practitioner at Sarah Cannon Cancer Center, voiced her support for this approach as well. “I would say that if the [lesions] were 3 millimeters or 4 millimeters, I might consider reimaging in 6 weeks or so, and that they have a nice discussion with the radiation oncologist,” she added. “But SRS would be my recommendation.”

Jeanine Showalter, MSN, APRN, FNP-BC, AOCNP

Is Radiation Always Necessary?

Both McGinn and Showalter said that for this patient, they would recommend radiation. However, Graff, a physician at the Lifespan Cancer Institute, noted that there are instances in which systemic therapies alone could be effective in this setting.

Stephanie L. Graff, MD, FACP

“The HER2CLIMB [NCT02614794] data gives us compelling [evidence] that oral agents are effective for controlling [progression] in the brain,” she said. “You may have patients who really do not want radiation, whose insurance coverage for stereotactic radiosurgery is poor, or who live in rural [areas] so their access to stereotactic radiosurgery is difficult, or who just really do not want 1 more thing right in their life with metastatic breast cancer. In all those scenarios, no radiation is reasonable.”

She conceded that, in her experience, many patients will opt for radiation when presented with the choice to add it to systemic treatment, because when most people hear that there is progression in their brain, they are eager to try the most aggressive treatments to control it. For these reasons, she emphasized the importance of having these conversations and truly understanding the patients’ treatment goals and expectations.

“This is what shared decision-making looks like,” she said. “It is having that conversation and engaging your patient in that discussion.”

Tucatinib Yields Strong Intracranial Responses

Findings from the phase 2 HER2CLIMB trial showed that a triplet regimen comprised of tucatinib (Tukysa), capecitabine (Xeloda), and trastuzumab (Herceptin) improved both progression-free survival (PFS) months and overall survival (OS) in pretreated patients with HER2-positive metastatic breast cancer, over capecitabine and trastuzumab alone. For most patients in the trial, this was their third line of therapy.³

The panelists noted that HER2CLIMB was an innovative trial because it allowed patients with previously untreated or progressing brain metastases, who did not need urgent intervention, to enroll.

Patients with active brain metastases who received tucatinib achieved a median OS that was 9.6 months longer compared to their counterparts in the control arm (21.4 months vs 11.8 months; HR, 0.524, 95% CI, 0.356-0.771; P < .00087). Patients with stable brain metastases achieved 5.6 more months median OS compared with those in the doublet arm (21.6 months vs 16.4 months; HR, 0.695, 95% CI, 0.416-1.160; P = 16223).⁴

“When we look at the group of patients that had active brain metastasis, we see a remarkable benefit with the addition of tucatinib,” Graff remarked, adding that these findings created questions in the oncology community about whether or not the presence or absence of brain metastases should be a selective predictor of which agent is chosen.

Trastuzumab Deruxtecan Shows Potential Benefit

In the phase 3 DESTINY-Breast03 trial (NCT03529110), trastuzumab deruxtecan significantly improved the PFS of patients with metastatic, HER2+ disease, including those with brain metastases and those without brain metastases, compared with trastuzumab emtansine.⁵

Specifically, among those with brain metastases, the median PFS was 15.0 months vs 3.0 months between trastuzumab deruxtecan and trastuzumab emtansine (HR, 0.25, 95% CI, 0.13-0.45).

According to the panelists, the DESTINY-Breast03 trial shows that there may be some benefit with this agent for those with brain metastases, and some other, smaller studies have also suggested that trastuzumab deruxtecan can generate intracranial responses, but these findings are not prospective randomized data, and therefore, the quality of evidence is much stronger for tucatinib.

When to Change Systemic Therapy

During the presentation, many of the audience members shared via a virtual poll that in this scenario, they would change their patient’s regimen to tucatinib, trastuzumab, and capecitabine.

However, if there had been no sign of systemic progression, McGinn shared that she would consider keeping this patient on trastuzumab deruxtecan and adding the SRS.

“If you have just imaged the brain for the recent headaches, you would also want to update the imaging CT for the chest, abdomen, and pelvis,” she said. “Then, if there is no systemic progression of disease, you could consider continuing with the same treatment.”

Graff agreed, adding that when an individual shows systemic disease progression, it is an easier decision to change treatments, but if the only metastatic site is in the brain, then both switching or keeping treatment are reasonable options.

References

1. Graff SL, McGinn C, Showalter. Improving outcomes for patients with metastatic HER2-positive breast cancer. Presented at: 2023 JADPROLive. November 9-12, 2023; Orlando, FL.
2. Vlachos N, Lampros MG, Filis P, Voulgaris S, Alexiou GA. Stereotactic radiosurgery versus whole-brain radiotherapy after resection of solitary brain metastasis: A systematic review and meta-analysis. World Neurosurg X. 2023;18:100170. Published 2023 Feb 1. doi:10.1016/j.wnsx.2023.100170
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
4. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; virtual. Abstract 858.
5. Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with her2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA1.