Complete Response With Alpelisib and Trastuzumab in a Patient With Estrogen Receptor–/Progesterone Receptor–Negative, Human Epidermal Growth Factor Receptor 2–Positive Refractory Metastatic Breast Cancer

Introduction

Apart from skin cancers, breast cancer is the most commonly diagnosed cancer in females within the United States and accounts for 30% of all newly diagnosed female cancers each year.¹ Heightened awareness regarding the importance of screening and improved imaging modalities have led to a decrease in diagnosis at advanced stages of disease and overall mortality.² Despite this, metastatic disease is not infrequently diagnosed on initial detection and presents a significant challenge in terms of treatment.³ Treatment requires the hormonal and molecular profile of the underlying malignancy, with targeted therapy often being preferred over systemic chemotherapy. Advancements in molecular detection techniques (ie, next-generation sequencing [NGS]) have helped identify more treatment options especially for patients with disease that is refractory to initial therapy.

The PIK3CA gene is one example of this concept; it encodes a portion of phosphatidylinositol 3-kinase (PI3K) that plays an important role in downstream cell signaling that promotes cell cycle regulation and ultimate division.⁴ Mutations in this gene can lead to overactivation of PI3K and subsequent unregulated cell division. In breast cancer specifically, mutations in PI3KCA have been associated with a worse prognosis both in human epidermal growth factor receptor 2 (HER2)–negative and HER2-positive diseases and is associated with poor response to HER2-targeted therapy.^5,6 This mutation is not infrequently identified in HER2-positive disease as well, with some studies approximating a roughly 20% identification rate.⁷ Owing to this, much research effort has been devoted to identifying targeted agents that block PI3K signaling. One specific agent that achieves this is known as alpelisib, an oral alpha-specific PI3K inhibitor that has shown encouraging results when combined with fulvestrant in advanced hormone receptor (HR)–positive HER2-negative breast cancer.⁸ Alpelisib is not currently US Food and Drug Administration–approved in HER2-positive disease, and no study has examined its effectiveness in this clinical scenario.

Herein, we present a case of HR-negative, HER2-positive metastatic breast cancer (mBC) refractory to numerous lines of therapy. Ultimately, biopsy of a metastatic lesion demonstrated a PI3KCA mutation. Alpelisib and trastuzumab were combined in an off-label fashion with excellent clinical and imaging response.

Case Presentation

Our patient is a 63-year-old female who was initially diagnosed with stage I (T1aN0M0), estrogen receptor–(ER)/progesterone receptor (PR)–negative, HER2-positive, p53-negative breast cancer in 2014 outside of the United States. She was initially managed with left mastectomy and remained in remission until 2017 when a surveillance positron emission tomography/computed tomography (PET/CT) performed at an outside facility demonstrated a hypermetabolic lesion in the right axilla. Biopsy of the suspicious node demonstrated poorly differentiated carcinoma consistent with breast primary. Immunohistochemistry (IHC) revealed ER-/PR-negative, HER2-positive staining. She started neoadjuvant chemotherapy with trastuzumab and underwent axillary nodal dissection followed by local radiation. Surgical pathology demonstrated metastatic carcinoma consistent with breast primary in seven of eight lymph nodes sampled. She was started on capecitabine at this time with good control of disease. CT scan performed in 2019 subsequently demonstrated progression of disease in the right axilla and breast, at which point lapatinib was added to capecitabine. She demonstrated partial response on subsequent CT but had unacceptable toxicity with severe fatigue and erythrodysesthesia. She paused therapy for roughly 2 months and then started paclitaxel and trastuzumab. She eventually progressed on this regimen as well and was transitioned to vinorelbine and trastuzumab which were continued until she transferred care to our facility.

She established care with our facility in 2020. Imaging at the time revealed progression in the right chest wall, and echocardiogram demonstrated reduced ejection fraction. Further trastuzumab therapy was deferred, and she was restarted on paclitaxel. Repeat echocardiogram 3 months later demonstrated normalization of ejection fraction, and thus, she was transitioned to trastuzumab deruxtecan. She completed six cycles with near complete response, but eventually progressed in the right chest wall and skin after cycle 14. Therapy was transitioned to trastuzumab emtansine for six doses with subsequent progression. She was then started on margetuximab-CMBK and eribulin with excellent response but developed severe mucositis requiring dose adjustment. After seven cycles, PET/CT demonstrated local progression, and therapy was switched to trastuzumab and capecitabine. Repeat PET/CT again showed progression in the right chest wall. She received a biopsy of a right chest wall lesion, which showed invasive ductal carcinoma, staining significant for ER-/PR-negative, HER2-positive, and Ki-67 >90%. NGS obtained from a biopsy of a metastatic chest wall lesion demonstrated a PIK3CA mutation in addition to her known HER2 mutation; no other targets were identified. Given the progression of her malignancy despite HER2 blockade previously, alpelisib was added to trastuzumab in an off-label fashion. After initiation of this regimen, her skin lesions/nodules demonstrated complete response on physical examination and PET/CT showed no progression and decreased fluorodeoxyglucose uptake in multiple subcutaneous nodules (Fig 1 and 2). She continued to tolerate therapy with alpelisib and trastuzumab for roughly 7 months with the adverse effect of grade 2 mucositis. After 7 months, the patient progressed with new chest and abdominal wall lesions, at which point alpelisib was discontinued and her treatment regimen was changed.

FIG 1.

PET-CT findings before and after alpelisib therapy. The figure compares metastatic chest wall lesions before and after initiation of alpelisib. The image on the left was obtained approximately 1 month before starting therapy, whereas the image on the right reflects the status after roughly 4 months of treatment. The predominant right retroareolar lesion (highlighted by the red oval) initially measured 1.8 × 1.1 cm with a maximum SUV of 13.1. After alpelisib therapy, the lesion decreased in size to 1.7 × 0.7 cm, and the SUV max declined to 5.4. An additional subcutaneous lesion (yellow circle) demonstrated a decrease in SUV max from 7.8 to 6.2. CT, computed tomography; PET, positron emission tomography.

FIG 2.

Physical examination findings before and after alpelisib therapy. The image on the left was taken approximately 1 month before the patient began alpelisib therapy and shows multiple subcutaneous metastatic nodules (red circle). The image on the right was taken about 3 months after treatment initiation and demonstrates complete clinical resolution of these nodules.

Patient Consent Statement

Written informed consent was obtained from the patient for participation and publication of this report. A copy of the consent form is available for review by the journal's editorial office upon request.

Discussion

Our case demonstrates that treatment of mBC is difficult, often requiring multiple lines of therapy and frequent adjustments based on disease progression and toxicities. The hormonal profile and IHC of the malignancy are paramount in determining initial lines of therapy. In ER-/PR-negative HER2-positive disease, classic first-line therapy includes trastuzumab or trastuzumab and pertuzumab. Second-line treatment has recently been called into question and now favors trastuzumab deruxtecan over T-DM1 based on the results of the DESTINY-Breast03 trial. Third-line treatment and beyond is highly variable; continuation of HER2 blockade (eg, trastuzumab, pertuzumab, margetuximab, T-DM1) is indicated no matter what ancillary agents are selected. Other reasonable additions in this line of therapy include tucatinib, capecitabine, and lapatinib.⁹

Despite the above treatment options, progression of disease unfortunately remains common. Historically, treatment after progression on third-line therapy and beyond has been extremely limited and most often includes systemic chemotherapy. NGS has helped to provide further treatment options to clinicians and patients by surveying the molecular fingerprint of the malignancy at the time of progression. Genetic abnormalities with targeted treatment options are frequently identified. In one retrospective analysis by Bruzas et al, 83 of 95 patients with previously treated mBC were found to have actionable mutations on NGS. Those treated with targeted therapy after multidisciplinary tumor board discussion (n = 30) demonstrated improved 1-year overall survival (62.9% v 22.7%) when matched with those treated with standard therapy (n = 65).¹⁰ Similar results were demonstrated in the SAFIR02-BREAST trial, in which 1,462 patients with HER2-negative mBC previously treated with one line of chemotherapy at maximum underwent NGS. A total of 646 patients were found to have an actionable mutation, and 238 were randomly assigned between maintenance chemotherapy (n = 81) versus targeted therapy (n = 157). In patients with ESCAT I/II (n = 115) mutations, targeted therapy was associated with significantly improved PFS versus maintenance chemotherapy (9.1 months v 2.8 months, respectively).¹¹

As mentioned before, PIK3CA is a mutation that is not infrequently identified in mBC. In the SAFIR02-BREAST trial, for example, 31 of 115 (27%) ESCAT I/II mutations were found to be PIK3CA-related.¹¹ One review of five prospective trials demonstrated that PIK3CA mutations were associated with lower rates of pathologic complete response (pCR) in HER2-positive disease.⁶ This further exemplifies the importance of targeted therapies, such as alpelisib, which has previously demonstrated efficacy in HER2-negative disease harboring PIK3CA mutations (SOLAR-1⁸). There are active clinical trials underway to explore alpelisib's role in HER2-positive, PIK3CA-mutated disease (ALPHABET). Our case is one piece of evidence which suggests that alpelisib might play a role in this setting. However, prospective and case-matched data are needed to further explore this.

The above studies and the presented case demonstrate two major principles in the management of mBC. First, NGS should be obtained in every patient who demonstrates POD on initial lines of therapy. This may reveal actionable mutations that can possibly change future lines of therapy by allowing for targeted treatment which often has a favorable toxicity profile. Second, we hope that this case serves as an initial step in exploring alpelisib's possible role in HER2-positive mBC. Future clinical trials will help further elucidate the possible therapeutic benefit of alpelisib in HER2-positive mBC.

In conclusion, while the treatment options for mBC have increased significantly over the years, progression of disease remains common and presents a challenge for both patients and clinicians. Integrating precision medicine with NGS can help elucidate mechanisms of resistance and actionable mutations, such as PIK3CA, which can reveal treatment options with combination and targeted therapies that are clinically effective and well-tolerated.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Provision of study materials or patients: Ritesh Parajuli

Collection and assembly of data: Farah Shah, Ritesh Parajuli

Data analysis and interpretation: Farah Shah, Ritesh Parajuli

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

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