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Test Your Skills: 1L HR Pos HER2 Pos mBC
Management of a Patient With Newly Diagnosed HR+/HER2+ mBC on Medication for Comorbidities

Released: April 21, 2024

Expiration: October 20, 2024

Stephanie L. Graff
Stephanie L. Graff, MD, FACP, FASCO
Laura Spring
Laura Spring, MD
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The patient was given first-line THP with improvement in bone lesions and reduction in liver metastasis size (partial response) observed after 6 months of treatment. The patient was started on maintenance trastuzumab and taxane plus ET and continued to follow-up until signs of disease progression. You discussed with the patient the possibility of future disease progression, including risk of CNS disease metastases.

Case Discussion
The patient was given first-line THP for 6 cycles followed by pertuzumab, trastuzumab, and ET maintenance with improvement in bone lesions and reduction in liver metastasis size. Unfortunately, at a 12-month follow-up visit, the patient reported new vision disturbances, dizziness, and disorientation. Brain MRI confirmed central nervous system (CNS) progression with one 1-cm parietal and one 2-cm temporal lobe lesions. CT discovered interval increase in the known liver metastases, which previously had been shown to be responding: Originally 4.0 cm, a CT scan after 12 weeks showed partial response with a reduction to 2.2 cm, and now area measures 3.7 cm with increased enhancement as compared with a previous assessment. Per institutional policy, she undergoes genomic sequencing to evaluate for potential clinical trial options (no actionable mutations identified) and dihydropyrimidine dehydrogenase (DPD) testing in consideration of next lines of therapy. She is identified as having DPYD*2A homozygosity, a mutation expected to render the DPD enzyme inactive and is indicative of a patient for whom treatment with a fluoropyrimidine is discouraged because of the potential for severe adverse effects.

Additional factors to consider when choosing a next best treatment strategy for this patient include current prognosis, performance status, patient preferences, presence of symptoms, location of progressive disease (CNS, body, both), number and size of metastatic lesions, the potential for resection, and previous therapy received.9

Upon disease progression, including in CNS metastases, after approximately 12 months of THP, you discuss her options. Per institutional policy, she undergoes genomic sequencing to evaluate her eligibility for available clinical trials and undergoes genomic profile that may inform toxicity with available chemotherapeutic agents used for patients with rapidly progressing mBC. You call her to go over the genetic testing results. Thus far, the patient is feeling well-informed about the next steps in her care and has an appointment scheduled to talk to you about her treatment options in the coming week.

Research and Summary

About HER2 Testing and Use to Inform Therapy Selection in mBC
The American Society of Clinical Oncology and the College of American Pathologists have published guidelines that define HER2 positivity, including addressing HER2-low status and no changes to reporting practices or scoring system updates (positive, equivocal, negative); semiquantive score must be reported.10,11 There is also renewed consideration for distinguishing between HER2 IHC of 1+ from 0, using high-power lenses and more robust controls (including HER2 IHC of 1+), considering second pathologist opinion when closer to threshold, and paying close attention to preanalytical sample conditions.

Treatment Options Considerations
Current first-line treatment options for patients with HER2-positive mBC include a combination of guideline recommendations and collaborative patient–healthcare professional shared decision-making.5 It is also important to note that approximately 70% of patients diagnosed with HER2-positive mBC also have HR-positive disease.1 This group of patients with dual HR-positive/HER2-positive mBC benefit from standard recommended first-line HER2-targeted therapy plus chemotherapy along with the addition of ET to ongoing HER2-targeted maintenance therapy following the completion of chemotherapy.1,2,4,5

In this interactive case challenge, the importance of shared decision-making was highlighted regarding comorbidities and comedications where there are limited data for concomitant use with anticancer therapy. It was also important to assess patient considerations, such as goal of treatment, underlying medical and social issues, convenience of therapy, and associated treatment toxicities that may affect the patient’s normal functioning. Moreover, determining which cancer-driver mutations or biomarkers were the key factors in informing first-line and subsequent therapy selection was also critical.

Emerging Data on Maintenance Therapy
Recent emerging data in the field of HR-positive/HER2-positive mBC include the report of efficacy and safety from the phase III PATINA trial. The randomized, open-label phase III PATINA trial is evaluating the efficacy and safety of adding CDK4/6 inhibitor palbociclib to anti-HER2 therapy plus ET compared with anti-HER2 therapy plus ET alone after induction treatment (6-8 cycles of THP) in patients with HR-positive/HER2-positive mBC (N = 518).4 The primary endpoint of the study was PFS by investigator assessment and the secondary endpoint was OS. The PATINA study met its primary endpoint of improving PFS. At a median follow-up of 52.6 months, the mPFS by investigator assessment was 44.3 months with the combination of palbociclib with anti-HER2 therapy plus ET vs 29.1 months anti-HER2 therapy plus ET alone (hazard ratio: 0.74; 1-sided P = .0074). There was an absolute improvement in PFS rate at 5 years of approximately 10% (42.3% with addition of palbociclib vs 33.4% without). All patient subgroups analyzed showed a benefit in PFS, as well as the confirmed overall response rate and clinical benefit rate, with the addition of palbociclib. The OS data had not reached maturity, but they favored of the combination of palbociclib with anti-HER2 therapy plus ET vs anti-HER2 therapy plus ET alone (median OS was not reached vs 77.0 months, respectively; hazard ratio: 0.86; 95% CI: 0.60-1.24). Finally, the 5-year OS rate was 74.3% vs 69.8%, respectively.

Considerations for Progressive Disease
For patients with oligometastatic disease progression that is limited to a few sites while they are receiving systemic therapy, experts recommend consideration of local therapy (eg, surgery or radiation therapy) to control disease progression in preference to switching systemic therapy.

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