Tuesday, July 23, 2024

Brief Blog: The Experience and Dilemmas of Triple-Negative Breast Cancer

Thanks to Joe Lennerz MD for highlighting, at Linked In, an absorbing new article on the experience and dilemmas of managing triple-negative breast cancer.  The article is Kok et al. (2024) PMID 39038259.

In the study, pembrolizumab was given both as neoadjuvant and as adjuvant add-on therapy, and in the end, we don't know if either phase or both phases made the important contribution.  In addition, while the index patient discussed here at favorable biomarker(s), their scale of impact is uncertain.

Lennerz here:

https://www.linkedin.com/posts/joe-lennerz-90029219_fda-biomarker-regulatory-activity-7221478324882083840-RMei/?utm_source=share&utm_medium=member_desktop

The article is here ("partial open access"):

https://ascopubs.org/doi/full/10.1200/JCO.24.00372


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The July 23/30 JAMA has a pair of letters on tumor infiltrating lymphocytes in TNBC. (332:337). Comment on Leon-Farre 331:1135.
The July 23/30 JAMA has a personal essay by a physician with breast cancer ("Even Better," 332:283)

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AI Corner

Here's an AI summary of Kok et al.

Summary for Cancer Experts: 

Personalizing Treatment for Stage II/III Triple-Negative Breast Cancer

Article: "Academic Uphill Battle to Personalize Treatment for Patients With Stage II/III Triple-Negative Breast Cancer" by Marleen Kok et al. (JCO, 2024)

Key Findings:

  1. KEYNOTE-522 Phase III Trial:

    • Investigated the combination of pembrolizumab with neoadjuvant chemotherapy (carboplatin/paclitaxel followed by doxorubicin/cyclophosphamide) for patients with stage II/III triple-negative breast cancer (TNBC).
    • Showed an approximate 7% improvement in pathological complete response (pCR) rates and a 9% improvement in event-free survival (EFS) compared to chemotherapy alone.
    • Despite benefits, only a subset of patients benefit from this combined therapy, and the value of the adjuvant pembrolizumab phase remains unclear.

  2. Case Study and Patient Perspective:

    • Highlights the experience of a 48-year-old physician with stage II, node-negative TNBC who questioned the necessity of continued intensive treatment after a favorable early response.
      • [The physician provides an essay about her experience; see Page 10.]
    • Emphasizes the importance of personalized treatment plans based on biomarkers like tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, which were significant in her case but underappreciated by her clinicians.

  3. Challenges in Personalized Treatment:

    • The trial design did not incorporate a second randomization post-surgery to evaluate the necessity of continued pembrolizumab, leading to uncertainties about the contributions of neoadjuvant versus adjuvant therapy.
    • Current treatment guidelines recommend continuation of pembrolizumab in the adjuvant setting based on trial protocols, not individualized patient response.

  4. Lack of Reliable Biomarkers:

    • There is a significant need for biomarkers to predict which patients will benefit from immunotherapy and to tailor treatments accordingly.
    • Potential biomarkers like TILs and MHCII have not been prospectively validated, making it difficult to personalize treatments effectively.

  5. Future Directions and Ongoing Trials:

    • Several ongoing trials aim to refine immunotherapy strategies for TNBC by exploring shorter treatment durations, alternative chemotherapy backbones, and predictive biomarkers.
    • Regulatory and academic collaboration is crucial to ensure trials are designed to minimize overtreatment and toxicity while maximizing patient-specific benefits.

Conclusion: Personalizing treatment for TNBC is a complex challenge that requires a delicate balance between adhering to trial protocols and adapting to individual patient needs. Advancements in biomarker research and trial design are essential to optimize treatment efficacy and reduce unnecessary toxicity. The article underscores the importance of ongoing efforts to integrate personalized approaches into clinical practice for better patient outcomes.

For a deeper dive, refer to the original article: DOI 10.1200/JCO.24.00372

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PATIENT'S ESSAY

Summary of the Appendix: Patient Experience

Appendix - Patient Perspective:

Patient Background:

  • The appendix features the personal account of a physician who survived stage II triple-negative breast cancer (TNBC) and underwent the KEYNOTE-522 regimen.
  • Initially diagnosed with marked tumor-infiltrating lymphocytes (TILs), the patient had to seek out experts to understand the significance of these findings, as local clinicians were unprepared to discuss them.

Treatment Journey:

  • The patient began the prescribed KEYNOTE-522 therapy, consisting of neoadjuvant chemotherapy and pembrolizumab, amidst significant scare tactics emphasizing the importance of following the study protocol.
  • Despite discovering high PD-L1 expression and 85% TILs in the tumor, which indicated a potentially excellent prognosis, the patient’s oncologists insisted on adhering strictly to the treatment regimen.

Adverse Effects:

  • The patient experienced severe side effects, including loss of thyroid function, fatigue, dehydration, nausea, diarrhea, thrush, sleep disruption, hair loss, bone and joint pain, and significant cognitive and mobility issues.
  • These effects resulted in loss of salary, independence, confidence, and overall quality of life.

Advocacy for Personalized Treatment:

  • The patient requested reimaging and reassessment to potentially reduce treatment intensity after significant early response, but these requests were denied in favor of completing the full regimen.
  • Continued through 12 weeks of paclitaxel, carboplatin, and pembrolizumab, followed by 12 weeks of doxorubicin and cyclophosphamide, despite believing this constituted overtreatment.

Outcome and Reflection:

  • Achieved a complete pathological response with no residual tumor detected in the final MRI and surgery.
  • Opted against adjuvant pembrolizumab based on personal research, contrary to oncologists' advice.
  • Concerns about the potential long-term effects of the extensive treatment and the overall approach to TNBC treatment protocols that do not sufficiently account for individual patient biomarkers.

Call for Change:

  • The patient emphasizes the need for more personalized treatment plans, better understanding, and utilization of biomarkers.
  • Critiques the influence of pharmaceutical companies on research and treatment protocols, advocating for a more patient-centered approach in clinical trials and medical practice.

Conclusion:

  • Highlights the disparity between standardized treatment protocols and the need for personalized, biomarker-driven approaches to improve patient outcomes and reduce unnecessary treatment burdens.