Difficult to consider side effects of Perjeta akain isolation because
- It’s been tested in combination therapies, usually with Herceptin aka and also often . (low neutrophil count), febrile neutropenia, alopecia, nausea, fatigue, and infusion reactions are already common side effects of docetaxel.
- Most clinical trial patients have usually been on other Rx previously, some of which may leave long-term adverse effects on various organ systems.
That said, side effects particular to drugs like Perjeta are dictated by expression pattern of their targets. Like Herceptin, Perjeta targets, an extracellular human EGFR ( ). Both used to treat HER2 positive breast cancer, Perjeta and Herceptin have complementary modes of action. Binding HER2’s extracellular domain, Perjeta prevents it from heterodimerzing with EGFR ( ). This blocks transmission of proliferative signals into HER2-positive tumor cells.
Though targeting something expressed by some breast cancers, nevertheless Rx such as Perjeta and Herceptin are still non-specific since HER2 is also expressed by other tissue types.
- Colonic epithelial cells hence diarrhea is possible.
- Studies (1) have shown HER2 blockade can cause non-life threatening diarrhea, presumably as a result of excess chloride secretion by EGFR blockade on colonic epithelial cells.
- 40 to 80% of patients who got Perjeta in clinical trials experienced diarrhea ( , , , , ).
- Specifically, grades 1 to 3 diarrhea ( , page 20, grades 1 thru’ 3 are milder, grade 4 is life-threatening, grade 5 is death) were a common symptom in 3 breast cancer trials testing Perjeta with other drugs, CLEOPATRA (n=804, ) for metastatic, and NeoSphere (n=416, ) and TRYPHAENA (n=223, ) for early-stage.
- Highest during the first Perjeta-containing cycle, diarrhea incidence decreased with subsequent cycles.
- The data suggest diarrhea is more common when Perjeta‘s given since rate was 68% for Docetaxel plus Hercpetin and Perjeta compared to 49% for Docetaxel plus Hercpetin in CLEOPATRA ( ).
- Cardiac myocytes hence heart toxicity is possible (
- However, the way these drugs affect heart function is highly reversible ( ).
- As well, low numbers of patients tend to be affected. For example, 6 of 92 (6.5%) in one trial ( ).
- Keratinocytes so rashes, and skin and nail infections, typically Staphylococcus aureus (11).
- Detailed meta-analysis suggests Perjeta significantly increased risk of rash (12).
However, these trials and meta-analyses also conclude these side effects are well manageable.
1. Gao, Jennifer, and Sandra M. Swain. “Pertuzumab for the treatment of breast cancer: a safety review.” Expert opinion on drug safety 15.6 (2016): 853-863.
2. Baselga, José, et al. “Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.” New England Journal of Medicine 366.2 (2012): 109-119.
3. Gianni, Luca, et al. “Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.” The lancet oncology 13.1 (2012): 25-32.
4. Schneeweiss, A., et al. “Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).” Annals of oncology 24.9 (2013): 2278-2284.
5. Cortés, Javier, et al.
6. Baselga, José, et al.
8. Valachis, Antonis, et al. “Cardiac toxicity in breast cancer patients treated with dual HER2 blockade.” International journal of cancer 133.9 (2013): 2245-2252.
9. Lenihan, D., et al. “Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab.” Annals of oncology 23.3 (2012): 791-800.
10. Portera, Chia C., et al. “Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2–positive metastatic breast cancer.” Clinical Cancer Research 14.9 (2008): 2710-2716.
11. Mortimer, Joanne E., et al. “Skin, nail, and staphylococcal infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy.” (2015): e11610-e11610.
12. Drucker, Aaron M., et al. “Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis.” Breast cancer research and treatment 135.2 (2012): 347-354.