Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
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In the CLEOPATRA trial, pertuzumab, trastuzumab, and taxane improve PFS and
ORR compared with a placebo. Based on this result, currently the NCCN guidelines
recommend pertuzumab as the first-line treatment of HER2 + metastatic breast cancer
in combination with trastuzumab and docetaxel, and also as neoadjuvant therapy
prior to surgery for breast cancer. 79
PATIENT CASE 6
ML is a 57-year-old Hispanic female who was diagnosed with grade 3 ER/PR negative
Her2/neu-positive breast cancer in March 2011. Her CT scan showed 10 lymph
node involvements. Her social history includes heavy use of alcohol but she denies
smoking.
ML’s treatment history includes TCH × 6 cycles, bilateral mastectomy, and radiation.
Trastuzumab was completed in August 2012 to complete one year of treatment.
Her latest CT scan showed new lung nodules with bilateral lung nodules. ML was
then treated with trastuzumab and capecitabine starting in October 2012.
Question: ML’s CT scan in April 2013 indicated progression of bilateral pulmonary
nodules/masses, suggesting progression of pulmonary metastases. ML was then
treated with trastuzumab, pertuzumab, and docetaxel × 4 cycles. In August 2013, CT
scan indicated further progression of bilateral pulmonary nodules with bone involvement.
What therapy should be used now for ML?
Answer: With the new development of antibody drug conjugate, ML is eligible to
receive ado-trastuzumab emtansine. ML’s condition is indicated for the use of adotrastuzumab
emtansine for these reasons:
• ML has previously received a taxane and trastuzumab.
• ML’s breast cancer is Her2/neu positive.
Ado-trastuzumab emtansine is a new, unique chemotherapy drug, because it is an
antibody drug conjugate that targets the HER2 receptor. After binding to the HER2
receptor subdomain IV, ado-trastuzumab emtansine causes receptor-mediated internalization
and subsequent lysosomal degradation, resulting in intracellular release of
DM1, which disrupts microtubule networks in the tumor cell. Upon binding to the
tubulin, DM-1 will disrupt the microtubule formation, ultimately resulting in cellcycle
arrest and apoptosis of the tumor cells. In addition to inhibiting HER2 receptor
signaling and ADCC, ado-trastuzumab emtansine also inhibits the shedding of
the HER2 extracellular domain in human breast cancer cells that overexpress HER2.
Ado-trastuzumab emtansine is indicated for the treatment of HER2+ metastatic breast
cancer patients who previously received trastuzumab and taxane in combination or
separately. Ado-trastuzumab emtansine marks an advancement in breast cancer therapy
as it improves PFS compared to capecitabine and lapatinib (9.6 vs. 6.4 months),
and it improves OS compared to capecitabine and lapatinib (30.9 vs. 25.1 months). 80
Both pertuzumab and ado-trastuzumab emtansine have shown marked improvements
in previously targeted HER2/neu therapies. These two drugs have added more
options for patients with metastatic breast cancer in previously untreated patients and
for patients who have progressed after adjuvant trastuzumab therapies.