Ma, Cynthia X. MD, PHD
CYNTHIA X. MA, MD, PHD
ASCO 2014 marked another successful year of progress in breast cancer clinical research. We are now armed with better treatment options to consider for our patients and more in-depth understanding of breast cancer biology. I have outlined below a few major findings reported at the meeting related to breast cancer.
Ovarian-Function Suppression Plus Exemestane: A New Treatment for Premenopausal Women with Hormone-Receptor Positive Breast Cancer
TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) are both randomized Phase III studies conducted by the IBCSG (International Breast Cancer Study Group) that examined adjuvant hormonal therapy options for premenopausal women with estrogen receptor positive breast cancer. Both trials compared five years of ovarian function suppression (OFS) in combination with either exemestane or tamoxifen.
The SOFT trial also contains a tamoxifen-monotherapy arm. OFS was achieved by five years of triptorelin, oophorectomy, or ovarian irradiation. In the combined analysis of TEXT (n=2,672) and SOFT (n=3,066), at a median follow-up of 5.7 years, disease-free survival was superior in women treated with OFS plus exemestane compared with those with OFS plus tamoxifen (91.1% vs. 87.3%; hazard ratio [HR], 0.72 (95% CI, [0.60-0.86]); p = 0.0002) regardless of chemotherapy or nodal status.
OS did not differ significantly; however, this could be due to short follow-up. These data provided level 1 evidence for the recommendation of OFS plus exemestane in this patient population. However, long-term side effects—for example, bone loss—from OFS and exemestane in this young patient population needs to be addressed. In addition, estradiol level may need to be monitored if a GnRH agonist is used for OFS.
Goserelin Reduced Incidence of Ovarian Failure and Improved Fertility Preservation in Premenopausal Women with ER-Neg Breast Cancer Receiving Chemotherapy
The IBCSG 34-05/SWOG 0230 Prevention of Early Menopause Study (POEMS) randomized premenopausal women with early-stage hormone receptor negative breast cancer to standard chemotherapy with (n=126) or without goserelin (n=131). Goserelin 3.6 mg was administered subcutaneously at least one week prior to the first dose of chemotherapy and then every four weeks during chemotherapy, and within two weeks of the final chemotherapy.
At two years, the rate of ovarian failure, defined as amenorrhea for the prior six months and FSH level in the postmenopausal range, was significantly lower in patients who received goserelin (8% vs. 22%, two-sided p = 0.04). Importantly goserelin was associated with a higher rate of successful pregnancy (22 out of 25 vs. 12 out of 18; adjusted odds ratio 2.45; adjusted p = 0.03) in women who attempted pregnancy and those who had more baby births (18 babies vs. 12).
Intriguingly goserelin use was associated with a significantly better disease-free survival (89% vs. 78%, p = 0.04) and overall survival (92% vs. 82%, p = 0.05).
This data justifies the use of goserelin to combine with chemotherapy in patients with hormone receptor negative breast cancer as a strategy to preserve ovarian function and fertility.
Correlation of HER2-E Subtype and Immune Cell Signatures with Pathologic Complete Response (pCR)
CALGB 40601 was a neoadjuvant trial of 16 doses of weekly paclitaxel in combination with either trastuzumab and/or lapatinib in newly diagnosed HER2-positive breast cancer. RNA Seq analyses of baseline and post-treatment tumors were presented at ASCO. The study demonstrated that clinical HER2-positive breast cancer is highly heterogeneous, composed of all breast cancer molecular subtypes, including HER2-E (31%), Luminal A (30%), and Luminal B (30%), basal (6%), claudin-low (1%), and normal-like (2%).
The pCR rate was 70 percent in the HER2-E tumors, compared with 34 percent in Luminal A, 36 percent in Luminal B, and 36 percent in basal-like. The benefit of dual targeting with trastuzumab and lapatinib was seen mostly in the HER2-E subpopulation.
In addition, immune cell signatures including IgG signature, and signatures of cell proliferation and p53 mutation were significantly associated with pCR. Also interestingly, there was a shift to luminal A subtype following treatment. The study calls for the need for molecular stratification of patient population in future trials of HER2-positive breast cancer.
14-Gene Predictor of Adjuvant Trastuzumab Benefit for HER2-Positive Early Breast Cancer
N9831 was a randomized Phase III study of adjuvant doxorubicin plus cyclophosphamide (AC) followed by paclitaxel (T) with or without concurrent or sequential trastuzumab therapy for patients with HER2+ breast cancer. Gene expression studies of tumor specimens collected from patients enrolled in this trial were reported, which identified 14 immune function genes that were highly predictive of trastuzumab benefit. The result was striking, and we eagerly await further validation of this result in independent cohorts of patients.
FDG PET as an Early Predictor of pCR to Neoadjuvant Treatment in HER2-Positive Breast Cancer
The AVATAXHER trial is an open-label, randomized, multicenter study investigating the addition of bevacizumab (B) to neoadjuvant trastuzumab (T) plus docetaxel (D) in patients with early-stage HER2-positive breast cancer (HER2+ BC) based on PET change after one therapy cycle. The study demonstrated that FDG PET (SUV 70%) after one cycle predicted pCR with a positive predictive value of 52.9 percent and a negative predictive value of 75 percent. Adding bevacizumab improved the pCR rate in those with less than 70 percent SUV from 24 to 42.5 percent. The study suggested that FDG PET could be a useful tool in tailoring therapy for HER2-positive breast cancer.
Assessment of TILs in TNBC
Tumor-infiltrating lymphocytes (TIL) were found to be associated with pathologic response to neoadjuvant platinum-based chemotherapy in the PrECOG0105 study. TILs were significantly associated with the immunomodulatory (IM) subtype of triple-negative breast cancer (TNBC). Using a gene-expression based computational approach, CIBERSORT (In Silico Flow Cytometry) of 23 leukocyte subsets, activated memory CD4+ T cells at baseline were significantly associated with pCR.
Similarly, in the Geparsixto trial, tumor lymphocytes infiltration was associated with pCR in both TNBC and HER2+ breast cancer. In addition, immune regulatory checkpoint markers by mRNA expression were associated with pCR.
These studies indicate the importance of tumor microenvironment in cancer biology and response to treatment. We look forward to future treatment strategies that target the tumor microenvironment and immune phenotype of the host.
Homologous Recombination Deficiency Score and Platinum Sensitivity in Triple Negative Breast Cancer
TBCRC009 evaluated biomarkers that predict response to single-agent platinum (carboplatin or cisplatin) as first- and second-line therapy for metastatic triple-negative breast cancer (TNBC). As expected, BRCA mutation carriers have a high response rate in this trial, although PFS or OS were similar to those in non-carriers.
In this study, high homologous recombination deficiency (HRD) score by HRD-loss of heterozygosity (LOH) (LOH regions of intermediate size (>15 Mb, < whole chromosome) and HRD-LST (large scale state transition) (the number of chromosome breaks between adjacent segments of at least 10 Mb in tumor genome) correlated with response (complete and partial response). We look forward to the further validation and development of HDR score for patient selection of platinum agents.
Identification of Potential Therapeutic Targets in Residual TNBC following Neoadjuvant Chemotherapy
RNA sequencing of residual TNBC after neoadjuvant chemotherapy (BRE09-146) demonstrated activated MAPK1 (Erk2), MAPK4K4, AMPK, DICER1, and DROSHA (mciroRNA machinery). Mir 663b may be associated with chemo-resistance. Treatment strategies directed to these pathways need to be evaluated.
Controversy of pCR as a Surrogate Endpoint for DFS
The negative results of two adjuvant trials, the ALTTO trial, which assessed lapatinib in combination with trastuzumab in HER2+ breast cancer and the E5103 study, which assessed bevacizumab in HER2- breast cancer, raised the concern that improvement in pCR rate may not translate into superior DFS in the adjuvant setting, and response in primary tumor may not reflect that of micrometastasis. Obviously, there are more questions than answers at this time.