Neoadjuvant Chemotherapy: Not the Best Option in Estrogen Receptor–Positive, HER2-Negative, Invasive Classical Lobular Carcinoma of the Breast?

Abstract

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010