Theresa A. Graves

Frequent Pathologic Complete Responses in Aggressive Stages II to III Breast Cancers With Every-4-Week Carboplatin and Weekly Paclitaxel With or Without Trastuzumab: A Brown University Oncology Group Study

PURPOSE To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel +/- weekly trastuzumab in resectable and locally advanced breast cancer. PATIENTS AND METHODS Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2) weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) -positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes. Postoperative therapies were at the discretion of the treating physicians. RESULTS Fifty-five patients were enrolled, and of these 43 had resectable disease. The median age was 54 years (range, 31 to 74 years). Treatment was well tolerated; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia, and there were only two instances of grade 3 peripheral neuropathy. Overall, the pCR rate was 45%. The pCR rate was 43% (95% CI, 28% to 58%) in patients with resectable disease. Higher pCR rates occurred in patients with HER2-positive tumors (76% v 31% for HER2-negative tumors; P = .003), with estrogen receptor (ER) -negative tumors (75% v 27% for ER-positive tumors; P = .001), or with triple-negative tumors (67% v 12% ER-positive and HER2-negative tumors; P = .002). At a median of 28 months postoperation, recurrence-free survival (RFS) was 88.7%. If patients with ER-positive and HER2-negative tumors are excluded from analysis, patients who achieved a pCR were less likely to experience disease recurrence (RFS, 86%) than those who did not achieve a pCR (RFS, 75%). CONCLUSION Neoadjuvant carboplatin and weekly paclitaxel +/- trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline. Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received. Additional study of this regimen in high-risk patients is warranted.

A comparative analysis of lobular and ductal carcinoma of the breast: presentation, treatment, and outcomes.

BACKGROUND Compared with invasive ductal carcinoma, invasive lobular carcinoma of the breast is considered by many to be a more indistinct and multicentric form of cancer that is detected later and is treated less optimally by breast-preservation techniques. This study analyzed the presentation, treatment trends, and survival rates of women who had invasive lobular and ductal breast carcinoma. The objective was to determine the utility of breast-preservation therapy for invasive lobular carcinoma by analysis of historic data on tumor features and survival. STUDY DESIGN Data on 291,273 women diagnosed with invasive carcinoma between 1985 and 1993 were obtained from the National Cancer Data Base. Analysis included the patients age at diagnosis; tumor histology, anatomic site, diameter, grade, and stage; treatment; and disease status 5 years after diagnosis. RESULTS The mean patient age at diagnosis was 61.0 years for invasive ductal carcinoma, 63.0 years for invasive lobular carcinoma, and 60.6 years for tumors with combined histology. The anatomic location, tumor diameter, and tumor grade were similar for each histotype. Breast-preservation therapy was less frequent for invasive lobular carcinoma. The 5-year overall survival and local disease-free survival rates for women treated with breast preservation were similar for invasive ductal carcinoma (84% overall survival; 97% disease-free survival) and invasive lobular carcinoma (87% overall survival; 98% disease-free survival). CONCLUSIONS Invasive lobular carcinoma presents with a similar age distribution, anatomic subsite, diameter, and grade as invasive ductal carcinoma. Breast preservation is selected less commonly for women who have invasive lobular carcinoma, but this choice of therapy does not compromise the disease-free or overall survival status of this group of patients.

Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer

BackgroundThe influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.MethodsWe performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.ResultsIncreased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.ConclusionsIncreased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

Can Sentinel Lymph Node Biopsy Be Spared in Papillary Carcinoma of the Breast

Background Papillary carcinoma (PC) of the breast represents ˜0.5% of all newly diagnosed cases of breast cancer and usually has an indolent course. The current data suggest lack of a consensus in the surgical management of this disease. Because patients can occasionally develop metastatic disease, sentinel lymph node (SLN) biopsy is often performed during surgery. Materials and Methods In the present study, we retrospectively evaluated the histologic characteristics of 99 cases of PC with or without associated frank invasive carcinoma, including 43 encapsulated or intracystic PCs, 24 solid PCs, and 32 intraductal PCs, and correlated these with the incidence of nodal metastasis. Results Of the 99 cases, 64 were tumor stage Tis (noninvasive), 5 were T1 microinvasive, 17 T1a, 5 T1b, 5 T1c, and 3 were T2. A total of 37 patients (37%) underwent axillary staging, including 31 SLN biopsies and 6 axillary dissections. Only 1 patient (2.7%) with noninvasive solid PC had evidence of nodal metastasis. Follow‐up information was available for 81 patients, with a mean follow‐up period of 4.9 years (range, 1‐13 years). Two local recurrences, no distant metastases, and no disease‐related deaths were recorded. Conclusion PC rarely involves the lymph nodes even in tumors with an associated frank invasive component, and the overall prognosis and long‐term survival is excellent. We propose that evaluation of the SLN should not be routinely indicated for patients with PC treated by local control lumpectomy. Micro‐Abstract We evaluated the clinicopathologic features of 99 cases of papillary carcinoma (PC). One patient had sentinel lymph node (SLN) metastasis, two patients had recurred locally, and none exhibited distant metastases or disease‐related death. PC rarely involves the lymph nodes, even in tumors with an associated frank invasive component. We propose that evaluation of SLN is not routinely indicated for PC cases.

Bisphosphonate use in metastatic breast cancer

Abstract Skeletal metastatic disease affects more than 70% of patients with breast cancer. These patients frequently demonstrate a prolonged survival with high morbidity. Hypercalcemia, bone pain, and fracture with potential neurologic compromise represent the major morbidity of skeletal metastases. The management of skeletal metastases in breast cancer revolves around the consequences of bone destruction. The lytic destruction of bone is a result of increased osteoclastic activity, prompting the use of bisphosphonates, which reduce osteoclastic activity and inhibit bone resorption. Their use has become the first line of therapy in hypercalcemia of malignancy. Studies with oral clodronate demonstrate efficacy in palliation of bone pain, reduction in analgesic use and of skeletal-related events, and reduction of hypercalcemia. Pamidronate is a second-generation aminobisphosphonate with a potent inhibition of osteoclastic activity and superior results, which can be demonstrated with IV rather than oral administration. This review intended to highlight the current published data on IV pamidronate use in patients with advanced skeletal metastases. Included are large, multi-institutional, prospective, randomized, blinded and nonblinded, controlled trials carried out through the Aredia Multinational Cooperative Group, and a well-designed, nonblinded, controlled trial with uniform crossover from a single institution. The studies are complementary, and each highlights questions and directions of study that are either currently under investigation or still require the development of well-designed studies. Protocol 19 of the Aredia Breast Cancer Study Group produced a large database to establish the safety and efficacy of long-term IV pamidronate use, expanding the treatment and follow-up of the original study patients over 2 years. Significantly fewer skeletal complications were noted in the pamidronate group, which was maintained for the 2 years of study. The treatment was given in conjunction with IV cytotoxic therapy and, consequently, the pamidronate-specific benefit may be partially obscured by the palliative effects of cytotoxic therapy. The trial by Conte is similarly affected with the use of concomitant chemotherapy. Significant data were accrued, however, to reflect both the efficacy and safety of this therapeutic regimen. The use of a blinded controlled trial has been criticized in this population of patients, and the Conte trial overcame this issue by using a nonblind controlled design and subsequent blinded extramural review. The data supporting prolonged PD allow speculation on the use of bisphosphonates to prevent further disease formation or prevent skeletal metastases in an adjunctive setting. The adjuvant use of bisphosphonates in the prevention of skeletal metastases is currently in a trial development phase with consideration of the use of more potent, third-generation IV bisphosphonates or oral clodronate. The issue of length of treatment is unclear, with data suggesting that a protective effect is lost after therapy is discontinued. Long-term use would favor an oral and more cost-effective and quality-of-life-effective route of administration. Evidence for dose responsiveness prompted the use of higher-dose, single-agent, and prolonged therapy. The trial by Coleman et al reflects these study modifications and further advances our knowledge of the metabolic response of bisphosphonates charted with the clinical and qualitative subjective response to treatment. This study helps to elucidate a population of patients with bone metastases, which are more likely to respond, and a method of clinically monitoring response to treatment through the more cost-effective and reproducible ELISAs of bone metabolism. Although higher doses of IV pamidronate were not more effective in obtaining greater rates of subjective response, ELISAs did demonstrate effective bone resorptive activity. A decrease in the incremental change in subjective scoring was seen over time despite objective evidence of bone resorption. Consequently, this prompts the question of whether a third-generation bisphosphonate—such as zoledronate, with a potency that has been demonstrated to be greater than 100 times that of second-generation bisphosphonates—could affect an improved or sustained, subjective clinical benefit. Studies might also be designed to elucidate and overcome mechanisms of bisphosphonate resistance. The development and utilization of agents to affect non-osteoclastic-mediated mechanisms of bone destruction could lead to a greater subjective response when used in conjunction or independently of bisphosphonates. Certainly the results of these studies highlight the multifactorial process associated with subjective and clinical skeletal-related events. The long-term survival of patients with skeletal metastases and the associated morbidity underscore the crucial, beneficial, palliative effects of the bisphosphonates in breast cancer. The potential for long-term use in both the metastatic and adjunctive settings should prompt the addition of formal cost-benefit analyses to future prospective study designs.