Immunomodulation via Chemotherapy and Targeted Therapy: A New Paradigm in Breast Cancer Therapy?

Cytotoxic chemotherapy in the treatment of tumors has traditionally been thought to be immunosuppressive. Increasing evidence suggests the contrary and has introduced the concept of ‘immunogenic’ chemotherapy or, in other words, the concept that the innate and adaptive immune systems are critical in determining the long-term efficacy of some cytotoxic-based (and radiotherapy-based) regimens. The underlying mechanisms how these therapies can stimulate an antitumor immune response have been demonstrated recently. In this article, we review the background of this new paradigm and how combinations of traditional agents with the new immunotherapeutic therapies may significantly advance our treatment of breast cancer.     

Does Local Therapy Affect Survival Rates in Breast Cancer?

Background: The goal of this study was to challenge the hypothesis that local recurrence of breast cancer does not affect survival rates, by determining whether survival rates differ for conservative and radical surgical policies. Methods: This study used prospective long-term follow-up monitoring of two contemporaneous groups of patients, within a single unit, who were treated identically except for the one variable of local treatment policy, i.e., conservative or radical. A total of 451 patients with operable breast cancer were chosen from 567 consecutive patients with breast cancer who were treated between 1970 and 1979 in the University Department of Surgery. The rate of survival 132 months after treatment was used as an outcome measure.Results: Two hundred forty-one patients were treated using a conservative approach and 210 were treated using a radical approach. At 132 months, the survival rate (58% vs. 42%) and median survival time (>132 vs. 100 months) were significantly improved for the radically treated group (P < .01). The treatment groups were comparable in terms of age, menopausal status, tumor size, histologic grading, and Nottingham Prognostic Index values. The advantage of the radical policy persisted when examined in relation to each of these prognostic factors.Conclusions: Use of radical local treatment yielded a highly significant survival benefit (comparable to that obtained with adjuvant therapy), compared with a conservative approach. This was related to a reduced locoregional recurrence rate and provides evidence that local therapy influences long-term outcomes for patients with breast cancer. High-quality locoregional control should be emphasized, as is systemic therapy, in management policies. Assessment of surgical techniques, particularly in relation to locoregional recurrence rates, should be included in all studies in which surgery is a component of therapy.     

Options in Breast Cancer Local Therapy: Who Gets What?

Today, women with primary breast cancer may consider three surgical options: breast-conserving surgery (BCS), mastectomy (MT), and mastectomy with contralateral prophylactic mastectomy (MT?+?CPM). In each case, the ipsilateral axilla is generally managed with a sentinel node biopsy and possibly an axillary lymph node dissection. BCS generally requires breast radiotherapy, except in older women having tumors with a favorable prognosis who will receive endocrine therapy. In contrast, women treated with MT generally do not require radiotherapy, except for those with large tumors or metastases to the axillary nodes. Moreover, MT and MT?+?CPM are usually undertaken with breast reconstruction. Yet, most patients today are suitable candidates for BCS, with a few relative contraindications. Thus, early pregnancy, previous radiotherapy to the breasts, active collagen vascular disease, multicentric breast cancer, large tumors (although neoadjuvant systemic therapy can often reduce tumor size), and the presence of the BRCA mutation are all relative contraindications to BCS. BRCA mutation carriers should consider MT?+?CPM because their risk of contralateral breast cancer is greatly increased. In the U.S., the use of MT for the treatment of primary breast cancer has declined in recent years, while MT?+?CPM rates have increased, and BCS rates have remained relatively stable. The underlying reasons for these trends are not fully understood. Local therapy options should be discussed with each patient in considerable detail, and more studies are needed to better elucidate which factors influence a woman's choice of local therapy following a breast cancer diagnosis.     

A New Hormonal Therapy for Estrogen Receptor–Negative Breast Cancer

Background We postulate that the androgen dehydroepiandrosterone sulfate (DHEAS) may represent an innovative hormonal treatment for estrogen (ER), progesterone (PR) receptor–negative, but androgen receptor (AR)–positive breast cancers by inhibiting breast cancer cell growth through AR stimulation. Methods Three ER,PR–negative breast cancer cell lines (HCC 1137, 1954, and 38), were treated with DHEAS. DHEAS-induced growth was measured by a methylthiotetrazole (MTT) proliferation assay and apoptosis by TUNEL fluorescence. Androgen receptor gene expression levels were determined using quantitative real-time polymerase chain reaction (q-RT-PCR). Results HCC cell lines 1954 and 1937 were positive for AR expression; HCC 38 was weakly positive. MTT analysis showed DHEAS-induced decreases in cell proliferation of 47% in HCC 1937, 27% in HCC 1954, and 0.4% in HCC 38. Ten days of culturing HCC 1954 cells after the removal of DHEAS resulted in a 3.5-fold increase in growth. Continuous treatment for the same duration induced a 2.8-fold decrease in growth. Parallel experiments showed no significant changes in HCC 38 cultures. TUNEL assays showed DHEAS-induced apoptosis fold increases of 2.8 in HCC 1937, 1.9 in HCC 1954, and no significant difference in HCC 38 cultures. Q-RT-PCR of HCC 1954 cells showed a 6-fold DHEAS-induced decrease in AR gene expression at 4 h. Co-treatment with Casodex nullified this effect. Conclusions DHEAS inhibited growth of ER,PR–negative, AR–positive breast cancer cells. DHEAS was cytotoxic to these breast cancer cells via the apoptosis pathway. DHEAS may be an effective treatment for a population previously excluded from hormone therapy.     

Breast Cancer Local Therapy: What Is Its Effect on Mortality?

Until recently, the concept of biological predeterminism appeared pre-eminent and a worthy successor to the Halstedian doctrine of centrifugal spread of cancer. However, evidence has now emerged from clinical trials to cast doubt on the universal application of this concept to breast tumors. Prevention of local recurrence can save lives, local control does matter, and rates of local recurrence should be minimized in the first 5 years. In up to one quarter of cases of local recurrence the locally recurring disease will be a determinant and not simply a marker of risk for distant relapse and death. Both types of local recurrence are manifestations of the same biological processes and reflect intrinsic behavior of the tumor. This principle applies to reduction in local relapse from both adjuvant radiotherapy and surgical modalities.     

Menopausal Hormone Therapy and Breast Cancer Phenotype: Does Dose Matter?

Background  Duration and type of menopausal hormone therapy (HT) has been associated with increased breast cancer risk and the development of estrogen receptor (ER)-positive tumors. The effect of HT dose on breast cancer tumor characteristics remains undefined. We sought to determine if HT dosing regimens influence breast cancer phenotype. Methods  We conducted a retrospective review of incident female breast cancers occurring in the year 2003 listed in the Kaiser Permanente Northern California Cancer Registry. Type of HT, dose, number of tablets dispensed, tumor phenotype, stage, grade, and histology were obtained from electronic records for women aged ≥50 years who had more than 1 year of uninterrupted pharmacy data (n = 1701). A dose index of HT exposure was created and odds ratios were used to determine if tumor phenotype varied between exposure groups. These results were compared with a previously published analysis of HT duration on tumor phenotype conducted with the same dataset. Results  The cumulative effect of estrogen and progesterone hormone therapy as calculated by factoring both dose and duration of HT use prior to breast cancer diagnosis did not reveal any new associations that were not previously identified by analysis of HT duration of exposure alone. Low-dose-index combination-HT users were less likely to have tumors with an ER-positive phenotype. An overall trend developed in which low- and high-dose-index exposed women had the lowest rates of ER- and progesterone receptor (PR) -positive tumors. Conclusion  Duration of use is an adequate surrogate for determining overall exposure to HT when considering the effect of HT on breast cancer phenotype.     

Is Neoadjuvant Therapy Sufficient in Resected Pancreatic Cancer Patients? A National Study

Background

Despite the increasing use of neoadjuvant treatment, the question of whether preoperatively treated, successfully resected patients should receive additional postoperative adjuvant treatment remains unanswered. We evaluate the impact of adjuvant therapy following neoadjuvant treatment and pancreatectomy in pancreatic cancer patients in a large national study.

Methods

We used the National Cancer Data Base between 2006 and 2013 to identify resected, non-metastatic pancreatic adenocarcinoma patients who received neoadjuvant chemo(radio)therapy followed by pancreatectomy. Kaplan-Meier and multivariate Cox proportional hazard regression analyses were performed to compare survival between groups.

Results

In total, 1357 patients were identified. Of the patients, 38.6% (n = 524) were treated with postoperative therapy. There was no difference in unadjusted median overall survival between patients who did and did not receive postoperative therapy (median survival, 27.5 vs. 27.1 months, log-rank p = 0.5409). Postoperative therapy was not significantly associated with favorable prognosis in patients with positive resection margins (log-rank p = 0.6452) or positive lymph nodes (log-rank p = 0.6252). On multivariate analysis, receipt of postoperative therapy was not predictive of survival (hazard ratio 0.972; 95% CI 0.848–1.115; p = 0.6876).

Conclusions

Our results using national data suggest that after receipt of neoadjuvant therapy and pancreatectomy, additional postoperative therapy may not provide additional survival benefit. These data warrant further prospective data collection and consideration for clinical trials.