Alice Chung

B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis.

Objective: B7 ligand family members have been shown to be important immunoregulatory factors in host tumor immune responses. We hypothesized that B7–H3, a coinhibitory factor, is expressed by primary breast cancer cells and associated with metastasis to regional tumor-draining lymph nodes. Experimental Design: American Joint Committee on Cancer stage I to III primary breast cancers (n = 82) and normal breast specimens (n = 17) were assessed for B7–H3 expression using paraffin-embedded archival tissues. B7–H3 expression by breast cancer cells was assessed by a quantitative real-time reverse transcription-polymerase chain reaction, and B7–H3 protein expression was evaluated using immunohistochemistry. Results: B7–H3 mRNA expression was detected in 32 of 82 (39%) primary breast tumors but not in normal breast tissues (P = 0.0029). B7–H3 expression in primary tumors significantly correlated with increasing tumor size, American Joint Committee on Cancer stage, and lymphovascular invasion (P < 0.0001, P < 0.0001, P = 0.0071). B7–H3 expression was highly correlated to sentinel lymph node and overall number of lymph nodes with metastasis P = 0.003, and P = 0.004, respectively). In a multivariate analysis, B7–H3 mRNA expression of the primary tumor significantly predicted metastasis to regional lymph nodes (P = 0.021, and P = 0.023, respectively). Antibody staining analysis of paraffin-embedded archival tissue breast tumors and flow cytometry of breast cancer cell lines demonstrated B7–H3 protein expression. Conclusions: B7–H3 protein expressed by primary breast cancer cells is a tumor progression factor and is associated with extent of regional nodal metastasis.

Axillary staging in the neoadjuvant setting.

Neoadjuvant chemotherapy (NAC) is increasingly being used in the treatment of locally advanced breast cancer as well as for early breast cancer. Axillary lymph node dissection has been the standard method of staging the axilla in the neoadjuvant setting. Since the sentinel lymph node biopsy was introduced in the early 1990s, less invasive approaches to axillary staging in patients undergoing neoadjuvant therapy have been proposed. In this review, we discuss the effects of NAC, the imaging modalities that have been used to evaluate the axillary lymph nodes, and the role and timing of sentinel lymph node biopsy in the neoadjuvant setting. Finally, we propose a treatment algorithm for patients undergoing NAC on the basis of the current data.

Breast-Conserving Therapy for Triple-Negative Breast Cancer

IMPORTANCE The aggressive triple-negative phenotype of breast cancer (negative for estrogen and progesterone receptors and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2] [formerly human epidermal growth factor receptor 2 (HER2)]) is considered by some investigators to be a relative contraindication to breast-conserving therapy. OBJECTIVES To compare outcomes of breast-conserving therapy for patients with triple-negative breast cancer (TNBC) with those of patients with the luminal A, luminal B, and ERBB2 subtypes. DESIGN, SETTING, AND PARTICIPANTS Prospective database review at an academic tertiary medical center with a designated breast cancer center. We included 1851 consecutive patients ages 29 to 85 years with stages I to III invasive breast cancer who underwent breast-conserving therapy at a single institution from January 1, 2000, through May 30, 2012. Of these patients, 234 (12.6%) had TNBC; 1341 (72.4%), luminal A subtype; 212 (11.5%), luminal B subtype; and 64 (3.5%), ERBB2-enriched subtype. EXPOSURE Breast-conserving therapy. MAIN OUTCOMES AND MEASURES The primary outcome measure was local recurrence (LR). Secondary outcome measures included regional recurrence, distant recurrence, and overall survival. RESULTS Triple-negative breast cancer was associated with younger age at diagnosis (56 vs 60 years; P = .001), larger tumors (2.1 vs 1.8 cm; P < .001), more stage II vs I cancer (42.1% vs 33.6%; P = .005), and more G3 tumors (86.4% vs 28.4%; P < .001) compared with the non-TNBC subtypes. Multivariable analysis showed that TNBC did not have a significantly increased risk of LR compared with the luminal A (hazard ratio, 1.4 [95% CI, 0.6-3.3]; P = .43), luminal B (1.6 [0.5-5.2]; P = .43), and ERBB2 (1.1 [0.2-5.2]; P = .87) subtypes. Only tumor size was a significant predictor of LR (hazard ratio, 4.7 [95% CI, 1.6-14.3]; P = .006). Predictors of worse overall survival included tumor size, grade, and stage and TNBC subtype. CONCLUSIONS AND RELEVANCE Breast-conserving therapy for TNBC is not associated with increased LR compared with non-TNBC subtypes. However, the TNBC phenotype correlates with worse overall survival. Breast-conserving therapy is appropriate for patients with TNBC.

Current Status of Anti–Human Epidermal Growth Factor Receptor 2 Therapies: Predicting and Overcoming Herceptin Resistance

Human epidermal growth factor receptor 2-overexpressing (HER2+) breast cancer occurs in 20% to 25% of cases and is associated with poor prognosis. Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a monoclonal antibody targeting the HER2 extracellular domain that has been shown to significantly reduce relapse rates. However, some patients with HER2+ tumors do not respond to Herceptin, and 60% to 85% of patients with HER2+ metastatic breast cancer acquire resistance within a short time period. In this review, we discuss proposed mechanisms of action of trastuzumab and trastuzumab resistance and various drugs that have been developed to overcome drug resistance. We introduce the basal molecular subtype as a predictor of increased risk in HER2+ breast cancer and a possible alternative cause of drug resistance.

Not Performing a Sentinel Node Biopsy for Older Patients With Early-Stage Invasive Breast Cancer

Not Performing a Sentinel Node Biopsy for Older Patients With Early-Stage Invasive Breast Cancer Axillary surgery contributes to morbidity and has not been shown to improve survival in early breast cancer. Women 70 years of age or older with clinically node-negative breast cancer are more likely to have comorbidities and reduced life expectancy, and there is controversy as to whether or not a sentinel node biopsy is warranted in this population. The purpose of our study was to evaluate the safety of not performing a sentinel node biopsy for patients 70 years of age or older with clinically node-negative breast cancer.

The staging value of sentinel lymph node biopsy for breast cancer: translating pathologic findings to clinical practice.

Axillary nodal status is an important prognostic factor in guiding locoregional and systemic treatment for breast cancer. Sentinel lymph node biopsy (SNB) has revolutionized axillary staging by replacing axillary lymph node dissection (ALND) in node-negative women. Even in select patients whose sentinel lymph nodes (SLNs) contain metastases, SNB alone has become an accepted method of managing the axilla. Identification of micrometastases through immunohistochemical analysis of SLNs that are tumorfree on hematoxylin and eosin staining (H&E) does not confer additional clinical benefit. The use of SNB after neoadjuvant chemotherapy (NAC) remains controversial. In addition to axillary nodal status, tumor biology plays an increasingly important role in guiding therapeutic decisions.

Lymphatic Mapping and Sentinel Lymphadenectomy for Breast Cancer

The surgical management of the axilla in early breast cancer has significantly evolved over the past several decades. This chapter details the history of sentinel node dissection, as well as the indications, technical aspects, complications, histologic analysis, and oncologic outcomes of sentinel node biopsy as it compares to axillary dissection. The most current management recommendations are discussed, as are future directions.

Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics

ABSTRACT Resistance to anti‐tumor therapeutics is an important clinical problem. Tumor‐targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a “Trojan‐Horse” approach to combating these tumors by using a receptor‐targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non‐covalent self‐assembly with therapeutic cargo, forming HER3‐homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re‐introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here. Graphical abstract Figure. Tumor cells with resistance to HER2 inhibitors can be prime targets for HER3‐directed nanobiologics. Schematic summarizes several scenarios that may explain how drug‐resistant tumor cells can be targeted by HER3‐nanobiologics. In the first scenario, tumor cells with acquired resistance to HER2‐targeted inhibitors are characterized by increased cell surface display of HER3, cornering these resistant cells for attack by the HER3‐nanobiologics described here. These studies also suggest that pre‐treatment of sensitive or naïve tumors may yield the same result by shifting naïve tumor cells to a HER3‐elevated phenotype. In the second scenario, HER2‐sensitive tumor cells in a heterogenous population may be eliminated, leaving resistant cells that could be vulnerable to nanobiologic attack due to increased cell surface display of HER3. The studies described here also suggest that such tumors with inherent or pre‐existing resistance to HER2 inhibitors may likely have increased cell surface HER3, thus making them vulnerable to nanobiologic attack.

Author Reply: Re: Axillary Staging in the Neoadjuvant Setting

We appreciate the comments by Olsha and Carmon regarding timing of axillary lymph node dissection (ALND) in patients with a positive sentinel lymph node (SLN) undergoing neoadjuvant chemotherapy (NAC). In our review of axillary staging in the neoadjuvant setting we recommend performing ALND with the definitive breast surgery after completion of NAC in those identified as SLN-positive prior to NAC. The primary concern of the authors is that information regarding the remaining axillary nodes may be lost by delaying completion ALND until after the NAC is completed. They feel loss of this information may result in change in recommendations regarding lymphatic basin radiation or chest wall radiation in those undergoing mastectomy. A secondary concern of the authors is that delay of ALND requires reoperation of the axillary basin, which because of fibrosis and scarring may be more technically difficult than performing ALND in a field where there has been no prior surgery. They recommend performing frozen section at the time of SNB and completing the ALND at the same time if the sentinel node harbors metastases. This is, of course, a reasonable option. We agree that the nodal status of the nonsentinel nodes may be altered by NAC, potentially leading to downstaging of the axilla. The post-NAC status of the nonsentinel nodes may change the recommendations for lymphatic basin radiation. However, in the neoadjuvant setting, recommendations for nodal or postmastectomy radiation are often based on primary tumor size. Frequently, those who present initially with clinically palpable disease in the axilla and whose nonsentinel nodes have been downstaged by NAC would still be likely to receive third-field radiation. There is evidence to support third-field radiation even for small tumors in premenopausal women with lymph node involvement. Reoperative axillary surgery after a SNB is usually not technically different and is facilitated by dissecting around the planes of previous dissection. With increased use of preoperative axillary ultrasound and needle biopsy, many patients will be diagnosed with lymph node involvement without requiring SLN biopsy. In conclusion, we endorse the authors’ suggestion of performing ALND prior to NAC as an acceptable alternative pathway to axillary staging in patients undergoing NAC, acknowledging that there may be more ways than one to ‘‘skin a cat.’’ The only potential disadvantage of their approach is that there may be a delay in initiation of chemotherapy.