Elizabeth Comen

Tumor Entrained Neutrophils Inhibit Seeding in the Premetastatic Lung

Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H(2)O(2) and tumor secreted CCL2 is a critical mediator of optimal antimetastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, whereas tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Breast Cancer Tumor Size, Nodal Status, and Prognosis: Biology Trumps Anatomy

In the articles that accompany this editorial, Wo et al and Hernandez-Aya et al present two provocative clinical findings with respect to the relationship of tumor size and lymph node status to clinical outcome. Together, these articles highlight the less than perfect connection between a tumor size and its ability to colonize lymph nodes and distant organs. The first article, by Wo et al, reports that in cases of extensive lymph node involvement, very small tumors may confer a more aggressive subtype than larger tumors with the same degree of lymph node involvement. The second article, by HernandezAya et al, proposes that in triple-negative breast cancers, the worse prognosis associated with lymph node involvement may not be greatly affected by the absolute number of positive lymph nodes. Wo et al were motivated to conduct their study because of their hypothesis that very small tumors that generate extensive lymph node involvement may represent a unique subset of highly malignant breast cancers. To evaluate this idea, they used the Surveillance, Epidemiology, and End Results registry to identify 50,949 women who were diagnosed with nonmetastatic T1 and T2 invasive breast cancers and were treated with surgery and axillary lymph node dissection. In support of their hypothesis, among women who had four or more involved lymph nodes (N2), those women with smaller tumors (T1a) had a higher breast cancer–specific mortality (BCSM) than those with larger tumors (T1b). This difference was not seen in patients with fewer or no lymph nodes involved. Notably, among patients with estrogen receptor–negative cancer and four or more involved lymph nodes, patients with T1b tumors experienced significantly lower BCSM relative to patients with T1a tumors. On the contrary, no significant difference was noted among patients with T1a tumors relative to patients with T1c or T2 tumors. That is, the authors demonstrate that for very small tumors with extensive lymph node involvement, there is a decreasing BCSM as the tumors get larger. After a set threshold (Figure 2 in the article by Wo et al), however, BCSM increases as one would expect, with increasing tumor size conferring increased mortality. In another retrospective study, Hernandez-Aya et al investigated the prognostic relationship between tumor size and lymph node status in 1,711 women with triple-negative breast cancer. Their work indicates that in triple-negative breast cancers, any amount of nodal involvement denotes a worse relapse-free and overall survival. Essentially, once lymph nodes are involved, outcomes are not greatly affected by the absolute number of positive lymph nodes. In addition, when the authors compared node-negative to node-positive disease for all tumor sizes and all degrees of positive nodal involvement, there was a significant difference in outcomes. Unlike in the Wo et al study, Hernandez-Aya et al categorized patients according to T1, T2, and T3/T4, and did not additionally subcategorize the T1 tumors. Thus, it is not clear whether additional subset analysis would show that T1a tumors do particularly worse than T1b orT1c tumors. Why are these results surprising or, at least, deserving of being reported in this journal? The obvious answer is that they do not jibe with accepted—and profoundly influential—notions of malignant progression. From the beginning of our understanding of cancer as a disease of abnormal cellular growth, we have thought of malignant cellular expansion and metastases as a sequential process. By this concept, the initial defect in carcinogenesis is derangement in mitosis (or, later, the mitosis-apoptosis ratio), such that cancer cells accumulate as an abnormally large mass. With increasing cell accumulation and resulting additional changes in cell biology—now accepted as the consequence of genomic aberrancies—cells would be expected to acquire the ability to migrate, via blood and/or lymphatic channels, infiltrate organs other than their organ of origin, and proliferate in these sites as microscopic and then gross metastases. The fact that large breast cancers are more likely to be associated with axillary nodal metastases, and consequently distant metastases as well, has always been advanced as consistent with and, in fact, proof of this fundamental concept. Indeed, the push to diagnose breast cancers as early as possible after spontaneous tumor initiation, such as with mammography and now magnetic resonance imaging in selected cases, has been motivated by the idea that if a tumor can be removed before it learns metastatic behavior, distant metastases might be avoided. Hence, the success of breast screening programs to reduce mortality from this disease was the expected result and additionally increased our confidence in the malignant progression dogma. But nagging enigmas in breast cancer behavior have always added a tinge of uncertainty. One of the most disturbing is the fact that metastatic pathways seem to be predictable and unpredictable at the same time. Modern data on sentinel lymph node mapping seems to support the principle, popularized by Halsted in the nineteenth century, that the flow of cells from the breast tumor to the axilla is orderly: if the first nodes that receive lymphatic flow are free of cancer cells, it is almost certain that the rest of the axilla will be clean. However, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S

Abstract P5-18-20: Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer.

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0–1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6–1-12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-20.

Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites

Background:Cancer cell migration patterns are critical for understanding metastases and clinical evolution. Breast cancer spreads from one organ system to another via hematogenous and lymphatic routes. Although patterns of spread may superficially seem random and unpredictable, we explored the possibility that this is not the case.Aims:Develop a Markov based model of breast cancer progression that has predictive capability.Methods:On the basis of a longitudinal data set of 446 breast cancer patients, we created a Markov chain model of metastasis that describes the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Progression is modeled as a random walk on a directed graph, where nodes represent anatomical sites where tumors can develop.Results:We quantify how survival depends on the location of the first metastatic site for different patient subcategories. In addition, we classify metastatic sites as “sponges” or “spreaders” with implications regarding anatomical pathway prediction and long-term survival. As metastatic tumors to the bone (main spreader) are most prominent, we focus in more detail on differences between groups of patients who form subsequent metastases to the lung as compared with the liver.Conclusions:We have found that spatiotemporal patterns of metastatic spread in breast cancer are neither random nor unpredictable. Furthermore, the novel concept of classifying organ sites as sponges or spreaders may motivate experiments seeking a biological basis for these phenomena and allow us to quantify the potential consequences of therapeutic targeting of sites in the oligometastatic setting and shed light on organotropic aspects of the disease.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update

PurposeA joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).MethodsA recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.RecommendationsThe panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Translating Mathematical Modeling of Tumor Growth Patterns into Novel Therapeutic Approaches for Breast Cancer

In breast cancer, mortality is driven by the metastatic process, whereby some cancer cells leave their primary site of origin and travel to distant vital organs. Despite improved screening and therapies to treat breast cancers, metastasis continues to undermine these advances. The pervasive albatross of metastasis necessitates improved prevention and treatment of metastasis. To this end, clinicians routinely employ post-operative or adjuvant therapy to decrease the risk of future metastasis and improve the chance for cure. This article evaluates the limitations of breast cancer therapies within the context of growth curves, and in doing so, provides new insight into the metastatic process as well as more effective means for therapeutic delivery. Two critical developments evolve from this mathematical analysis: first, the use of dose dense chemotherapy to improve survival among breast cancer patients; and second, the theory of self-seeding, which fundamentally changes our understanding of metastasis and the trajectory of drug development.

Algorithms for the Treatment of Patients With Metastatic Breast Cancer and Prior Exposure to Taxanes and Anthracyclines

At present, metastatic breast cancer (MBC) remains an incurable disease, with the goals of care aimed at maximizing the patients duration and quality of life. Treatment options for a patient with MBC have become more efficacious and numerous. In addition to endocrine and chemotherapy agents, a number of targeted agents, including trastuzumab and bevacizumab, are available. The option to use novel agents combined with a multitude of standard chemotherapies has further enhanced the landscape of therapeutic options. As such, specific regimens must be evaluated within the framework of the individual patient, answering such questions as whether to treat with sequential single agents or combination regimens as well as which agents to use and in what sequence. The concept of personalized care is even more apparent in the setting of MBC, where the goal of palliation is intrinsically more nuanced than that of curative intent. This review will broadly assess the evidence for current treatment options with attention to varying clinical scenarios. Ultimately, delivering quality of care necessitates balancing an understanding of evidence-based data with sensitive attention to quality-of-life goals.

Somatic mutations in leukocytes infiltrating primary breast cancers

Background:Malignant transformation requires the interaction of cancer cells with their microenvironment, including infiltrating leukocytes. However, somatic mutational studies have focused on alterations in cancer cells, assuming that the microenvironment is genetically normal. Because we hypothesized that this might not be a valid assumption, we performed exome sequencing and targeted sequencing to investigate for the presence of pathogenic mutations in tumor-associated leukocytes in breast cancers.Methods:We used targeted sequencing and exome sequencing to evaluate the presence of mutations in sorted tumor-infiltrating CD45-positive cells from primary untreated breast cancers. We used high-depth sequencing to determine the presence/absence of the mutations we identified in breast cancer-infiltrating leukocytes in purified tumor cells and in circulating blood cells.Results:Capture-based sequencing of 15 paired tumor-infiltrating leukocytes and matched germline DNA identified variants in known cancer genes in all 15 primary breast cancer patients in our cohort. We validated the presence of mutations identified by targeted sequencing in infiltrating leukocytes through orthogonal exome sequencing. Ten patients harbored alterations previously reported as somatically acquired variants, including in known leukemia genes (DNTM3A, TET2, and BCOR). One of the mutations observed in the tumor-infiltrating leukocytes was also detected in the circulating leukocytes of the same patients at a lower allele frequency than observed in the tumor-infiltrating cells.Conclusions:Here we show that somatic mutations, including mutations in known cancer genes, are present in the leukocytes infiltrating a subset of primary breast cancers. This observation allows for the possibility that the cancer cells interact with mutant infiltrating leukocytes, which has many potential clinical implications.

Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

134 Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ MBC prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel (T) with HP (THP). METHODS Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. RESULTS As of 5-1-12, 33 of the planned 69 pts were enrolled; 16 were evaluable at 6 mo. Of the 16 pts, G 3/4 toxicities included sepsis (1pt, 6%), cholecystitis (1pt, 6%), fatigue (1pt, 6%), skin ulceration (1pt, 6%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 6%). G 1/2 toxicities included alopecia (16 pts, 100%), fatigue (15 pts, 94%), ALT/AST elevation (14 pts, 88%), neuropathy (14 pts, 88%), diarrhea (12 pts, 75%), rash (9 pts, 56%), nail changes (8 pts, 50%), nausea (7 pts, 44%), mucositis (7 pts, 44%), and dry skin (6 pts, 38%). Median LVEF was 63% at baseline, 60% at 3 mo and 58% at 6 mo. There were no cardiac events. At 6 mo, 12/16 pts (75%) were progression-free (2 CR, 7 PR and 3 SD); 4 pts progressed. CONCLUSIONS Our single-center phase II study continues to accrue, with no significant diarrhea or signal of increased cardiac toxicity to date. If the estimate of activity is similar to results with docetaxel in CLEOPATRA, this will provide support for THP as an alternative option in this setting.