Editorials

weeks. Although this timeline is generally quite respectable, I find it to

be unacceptably long for those articles that have practice-changing or
time-dependent research implications. Beginning immediately, for
those articles that are deemed to be of high interest to our clinical and
translational readership, we will institute a rapid review process
whereby the time from assignment to an Associate Editor to first
decision is approximately 72 hours, the time from final acceptance to
online publication is approximately 4 weeks, and such publications
are published without access controls so that the information can be
disseminated as widely as possible. This last point is of great importance to me because information of such timely relevance that has the
potential to affect the lives of our patients should not be restricted
solely to paid subscribers of JCO (or any other journal, for that matter). Although authors may indicate in their cover letters whether their
work has immediate practice-changing implications, the Editors will
ultimately determine whether a given article conveys enough importance to justify rapid review status. Given the current complexion of
manuscripts received at JCO, we anticipate that an average of one to
two articles per month will be published on a rapid review basis.
I consider myself very fortunate to have been chosen as the next
Editor-in-Chief of this highly prestigious journal. The last year has
been a transition period for me during which I have worked closely
with the superb administrative team at JCO to launch many of the new
initiatives that are described here. The fact that I am able to present the
readership with several new initiatives at the very beginning of my
tenure is a testimony to the high level of organization and collegiality at

JCO, and to the support of the Associate Editors who have made my
transition pleasant and have welcomed me. I am appreciative of the
trust that ASCO and JCO have placed in me to move this journal into
the next decade, and I intend to honor that trust by preserving and
enhancing the high quality and uncompromising standards for which
JCO is known. I look forward to an exciting adventure that will succeed only through the hard work of many individuals, including our
dedicated Associate Editors and Editorial Board, wonderful administrative staff, accomplished authors, and our readers, all of whom
contribute to make this journal great. Together we will ensure that
JCO maintains its reputation as one of the very best cancer journals in
the world.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES
1. Haller DG, Cannistra SA: Providing protocol information for Journal of
Clinical Oncology readers: What practicing clinicians need to know. J Clin Oncol
29:1091, 2011
2. Price TJ, Hardingham JE, Lee CK, et al: Impact of KRAS and BRAF gene
mutation status on outcomes from the phase III AGITG MAX trial of capecitabine
alone or in combination with bevacizumab and mitomycin in advanced colorectal
cancer. J Clin Oncol 29:2675-2682, 2011
3. Bass A: Impact of KRAS and BRAF gene mutations on targeted therapies in
colorectal cancer. J Clin Oncol 29:2728-2729, 2011

DOI: 10.1200/JCO.2011.36.7631; published online ahead of print at

www.jco.org on June 6, 2011

Breast Cancer Tumor Size, Nodal Status, and

Prognosis: Biology Trumps Anatomy
Elizabeth A. Comen and Larry Norton, Memorial Sloan-Kettering Cancer Center, New York, NY
Joan Massague, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
See accompanying articles on pages 2619 and 2628

In the articles that accompany this editorial, Wo et al1 and

Hernandez-Aya et al2 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 al1 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
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2011 by American Society of Clinical Oncology

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 cancerspecific 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 receptornegative 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 al1), however,
BCSM increases as one would expect, with increasing tumor size
conferring increased mortality.
In another retrospective study, Hernandez-Aya et al2 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
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Editorials

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 al1 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 acceptedand profoundly influentialnotions 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 biologynow 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 Halsted3 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.3,4 However,
negative axillary contents do not guarantee freedom from distant
metastases, nor do axillary metastases portend systemic spread with
certainty, even in the most extreme cases of nodal involvement. Indeed, the knowledge that cancers could disseminate early and yet spare
the axilla led to the suggestion by Fisher,5 Shapiro and Fugmann6 that
the use of anticancer drugs in the perioperative period could improve
cancer-specific outcomes, which has indeed been confirmed experimentally. Hellman7 recognized that Halsteds view of an orderly anatomic route of spread and Fishers of the lack of an obligatory
requirement for a strict route could both be true, but how could these
divergent views be reconciled biologically?
We have recently learned from well-conducted, randomized trials that the finding of isolated tumor cells in axillary lymph nodes does
not necessary convey dire implications.8 Furthermore, for patients
www.jco.org

who are undergoing breast-conserving surgery and radiotherapy to

the breast and low axilla, those with fewer than three involved sentinel
axillary lymph nodes do not suffer from not having had a complete
axillary dissection, although more than a quarter of patients so treated
have residual nodal metastases that are left behind.9
Now, adding to the confusion, are the respective findings of Wo
et al1 and Hernandez-Aya et al2 that indicate that a subset of small
tumors may be highly aggressive, despite their size, and that among
triple-negative breast cancers, once lymph nodes are positive, the
absolute number of lymph nodes involved does not change the inherent worse prognosis. Certainly, these findings might be regarded as
statistical flukes, although the large sample sizes and methodologic
competencies involved would render this unlikely. So assuming that
the results are reproducible and hence valid, what might they mean,
and how do they relate to the clinical enigmas cited above?
Some solace may be found in emerging novel concepts of cancer
that are centered on the relatively new science of cancer metastasis.
New data is, in fact, challenging the notion that cancer cells that leave
a primary tumor often called circulating tumor cells or CTCs
unidirectionally seed metastases in regional (lymph nodes) or distant
sites. In contrast, there is evidence in experimental animal systems that
CTCs can return to colonize and promote growth in their tumors of
origin.10,11 Moreover, the ability to seed is necessary but not sufficient
to generate colonies in seeded sites; indeed, cells can lie dormant for
decades in such sites without growing.12
That these concepts are rational is consistent with well-established
biologicprinciplesthataregroundedinmetastasisresearch.Usinghuman
cancer cells, it has been shown that the genetic tool kit for generating
successful metastases seems to be site specific, with different, barely overlapping signatures for lung, bone, and brain involvement.13-16
Moreover, the many barriers that CTCs face in infiltrating and
growing in regional and distant organsincluding tight vascular capillary endothelial walls and unfamiliar microenvironmentsare less
daunting in the cancer of origin.17,18 Here the cells encounter a leaky
neovasculature and a familiar microenvironment. The hypothesis of
cancer self-seeding was recently validated in diverse experimental
models that included breast and colon adenocarcinomas and melanomas.10 Tumor-derived inflammatory cytokines interleukin (IL) -6
and IL-8 act as CTC attractants. The self-seeding CTCs tend to express
matrix metalloprotease-1/collagenase-1 and the actin cytoskeleton
component fascin-1. These molecules, in addition to seed-derived
chemokine ligand 1, promote accelerated tumor growth, angiogenesis, and the recruitment of myeloid cells into the stroma.
Hence, a large tumor may not only be a cause of distant seeding
(the conventional concept) but also a result of self-seeding. This
concept certainly complicates the relationship between tumor size
and distant metastatic potential.
The site-specific nature of metastases has been confirmed not
only by in vivo experiments in mice using cell lines from human
sources, but also by the analysis of recurrence-free survival curves in
patients whose tumors have been classified by molecular signatures.
Although formal proof of the existence of self-seeding in human
cancer specimens will require advances in single-cell genomic sequencing and bioinformatics technology (comparing tumor cells
from primary and secondary sites), there are no a priori reasons why
the concept should not apply to all mammalian malignancies. On the
basis of these data, therefore, we could envision a case in which a
primary cancer is excellent at seeding axillary lymph nodes but not
2011 by American Society of Clinical Oncology

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Editorials

distant organs or vice versa: hence, the imperfect connection between

axillary involvement and the involvement of distant organs. Furthermore, a large primary cancer could be large because of its pronounced
mitotic activity or because it is an excellent self-seeder: hence, the
imperfect connection between tumor size and metastatic behavior.
Because of the site-specific nature of metastases, the abilities to selfseed or to seed distant sites should be imperfectly correlated as well.
Therefore, we could envision a case in which a primary cancer is
excellent at seeding axillary lymph nodes (via the sentinel node route)
and/or distant organs, but not itself. Moreover, a small cancer that has
demonstrated the capacity to seed a given number of lymph nodes
may express node-specific and distant-organ metastatic genes but not
self-specific ones. Therefore, it might be more aggressive, in terms of
ultimate outcomes, than a larger cancer that involves the same number of axillary nodes. The larger cancer, in this instance, is better at
seeding itself but less proficient at seeding regional lymph nodes or
distant sites, so it needed more cells in the primary mass to accomplish
the comparable degree of nodal involvement.
The important aspect of this discussion, then, is that simple
anatomic reasoningwhich has led to many advances in clinical
oncology but also the clinical enigmas described abovemay not be
the most productive way forward in understanding the clinical behavior of cancers and hence prognostication. Elucidating the molecular
mechanisms that underlie the biology of individual cancers would
seem to be a more useful focus of our attention. Fortunately for us and
for our patients, both technical and conceptual improvements are
now available and are resulting in headway. These, coupled with
insightful clinical observations as illustrated by the two articles in this
issue,1,2 herald a future of greater understanding and resulting clinical progress.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES
1. Wo JY, Chen K, Neville BA, et al: Effect of very small tumor size on
cancer-specific mortality in node-positive breast cancer. J Clin Oncol 29:26192627, 2011
2. Hernandez-Aya LF, Chavez-MacGregor M, Lei X, et al: Nodal status and
clinical outcomes in a large cohort of patients with triple-negative breast cancer.
J Clin Oncol 29:2628-2634, 2011
3. Halsted WS: The results of radical operations for the cure of carcinoma of
the breast. Ann Surg 46:1-19, 1907
4. Lyman GH, Giuliano AE, Somerfield MR, et al: American Society of Clinical
Oncology guideline recommendations for sentinel lymph node biopsy in earlystage breast cancer. J Clin Oncol 23:7703-7720, 2005
5. Fisher B: Biological and clinical considerations regarding the use of surgery
and chemotherapy in the treatment of primary breast cancer. Cancer 40:574-587,
1977 (suppl 1)
6. Shapiro DM, Fugmann RA: A role for chemotherapy as an adjunct to
surgery. Cancer Res 17:1098-1101, 1957
7. Hellman S: Karnofsky Memorial Lecture: Natural history of small breast
cancers. J Clin Oncol 12:2229-2234, 1994
8. Andersson Y, Frisell J, Sylvan M, et al: Breast cancer survival in relation to the
metastatic tumor burden in axillary lymph nodes. J Clin Oncol 28:2868-2873, 2010
9. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary
dissection in women with invasive breast cancer and sentinel node metastasis:
A randomized clinical trial. JAMA 305:569-575, 2011
10. Kim MY, Oskarsson T, Acharyya S, et al: Tumor self-seeding by circulating
cancer cells. Cell 139:1315-1326, 2009
11. Norton L, Massague J: Is cancer a disease of self-seeding? Nat Med
12:875-878, 2006
12. Zhang XH, Wang Q, Gerald W, et al: Latent bone metastasis in breast
cancer tied to Src-dependent survival signals. Cancer Cell 16:67-78, 2009
13. Minn AJ, Gupta GP, Padua D, et al: Lung metastasis genes couple breast
tumor size and metastatic spread. Proc Natl Acad Sci U S A 104:6740-6745, 2007
14. Bos PD, Zhang XH, Nadal C, et al: Genes that mediate breast cancer
metastasis to the brain. Nature 459:1005-1009, 2009
15. Lu X, Wang Q, Hu G, et al: ADAMTS1 and MMP1 proteolytically engage
EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes
Dev 23:1882-1894, 2009
16. Nguyen DX, Bos PD, Massague J: Metastasis: From dissemination to
organ-specific colonization. Nat Rev Cancer 9:274-284, 2009
17. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature
407:249-257, 2000
18. Rafii S, Avecilla ST, Jin DK: Tumor vasculature address book: Identification of
stage-specific tumor vessel zip codes by phage display. Cancer Cell 4:331-333, 2003

AUTHOR CONTRIBUTIONS

Manuscript writing: All authors

Final approval of manuscript: All authors

DOI: 10.1200/JCO.2011.36.1873; published online ahead of print at

www.jco.org on May 23, 2011

Expanding Our Therapeutic Options: Beta Blockers

for Breast Cancer?
Patricia A. Ganz, University of California, Los Angeles (UCLA) School of Public Health; Jonsson Comprehensive Cancer Center
at UCLA; David Geffen School of Medicine at UCLA, Los Angeles, CA
Steven W. Cole, Jonsson Comprehensive Cancer Center at UCLA; David Geffen School of Medicine at UCLA; Norman Cousins
Center for Psychoneuroimmunology at UCLA; and UCLA Molecular Biology Institute, Los Angeles, CA
See accompanying articles on pages 2635 and 2645

Despite the many advances in cancer therapy during the past 50

years, standard adjuvant chemotherapy for breast cancer has provided
only modest benefit in terms of improvements in disease-free and
overall survival, with many patients relapsing despite therapy and
others likely not needing chemotherapy.1,2 The survival benefit from
adjuvant chemotherapy in younger women with breast cancer is likely
derived in part from the secondary effects of treatment-induced
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2011 by American Society of Clinical Oncology

amenorrhea, especially in hormone receptorpositive tumors, which

affects the tumor microenvironment.3,4 In contrast, targeted therapies, such as trastuzumab and tamoxifen, have had major impacts on
mortality by their selective effects on tumor cells that overexpress
specific characteristics within a particular breast cancer tumor. Historically, most drug development strategies have targeted metabolic and
signaling pathways within the malignant epithelial cell,5 with limited
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