Yes. Even without evidence of secondaries a primary has been removed by mastectomy and local radiotherapy, new secondaries can crop up in many different sites, even after 30 years, although one would never be sure that the secondaries are not already in the new locations at the time of primary treatment.

That's an interesting question. I'm not sure if there is any basic scientific research done about this as I'm no a lab guy. In clinical setting, we do see a lot of patient who have the primary breast cancer treated years ago, recurs in a distant site and luckily it can be removed surgically, and then it recurs at a new location again some time later. But it's hard to proof whether this "second recurrence" is from the original breast primary or from the first recurrence.

Thanks Alan and Macy

The most frequent sites of metastases are liver, lung and bone however, breast cancer also metastasize in brain.

COX-2 drives metastatic breast cells from brain lesions into the cerebrospinal fluid and systemic circulation.

Cancer Res. 2014 May 1;74(9):2385-90. doi: 10.1158/0008-5472.CAN-13-2660. Epub 2014 Mar 10.

Chandra:

In fact, we have not only robust data from the Netherlands Cancer Institute [Weigelt et al., Nature Rev Cancer Aug 2005], the US NCI, JCCRI in Japan, and numerous other cancer authorities throughout the world (updated in an internal review of my own as of early 2014), but also the aggregated reported experience in registry records of breast cancer organizations (including my own, the No Surrender Breast Cancer Foundation (NSBCF) where I serve as Director of Medical Research) that breast cancer can (and has) significantly metastasize to 18 different organs and viscera, and these are listed below in rough order of overall incidence:

Bone

Lung

Liver

Pleura

Adrenal glands

Stomach/gastrointestinal (including colon, jejunum, and rectum)

Peritoneum-retroperitoneum

CNS (which includes: brain and/or leptomenigeal)

Skin

Pericardium

Ovary

Kidney

Thyroid

Spleen

Pancreas

Heart

Uterus

There are some sporadic reports of metastatic migration to still other sites, but these have not been decisively confirmed and remain speculative pending dispositive confirmation.

Furthermore, it's very important to note however that these are general incidence stats across all breast cancer types indifferently. However, individual subclasses and subtypes have differential preferences. So, for instance bone metastases are highly uncommon in the basal subclass (which largely but not exclusively includes triple negative breast cancer (TNBC)), but significantly more common in endocrine-positive BC, while in contrast CNS mets (either brain or leptomeningeal or both) are vastly more common in both TNBC and HER2-positive disease where the brain serves as metastatic sanctuary, than in endocrine-positive disease. We therefore say that BC metastases are subclass/subtype-preferential.

Constantine,

I have gone through the publications mentioned above. They represent very valuable and elaborate research. But picking up where Chandra left the question thread, I would like to know that does it matter if the secondaries are from the primary tumor or whether it is the secondaries seeding in a widespread fashion? Would they not stillbe considered as mets, so long as it is established that the HP and other surface markers are the same? Does one need to establish this? Considering for the moment that it is possible to do so, will it change the treatment? What I mean to ask is that does it matter if the metastatic lesion in the brain came from the breast directly or whether it spread from the breast to the bone first and then from there to the brain?

Neeta:

Great question!, about issues often garbled and misunderstood, so let me try to clarify based on the best evidence we have to data.

SECOND PRIMARIES VERSUS SECONDARY TUMORS VERSUS SECONDARY CANCERS

Most of the confusions arise from a slurring together of distinct concepts concerning tumors other than the original primary, the tumor of origin:

1. Synchronous versus metachronous tumors, a distinction that gives rise to second primaries, but NOT to other secondary TUMORS NOR secondary CANCERS.

2. Primary versus secondary tumors versus primary versus secondary cancers.

3. Outbound seeding: the seeding of metastatic tumors from dissemination of circulating/disseminating tumor cells, either by linear hematogenous or lymphatic spread, from the primary tumor.

4. Inbound (re-)seeding: the re-seeding of the primary tumor by circulating/disseminating tumor cells migrating from a metastatic site, back to the original primary, the cancer of origin.

5. Cross-metastatic seeding? (see below).

6. Cross-primary seeding? (see below).

Re synchronous versus metachronous tumors, it's been established that two or more primary tumors can coexist at the time of diagnosis (synchronous tumors), or develop consequently (metachronous tumors), sometimes years after resection of the first primary [1]. This gives rise to multiple primaries, but although these may even by separated in development by years in time span, the second or later tumors are NOT secondary tumors, only additional primary tumors. Thus, second primaries are NOT derived from outbound dissemination from the tumor of origin, and hence cannot be secondary tumors, all of which are gestated from the tumor of origin. And both synchronous versus metachronous share the cancer type of the tumor of origin: if the tumor of origin is a breast carcinoma, then both any synchronous versus metachronous tumors MUST be breast carcinomas.

Furthermore, a secondary tumor arises only from dissemination from the tumor of origin, so necessarily ALL metastatic tumors are definitionally secondary tumors either from hematogenous or lymphatic spread from the tumor of origin.

BUT a secondary TUMOR is NOT the same as a secondary CANCER: thus, it is documented that lung cancer, especially NSCLC (as well as ovarian cancer and certain lymphomas or leukemias such as MDS and AML), is a not uncommon secondary cancer associated with - BUT in no way deriving from - breast cancer. A secondary cancer - as opposed to a secondary tumor - is a completely NEW malignancy, and they are NOT metastatic nor in any oncopathological sense related at all to the cancer of origin, breast cancer.

Distinguishing whether a discovered tumor represents a de novo cancer (that is, a secondary cancer) versus a recurrence or metastasis of the first cancer of origin is of course critical for appropriate treatment and management, and we have many tools for such differentiation (for example, recurrent/metastatic disease is favored by short interval to second cancer formation, similar histology with increased anaplasia in the second (NOT SECONDARY) tumor and the absence of in situ malignancy and multifocal tumor deposits), and in complex cases, a panel of gene alterations can provide the necessary scope to define critical differences in genotypic profile) [2].

THE QUESTION OF BIDIRECTIONAL (VERTICAL) SEEDING

Now, as to the issue of seeding, the traditional perspective has always been that cancer progression is a sequential tumorigenic process: tumor cells at the primary sites acquire over time the capability to invade and intravasate into systemic circulation, these outbound circulating tumor cells (CTCs) serving as conduits for the migration to and colonization of distant organs that become metastatic sites. What's new and extraordinary is, first, that disseminated tumor cells (from the tumor of origin) are in fact present in the circulation in large proportions even at the very early stages of cancer, way before any metastatic growth at distant sites is detectable [3], and that even arguably untransformed mammary epithelial cells can actually become resident at distant organs like the lungs for protracted periods of time, with only subsequent induction of transformation then inducing metastatic growth [4].

But of course also new and extraordinary, is the demonstration through the brilliant self-seeding hypothesis developed by Larry Norton and Joan Massagué at MSK, that the flow of circulating tumor cells is NOT one-way / unidirectional, but rather bidirectional ("duplex flow") where circulating cancer cells reinfiltrate tumors at their organs of origin and promote the further growth of the primary tumors, as well as enhance angiogenesis and recruit stromal components, with the recipient primary tumors being preferentially seeded by highly metastatic derivatives from the tumor cell lines [5,6], but ultimately re-seeding the primary from the original outbound circulating populations that left the primary to establish metastatic colonies, , and an avalanche of ingenious evidence was confirmed that primary tumors can seed distant (metastatic) sites as well as reseed the primary tumor itself, with the facilitation by, in this theory, the "soil" (premetastatic niche).

Furthermore it is critical to note, that these “seeder” cells colonize only to pre-existing tumors, with gene expression analysis of these metastatic seeder populations identifying a profile characteristic of mammary metastatic cells (whether from the brain, bone, or lung). So we can have different classes of primary tumors based on "seeding behavior": some primary tumors are poor self-seeder but aggressive distant seeders (highly metastatic transformative) like pancreatic carcinomas while other primary tumors might be strong self-seeders but poor distant seeders and hence never metastasize, only increasing the size and aggressiveness of the primary tumor. And tumor heterogeneity (see my extensive treatment of this issue elsewhere on ResearchGate) provides for divergent clones within a primary tumor, each adapting independently to varying organ-specific environments [7], and each in turn with varying degrees of self- (re-invasion of the source tumor) and outbound seeding (metastatic migration) capacity.

THE QUESTION OF WHETHER THERE IS CROSS-SEEDING?

Now, with this understanding as a critical foundation, we can turn to the issues of what I have elsewhere called horizontal or lateral cross-seeding (neither strictly outbound nor inbound), which stems from the temptation, given that primaries seed metastases, and metastases re-seed primaries, to speculate that:

(1) metastases might be able to seed other metastases; and if this is possible, that

(2) one primary can seed another (synchronous) primary.

The answer it that although technically theoretically possible, this has never been observed in any context whatsoever (and we have sophisticated tracing and fingerprinting tools to track this), with no supporting in vitro, in vivo, let alone human clinical data, not even supporting mathematical modeling data. I have speculated elsewhere as to why this might be so, an incredibly complex issue, but to simplify, primary and secondary tumors have oncogenetic/ genomic and epigenetic "attratant" bonds between them - they are intimately related and bound together even if not biologically identical, and this is apparently absent between primaries which develop independently, and also absent between different metastases which do not cross-communicate across distinct organs or viscera (in a loose sense, a primary tumor has much to say to a secondary metastatic pulmonary or hepatic or brain tumor, and vice versa (via re-seeding), but a brain tumor appears to have nothing to say to a bone tumor, nor a bone tumor to any other metastatic tumor - remember for example that we have hundreds and thousands of patients with bone-only metastases). Whether new evidence will ever be uncovered to establish cross-seeding (primary-to-primary or secondary-to-secondary) therefore remains speculative and to date unevidenced. Thus, a metastatic lesion (by definition, a secondary tumor) in the brain is oncogenically derived from a breast primary, and tracking and fingerprinting does not support that it originated from, say, a bone secondary metastatic tumor.

THE QUESTION OF PRIMARY/SECONDARY TUMOR DISCORDANCE

The final critical issue is therefore not whether a brain (or other site) metastatic tumor has a non-primary tumor origin - it does not, it is a secondary seeding from outbound dissemination from the primary - but more importantly whether primary and secondary tumors can be biologically discordant, and we know that this does indeed happen: we can have an endocrine (hormone-) positive primary (ER+) and an ER-negative (non-endocrine) liver (or lung, or brain, etc.) metastasis, or vice versa. In other words primary and secondary tumors sometimes are receptor-discordant (different ER, PR or HER2 receptor status). This matters very much clinically: if we have been treating an ER-positive primary breast cancer tumor with, appropriately, endocrine therapy (tamoxifen or aromatase inhibitors, etc.), but metastases to say liver and lung occur yet second biopsy confirms that the metastases are ER-negative and may be also HER2-negative, then since endocrine therapy is wholly ineffective for ER-negative tumors (like triple negative breast cancer (TNBC) tumors, it would be catastrophic to the patient to continue with endocrine therapy for hormone-unresponsive metastases. Similarly, we would not want to continue treating with chemotherapy alone a patient who was original HER2-negative in primary disease but developed a HER2-positive lung metastasis, since we know that survival is compromised if anti-HER2 therapy is withheld.

Given this, what is critical to note here is that although genetic/genomic/miRNA fingerprinting and CTC tracking can indisputably establish that a secondary ER-negative metastatic tumor was gestated from an outbound disseminating ER-positive primary tumor, it does NOT follow, as this real-world example shows, that the two tumors (primary and secondary/metastatic) have to agree in tumor biology - they do not always (they are called receptor-discordant). Under complex circumstances of treatment, as well as genetic/genomic and epigenetic factors (not all fully understood), receptors can shift, and this appears to be an at least partial consequence of tumor heterogeneity: no tumor is constituted solely of one uniform cell type - within hormone-negative tumors there are some proportion of cells that are hormone-positive, some that are HER2-positive, some HER2-negative, etc., and that the relative proportions of these subpopulations can shift under therapy and other factors to effect a transformation in tumor biology.

So we are in fact, to sum up, less concerned with the origin of a secondary tumor, but rather more concerned with the clinically relevant issue of its tumor biology, regardless of whether this tumor biology agrees or disagrees with that of the primary tumor. For if they are discordant, then we must bend all efforts to change treatment to that dictated by the biology of the metastatic tumor, since the vast majority of patients die from metastatic disease, not from primary tumor growth. And we get a "bonus": as we target effectively the secondary metastatic tumor, we dramatically decrease its ability to re-seed the primary tumor, and that's a good thing, since a re-seeded primary tumor can continue to seed more metastases.

Clearly, therefore even further progress is needed, and will come only from deciphering, and ultimately designing tools to modulate and influence the flow of the ultra-complex multidirectional cross-talk between a primary tumor, circulating and disseminating tumor cells, secondary tumors, and metastatic niches.

REFERENCES

1. Tziris N, Dokmetzioglou J, Giannoulis K, et al. Synchronous and metachronous adenocarcinomas of the large intestine. Hippokratia 2008; 12(3):150-2.

2. Rolston R, Sasatomi E, Hunt J, Swalsky PA, Finkelstein SD. Distinguishing de novo second cancer formation from tumor recurrence: mutational fingerprinting by microdissection genotyping. J Mol Diagn 2001; 3(4):129-32.

3. Hüsemann Y, Geigl JB, Schubert F, et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008; 13(1):58-68.

4. Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 2008 Sep 26; 321(5897):1841-4.

5. Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell 2009 Dec 24; 139(7):1315-26.

6. Norton L, Massague J: Is cancer a disease of self-seeding? Nat. Med.12,875–878 (2006).

7. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883-892, 2012.