Is 4-step kidney cancer curable
Breast cancer: cancer registry reveals metastatic process
Data from the Munich Tumor Register confirm the tremendous success of adjuvant therapies in the last few decades, the resulting differential eradication of the metastases and the apparently paradoxical shorter survival after metastasis.
Early detection and adjuvant therapies (AT) have increasingly improved survival rates for breast cancer (MK) over the past 40 years. Data from the Munich Tumor Register (1; 17) show improvements for 4 periods since 1978 for tumors with a diameter of 10–20 mm (pT1c) and 20–50 mm (pT2) (Figure 1A).
While around 30% of pT1c and pT2 patients died after 15 years in the mid-1980s, less than 10% of pT1c and pT2 less than 30% of patients will die from tumor-related causes with current treatment. These results within the pT categories were mainly achieved through adjuvant therapies (2).
In addition, there is the early detection effect, the shift to smaller tumors: If breast cancer is detected not at pT2 but at pT1c in a patient cohort, the 15-year mortality falls by more than 20% in absolute terms. However, the survival of all patients only increases by 2% if 10% is detected with pT1c instead of pT2. This underlines the magnitude of the effect of the adjuvant therapies.
On the other hand, it is still not possible to cure patients with distant metastases (MET). At least for HER2-positive breast cancer, the prolongation of survival from metastasis of more than 5 months (3), which has been confirmed in studies, was achieved for all patients. It therefore seems strange or even inexplicable that survival from metastasis after the primary M0 finding has even decreased over time (Figure 1B).
The shortening is only apparently a contradiction! Because this effect of the adjuvant therapy specifies the multi-stage, largely unknown metastasis process in some points, as will be explained below.
Initiation and colonization
With every millimeter, a growing breast cancer initiates almost 1.4% metastases that lead to tumor-related death within 15 years. This linear relationship applies to about 5–50 mm (M.15 years= −5.9 + 1.4 * dDiameter (mm)) and is slightly cheaper with today's adjuvant therapy. The first metastases are likely to be initiated by a breast cancer about 1 mm in size (Figure 2a, b), which happens very rarely.
The cause of the metastasis - the haematogenic or lymphogenic spread of tumor cells (4) or tumor cell clusters of breast cancer (5, 6) - continues even after the first successful initiation until the R0 resection.
Metastasis is a sequential process by which further foci can be initiated in the same and in other organs (7, 8). If tens of thousands of tumor cells are scattered daily (9), only a few can be successful in this complex, multi-step process (“Poisson process”).
Although initiation can be attributed to a diameter, there are many hypotheses as to how and when metastasis growth, colonization, and the successful formation of secondary foci occur. Niche formation, Dormancy phases with a long delay or immediate growth of successful tumor cells are discussed alternatives.
It is not plausible that metastases can form metastases again themselves - and that that would even be frequent (10). The distribution of multifocal metastases in different segments of the lungs and liver, the successful local control after R0-MET resections (11) and the time it takes for metastases to grow until they are detected speak against this.
Growth time of metastases
Data from tumor registries with long-term follow-up offer two approaches to the growth duration of metastases.
- First, the growth of the primary tumor provides a reference. A pT1c-MK (14 mm) needs 3 doubles in volume and then reaches the size of a pT2-MK or 28 mm after about 14 months (12). That means: up to a size of 14 mm, around 30% of metastases are initiated according to Figure 1A (in the 1980s). If the R0 resection only takes place at 28 mm, a further 22% metastases are initiated.
Should this growth period also apply from a tumor size of 3.5 mm, a distant metastasis initiated by this would grow for about 3.5 years parallel to the primary tumor up to a diameter of 28 mm. Note the variability in breast cancer growth, which ranges between 1.6 and 7.6 years for the 25% and 75% percentiles of MK growth (12).
There is already a pT2-M1 finding in about 4.5%. This means that these METs were usually initiated early and, in parallel with breast cancer, have grown to the detection limit. Because the primary tumor and metastases grow in parallel for a long time, metastases initiated early are molecularly very different from breast cancer in contrast to metastases initiated shortly before the R0 resection with more common mutations (13).
- The second access is the MET-free time. Figure 1C shows the distribution of MET-free times for the patient cohorts from 1978 to 1987 and 1988 to 1997 with more than 20 years of follow-up. That is, about 20-10% of distant metastases grow at least 10-15 years before they are diagnosed. Dormancy of tumor cells and cell clusters could be a cause for this long duration in individual cases (14, 15).
However, this is not clinically relevant, because adjuvant therapy has been shortened to 4–6 months over decades - without any disadvantage for patients (16). This can only be the case if no METs are initiated after 4–6 months; This means that the Dormancy is also limited in time and essentially takes place before the primary therapy.
On the other hand, breast cancers with a short metastasis-free interval of only 1.5 years are more frequently LK-positive, HR-negative, grading 3 or pT3 / 4 tumors. That means: These metastases were initiated early and grew parallel to the breast cancer. In addition, the 5-year survival from metastasis is only 10 months compared to 40 months after a metastasis-free interval of> 11 years (17).
Combining the two times results in a median growth time of the distant metastases of 7 years until detection. It is important to note the great variability of cancer cell growth (e.g. of the triple-negative or luminal A subtype), which is transferred to the distant metastases and for whose growth a relativity principle is based: How fast a breast cancer grows, its initiated distant metastases grow about twice as fast.
For comparison: Molecular biology estimates the survival time from the onset of metastasis - for example, for pancreatic cancer at 2.7 years and for colon cancer at 5 years (18, 19).
Effect of systemic therapies
With neoadjuvant therapies, complete remission is achieved in almost 40% of larger breast cancers (20). However, distant metastases of primarily advanced breast cancer are no longer curable. This also applies to metastases that are just below the detection threshold. Because in studies there is usually no difference in metastasis-free survival in the first few months. Only then do survival curves open like scissors in favor of improved therapy (2).
Since the shortening of the adjuvant therapy was not disadvantageous, new metastases are very rarely initiated after the R0 resection and the end of the adjuvant therapy.
If, in pT1c / pT2-MK, the 15-year mortality of the 1980s (30/52%) is taken as the basis for the initiated metastasis (Figure 1A), with today's adjuvant therapy, mortality in both groups is reduced by 20% in absolute terms. reduced. This means that the systemic disease (21) that existed at the time of diagnosis can now be cured in 20% of cases by adjuvant therapy.
As a rule, therefore, several metastases are already present in one and different organs when the breast cancer is diagnosed, even if they are only detectable after 10 or more years. These foci have grown for different lengths of time: a few days and are only small tumor cell clusters or several years and are almost detectable (Figure 2c). Adjuvant therapies are partially successful on these foci of different sizes and ages. This success story of adjuvant therapy only becomes apparent with historical data and long-term follow-up.
It should be emphasized that adjuvant therapies have a cytotoxic effect when metastases are eradicated, and not just cytostatically by stopping the cell cycle during adjuvant therapy. In addition, there are partial effects of adjuvant therapies in which only part of the metastases is eradicated.
MET patterns and MET-free times
The metastasis process is often compared to a decathlon because of the many steps a successful tumor cell has to complete (6, 22, 23). Many details are unknown, for example why tumor cells can initiate metastases in which organ. The organotropy is not related to the volume of blood (8) with which tumor cells are transported to each organ. Although there are indications of metastasis-specific driver genes, these have not yet been therapy targets (24).
The obvious thing to do is to analyze the well-documented course of the disease: Have successful adjuvant therapies changed the metastatic pattern? The reference for answering the question is primarily metastatic breast cancer.
There is no evidence that the biology of breast cancer has changed in recent decades. Therefore there are no significant changes in the distribution of metastases in primary M1, not even through more sensitive diagnostics, with which 40% more M1 findings have been discovered in recent years despite mammography screening. Even the division into unilocular and multilocular findings has not changed significantly (25).
However, even more recent systemic therapies in the metastatic stage have not brought any cures. Survival has been extended to a relevant extent in small subgroups, but not for all primary metastatic breast cancers. This underlines the importance of the knowledge that adjuvant therapies can successfully eradicate organ metastases.
The obvious question then is whether adjuvant therapies have a differential effect, i.e. whether organ metastases are eradicated differently or remain resistant or become resistant with adjuvant therapy. The answer to the question is yes; adjuvant therapies have a differential effect. In the 1980s, the metastatic pattern of the primary metastasis and the metastasis that occurred later were still comparable.
Today the patterns in the course of the disease are different: 50% fewer skeletal and 30% fewer lung metastases and no relevant changes in liver and brain metastases. Metastases that appear after a short metastasis-free period grow faster and can be assigned to larger breast cancers. That means: They are usually initiated by a small primary tumor and have grown parallel to the tumor over the years.
Metastases that appear late are prognostically favorable breast carcinomas, grow slowly and are more likely to have been initiated shortly before the R0 resection. The earlier it is initiated, the greater the genetic distance between the metastases and the initiating breast cancer.
A different effectiveness of the adjuvant therapy on early or late metastasis cannot be seen (Figure 1C-D) and means that foci of all sizes are eradicated in skeletal or lung metastases - up to the limit of effectiveness, perhaps to the angiogenic stage of development ("angiogenic switch") ) (23). Because angiogenesis inhibitors show no relevant effect, this is the unknown point in time from which eradication is no longer possible, as is the case with primary M1.
It follows from this that the resistant metastases also show no dependence on the age of the metastases. They are not particularly aggressive, they are initiated early or late by small or large tumors and grow slowly or quickly.
If the sequential initiation of metastases is taken into account, there is no evidence that only unilocular metastases in the skeleton and / or lungs can be eradicated. The efficacy is also likely to relate to multiple herds that are staggered and initiated by evolutionarily developing breast cancers.
The reason or target for the differential effectiveness of adjuvant therapies is unknown and a challenge for clinical research.
Paradoxical but plausible effect
The trend in population-based data is clear: long-term survival is significantly improved through eradication of prevalent metastases, the metastasis-free interval is lengthened, and survival from metastasis in primarily non-advanced breast cancer has become shorter - despite relevant advances such as with HER2-positive breast cancer with metastases (3) .
The data also provide a simple explanation of both the metastasis process and the effect of the adjuvant therapy. In parallel to the growth of breast cancer, metastases are initiated in one or more organs over time (Figure 2a – c).
When MK is diagnosed, all metastases are prevalent and, depending on the time of initiation, of different sizes or of different ages (Figure 2c).
Adjuvant therapies eradicate all metastases in some of the patients (Figure 2d), and long-term survival is improved.
In other patients, only some of the metastases are eradicated, preferably skeletal and lung metastases. Since these metastases often occur at the beginning of the metastasis, their eradication extends the MET-free time until later metastases (e.g. liver and CNS metastases).
Survival after metastasis is shorter due to the elimination of early metastases (Figure 2e). This is a plausible explanation, especially since the data do not give any indications of increasing aggressiveness of the remaining metastases.
Generation of hypotheses
Perhaps because the effect is so plausible, questions arise:
1. The evolutionary development of primary tumors to greater heterogeneity through nonsynonymous mutations has been proven many times (13, 26). Does this heterogeneity, which is given to the metastases in the course, also have a meaning for eradicability? Does intrinsic resistance increase with heterogeneity? In the diagnosis of prevalent, large metastases that are usually initiated early, there should be more differences compared to the primary tumor than small metastases that are initiated late in an evolutionarily advanced breast cancer (Figure 2c). The early-initiated metastases and breast cancers have long evolved in parallel and independently of one another.
2. If resistances are acquired during therapy, an effective adjuvant therapy would also have no effect on small and late-onset metastases. In the case of large metastases, remissions except for a few resistant tumor cells and a restart would result in an extension of the MET-free time. The distribution of the MET-free times would change with effective adjuvant therapies, both in the case of resistance induction and acquired heterogeneity effects.
3. Also the hypothesis that metastases themselves are subject to an evolutionary change and that they acquire progression competence parallel to the primary tumor (27) should eradicate small prevalent metastases more frequently and make metastases less frequent after a long metastasis-free time. Such a differential effectiveness with regard to certain organ metastases has not yet been identified. In addition, acquired resistances due to the ineffectiveness of adjuvant therapy for metastases in the liver and CNS are called into question. The shortened survival after metastasis cannot be explained by an induced resistance of particularly aggressive metastases (28).
The effects of adjuvant therapy in various organs, the dependence on the microenvironment (29), the connection with increasing heterogeneity and resistance mechanisms are too little known to determine the necessary patient numbers and meticulous observations. On the other hand, the partially successful eradication of metastases raises the question of why long-term endocrine therapies of 5 years and more are of benefit.
Has a new principle of action for long-term therapies been discovered with the trial-and-error principle? So far there is no explanation because the results are not compatible with either chronification due to cell cycle blockade or eradication.
Overall, it can be stated that due to the large number of molecular biological findings, many hypotheses proliferate. The simple facts about the metastasis process outlined here are the eye of a needle in reality through which hypotheses and effects should fit. Basic research is required for this.
- Current studies provide the modern therapy standards.The usually small progress and the short follow-up can hide impressive long-term results that a cancer registry with data from 4 decades and long follow-up can show.
- The topic presented is an example of the method of comparing cohorts over time, age and various therapeutic strategies on a multivariate basis (“comparative effectiveness research”) (30).
- Questions can also be derived from the results and impulses for preclinical and translational research can be given.
- It shows how important it is to closely network clinical cancer registries with basic oncological research and the results of patient care. Unfortunately, some of the clinical cancer registries are being set up with a distance to the universities (SGB V § 65 c).
- Insights that directly benefit patient care can only arise through continuous scientific exchange. ▄
DOI: 10.3238 / PersOnko / 2017.12.01.05
Prof. Dr. rer. biol. hum. Dieter Hölzel,
Dr. rer. biol. hum. Gabriele Schubert-Fritschle,
Prof. Dr. med. Jutta Engel, M.P.H.
Munich Tumor Register (TRM) of the Munich Tumor Center (TZM) at the Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Ludwig Maximilians University (LMU), Munich
Conflict of interest: The authors declare that there is no conflict of interest.
Literature on the Internet:
breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-92 CrossRefMEDLINE
trial of the AGO and GBG study groups. J Clin Oncol 2011; 29: 3351-7 CrossRefMEDLINE
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