Does adjuvant therapy reduce postmetastatic survival?
Authors: M.K. Fink
Journal: Annals of Oncology (2019)

Adjuvant therapy can eradicate tumors in a stage of microdissemination which would be incurable after manifestation of overt metastases. The curative effect of this treatment, especially in breast and colorectal cancer, is undisputed. But it is also known that many of the adjuvantly pretreated tumors will relapse. Therefore, it is unavoidable that adjuvant therapy also involves selection: the sensitive tumors are cured and the relapsing tumors are resistant, at least in this phase of microdissemination, where mechanisms of resistance may be different from those in overt metastases. If we then treat these tumors after overt dissemination, we call that the 'first-line' treatment, although in reality this is 'second line' after adjuvant therapy. It is known that second-line therapy is less effective than first line [1.Palumbo R. Sottotetti F. Riccardi A. et al.Which patients with metastatic breast cancer benefit from subsequent lines of treatment? An update for clinicians.Ther Adv Med Oncol. 2013; 5: 334-350Crossref PubMed Scopus (28) Google Scholar]. Thus, we have two reasons why in adjuvantly pretreated patients a shorter postmetastatic survival must be expected. Ten years ago, this journal published a consensus statement that characterized adjuvant chemotherapy as an unfavorable prognostic factor for metastatic breast cancer [2.Beslija S. Bonneterre J. Burstein H.J. et al.Third consensus on medical treatment of metastatic breast cancer.Ann Oncol. 2009; 20: 1771-1785Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar]. In this statement, it was also mentioned that increased use of anthracyclines and taxanes as adjuvant and neoadjuvant treatment has restricted their use in patients with relapse. However, for studies in this field, typical methodical problems exist. Most of these publications are retrospective evaluations of adjuvant studies, sometimes including antihormonal or anti-HER2 treatment, with rate and time of relapse as end points. Thereafter, therapy is usually individualized to new and more effective drugs that may have been approved during a study and which may prolong postmetastatic survival. Furthermore, adjuvant therapy depends on the initial tumor stage, which also influences postmetastatic survival [3.Hassett M.J. Uno H. Cronin A.M. et al.Survival after recurrence of stage I-III breast, colorectal, or lung cancer.Cancer Epidemiol. 2017; 49: 186-194Crossref PubMed Scopus (9) Google Scholar]. Thus, a complete presentation and evaluation of all relevant data is almost impossible. In 1981, the Milan group described [4.Valagussa P. Tess J.D. Rossi A. et al.Adjuvant CMF effect on site of first recurrence, and appropriate follow-up intervals, in operable breast cancer with positive axillary nodes.Breast Cancer Res Treat. 1981; 1: 349-356Crossref PubMed Scopus (36) Google Scholar] that in breast cancer the sites of relapse after 6 or 12 cycles of CMF adjuvant increased in liver and CNS and decreased in bone. This was later confirmed, with a higher number of patients, by the Munich group [5.Hölzel D. Eckel R. Bauerfeind I. et al.Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry.J Cancer Res Clin Oncol. 2017; 143: 1701-1712Crossref PubMed Scopus (26) Google Scholar]. An analysis of the results after adjuvant CMF and postrelapse treatment with anthracyclines was published by Bonneterre et al. [6.Bonneterre J. Mercier M. Response to chemotherapy after relapse in patients with or without previous adjuvant chemotherapy for breast cancer. The French Epirubicin Study Group.Cancer Treat Rev. 1993; 19: 21-30Abstract Full Text PDF PubMed Scopus (27) Google Scholar]. In 477 relapsing patients, risk was not balanced, with higher initial lymph node involvement in the group with (87%) than without (34%) adjuvant CMF, which was considered among other factors in a multivariate analysis. Overall response rate after relapse was 31.2% in patients with adjuvant treatment and 48% in those without (P = 0.03), time to treatment failure was 182 versus 268 days (P = 0.007), and survival after relapse 410 versus 560 days (P = 0.008). Overall survival after initial diagnosis was not significantly different. The largest study so far was published by Pierga et al. [7.Pierga J.Y. Asselain B. Jouve M. et al.Effect of adjuvant chemotherapy on outcome in patients with metastatic breast carcinoma treated with first-line doxorubicin-containing chemotherapy.Cancer. 2001; 91: 1079-1089Crossref PubMed Scopus (46) Google Scholar] who analyzed data on 1430 patients with metastasized breast cancer. This included studies of first-line therapy with anthracyclines after overt metastases between 1977 and 1992. Adjuvant therapy had been given to 446 patients based on assessment of their risk for recurrence. One hundred and sixty-five patients received 5-FU, doxorubicin and cyclophosphamide (FAC), 92 CMF, 98 cyclophosphamide, melphalan and methotrexate, and 64 other combination without anthracyclines; 27 had chemotherapy of an unspecified type. Mean disease-free interval was almost identical: 42 months in the adjuvant versus 43 months in the non-adjuvant group. The frequency of bone, liver and CNS metastases were not significantly different. In the multivariate analysis, prior adjuvant chemotherapy was associated with a lower response rate (56% versus 66%; P < 0.0001), a lower median survival after recurrence (19 versus 26 months; P < 0.0001) and a lower overall survival from initial diagnosis (61 versus 70 months). In this study, adjuvant anthracycline-based chemotherapy had no greater adverse effect on postmetastatic survival than CMF. However, in the study of Alba et al. [8.Alba E. Ribelles N. Sevilla I. et al.Adjuvant anthracycline therapy as a prognostic factor in metastatic breast cancer.Breast Cancer Res Treat. 2001; 66: 33-39Crossref PubMed Scopus (20) Google Scholar] adjuvant anthracycline-containing therapies resulted in a significantly poorer outcome in metastatic disease than anthracycline-free schedules. Hölzel et al. of the Munich Cancer Registry published in 2017 [5.Hölzel D. Eckel R. Bauerfeind I. et al.Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry.J Cancer Res Clin Oncol. 2017; 143: 1701-1712Crossref PubMed Scopus (26) Google Scholar] data on 60227 breast cancer patients diagnosed between 1978 and 2013. This registry has fairly complete pathological and clinical data including time and site of metastases, but no details about systemic treatment. The time from 1978 to 2013 was divided into four periods, which were separately analyzed. During these periods, 5-year relative survival increased from 80.3% to 93.6%, with an adjusted hazard ratio of 0.54 (P < 0.0001). Adjuvant therapies changed the pattern of metastases: the percentage of liver and CNS metastases more than doubled, the rate of lung metastases remained stable, and the rate of bone metastases decreased by half. Metastasis-free survival was prolonged with a hazard ratio of 0.75 (P < 0.0001), but postmetastatic survival declined, with a hazard ratio of 1.36 (P < 0.0001). Several groups described a particularly attenuated effect of palliative treatment after adjuvant therapy with taxanes. Miller et al. [9.Miller K. Wang M. Gralow J. et al.Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2708) Google Scholar] found with paclitaxel monotherapy in the first line after dissemination a progression-free survival of 6.5 months without previous adjuvant treatment (n = 237), after a taxane-free adjuvant treatment of a surprising 7.7 months (n = 328) and after a taxane-containing adjuvant treatment of only 3.0 months' duration (n = 108). Progression-free survival increased in all groups when paclitaxel was combined with bevacizumab, in the latter group from 3.0 to 12 months; however, this did not translate in a longer postmetastatic survival for the whole bevacizumab group. We published data in 2013 from a cancer research registry (Projektgruppe Internistische Onkologie) with real life data [10.Kleeberg U.R. Fink M. Tessen H.-W. et al.Adjuvant therapy reduces the benefit of palliative treatment in disseminated breast cancer – own findings and review of the literature.Onkologie. 2013; 36: 348-356Crossref PubMed Scopus (10) Google Scholar]. Relative postmetastatic survival of breast cancer patients after adjuvant therapy with taxanes was about one-third shorter than after adjuvant therapy without taxanes (P = 0.000025). This analysis was univariate and any influence of other factors cannot be excluded. But our findings are identical with those of Seidman et al. [11.Seidman A.D. Chan S. Wang J. et al.A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer.Oncologist. 2014; 19: 443-452Crossref PubMed Scopus (11) Google Scholar], who compared two different docetaxel-containing regimens in patients with disseminated breast cancer. The inclusion of adjuvant taxanes in the final analysis was not planned from the beginning; therefore, this treatment was not completely documented. In the multivariate analysis, not including initial tumor stage, patients without this documentation were considered to have received no prior adjuvant taxane. The hazard ratio for postmetastatic survival without adjuvant taxanes was 0.686 (P < 0.001) compared with patients who received this treatment. Complete documentation of the adjuvant taxane therapy would have increased this difference. Another approach for calculating the effect of adjuvant therapy on survival after dissemination is a comparison of outcomes in metastatic breast cancer after relapse versus de novo metastatic presentation, because survival in the latter group is not influenced by adjuvant treatment. In a recent paper Malmgren et al. [12.Malmgren J.A. Mayer M. Atwood M.K. et al.Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990–2010.Breast Cancer Res Treat. 2018; 167: 579-590Crossref PubMed Scopus (72) Google Scholar] found, for de novo metastasized breast cancer patients, in three cohorts from 1990 to 2010, an increase of the 5-year disease-specific survival from 28% to a surprising 55% (P = 0.008), while in the same time this measure dropped from 23% to 13% (P = 0.065) for patients with metastatic disease after relapse. A 78% of the latter group was pretreated with adjuvant chemotherapy. Brain metastases at initial diagnosis were more common in relapsed (8%) than in de novo metastasized patients (1%) (no P value given). The advent of effective targeted therapy for hormone receptor-positive disease, HER2 positive-disease and taxane therapy in the adjuvant/neoadjuvant setting coincided with improved de novo metastasized survival and a decline in incidence of relapse. In a similar study of den Brok et al. [13.den Brok W.D. Speers C.H. Gondara L. et al.Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed.Breast Cancer Res Treat. 2017; 161: 549-556Crossref PubMed Scopus (113) Google Scholar], more than 60% of patients with relapsed breast cancer had received some form of systemic adjuvant therapy. Overall survival of de novo metastasized patients was higher than for relapsed patients (29 versus 17 months, P < 0.0001) and each subgroup had a gain of survival which was 11 months for HR+/HER2− (P < 0.0001), 14 months for HER2+ (P < 0.0001), and 3 months for triple negative cancer (P = 0.02). In the study of Hölzel et al. [14.Hölzel D. Eckel R. Bauerfeind I. et al.Survival of de novo stage IV breast cancer patients over three decades.J Cancer Res Clin Oncol. 2017; 143: 509-519Crossref PubMed Scopus (23) Google Scholar], 4756 patients had distant metastases at diagnosis. In four periods from 1978–2013, the 5-year survival rate improved from 17.4% to 24.7%, while the pattern of metastases did not change. Karagiannis et al. [15.Karagiannis G.S. Pastoriza J.M. Wang Y. et al.Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism.Sci Transl Med. 2017; 9Crossref PubMed Scopus (275) Google Scholar] reported that neoadjuvant chemotherapy induces breast cancer metastasis through a 'tumor microenvironment of metastasis' (TMEM)-mediated mechanism. Chemotherapy increases the density and activity of TMEM sites and promotes distant metastasis. Once again, taxanes and angiogenesis seem to play a special role within these mechanisms, which is reminiscent of the above-mentioned results of Miller et al. [9.Miller K. Wang M. Gralow J. et al.Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2708) Google Scholar]. From the clinical point of view, adjuvant and neoadjuvant chemotherapy have in breast cancer almost identical results with only an increased local relapse rate after 15 years of 21.4% for neoadjuvant versus 15.9% for adjuvant chemotherapy (P = 0.0001), and this difference may be an effect of local treatment rather than of tumor biology [16.Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.Lancet Oncol. 2018; 19: 27-39Abstract Full Text Full Text PDF PubMed Scopus (529) Google Scholar]. Therefore, it looks possible that many of the mechanisms explored by Karagiannis for neoadjuvant therapy are also relevant for adjuvant treatment. Hormone receptors at diagnosis and after relapse were examined by Lindström et al. [17.Lindström L.S. Karlsson E. Wilking U.M. et al.Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression.JCO. 2012; 30: 2601-2608Crossref PubMed Scopus (349) Google Scholar]. The estrogen receptor was positive in 47.1% (n = 216) both in the primary and metastasis. Depending on the type of adjuvant therapy, tumors with initially positive estrogen receptors became receptor negative after chemo-hormonal therapy in 34.3%, after hormonal therapy in 29% and without adjuvant therapy in 11.5%. Initial nondemonstrable estrogen receptors turned positive in these groups in 4.0%, 4.3% and 12.6% of metastases. Women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio 1.48; 95% CI 1.08–2.05) compared with women with stable ER-positive tumors. An effect of adjuvant tamoxifen on subsequent hormone therapy in metastatic breast cancer was also confirmed in a recent paper by Mehta et al. [18.Mehta R.S. Barlow W.E. Albain K.S. et al.Overall survival with fulvestrant plus anastrozole in metastatic breast cancer.N Engl J Med. 2019; 380: 1226-1234Crossref PubMed Scopus (60) Google Scholar]. In this study, patients were treated in the first line after relapse with anastrozole alone versus anastrozole plus fulvestrant. Overall survival among women who had not received adjuvant tamoxifen was longer with the combination therapy versus anastrozole alone (median 52.2 versus 40.3 months; HR 0.73; 95% CI 0.58–0.92). Among women who had received tamoxifen previously, overall survival was similar in the two groups (median 48.2 versus 43.5 months; HR 0.97; 95% CI 0.74–1.27). Thus, the adjuvant estrogen antagonist tamoxifen reduced the effect of the palliative therapy with the estrogen antagonist fulvestrant. Trastuzumab is established in the adjuvant therapy of HER2 positive breast cancer, but the rate of brain metastases increases after adjuvant treatment with this antibody [19.Perez E.A. Romond E.H. Suman V.J. et al.Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31.JCO. 2011; 29: 3366-3373Crossref PubMed Scopus (593) Google Scholar]. Furthermore, patients relapsing after adjuvant therapy with trastuzumab had a significantly poorer outcome after retreatment with this antibody than trastuzumab-naïve controls [20.Rier H.N. Levin M.D. van Rosmalen J. et al.First-line palliative HER2-targeted therapy in HER2-positive metastatic breast cancer is less effective after previous adjuvant trastuzumab-based therapy.Oncologist. 2017; 22: 901-909Crossref PubMed Scopus (16) Google Scholar]. In colon cancer, Moertel et al. [21.Moertel C.G. Fleming T.R. Macdonald J.S. et al.Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report.Ann Intern Med. 1995; 122: 321-326Crossref PubMed Scopus (863) Google Scholar] described, after adjuvant 5-FU and levamisole, a postmetastatic survival of 11 months compared with 15 months in controls without adjuvant therapy. In his 2008 analysis of the ACCENT dataset, O'Connell et al. [22.O'Connell M.J. Campbell M.E. Goldberg R.M. et al.Survival following recurrence in stage II and III colon cancer: findings from the ACCENT data set.J Clin Oncol. 2008; 26: 2336-2341Crossref PubMed Scopus (160) Google Scholar] found a longer survival following recurrence in patients initially treated with surgery alone versus with 5-FU-based adjuvant therapy (P = 0.0005) and with initial stage II versus III disease (P < 0.0001). All relationships were maintained in multivariate models. Thus, as in breast cancer, no adjuvant therapy and lower initial tumor stage were independent predictors of longer postmetastatic survival. For studying the effect of adjuvant oxaliplatin in colorectal cancer patients, Andreou et al. [23.Andreou A. Kopetz S. Maru D.M. et al.Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases.Ann Surg. 2012; 256: 642-650Crossref PubMed Scopus (57) Google Scholar] identified 341 patients who underwent hepatectomy for metachronous liver metastases after a disease-free interval ≥12 months. Adjuvant treatment of primary colorectal cancer was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. A node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P< 0.0001). Mass-spectroscopy genotyping for somatic gene mutations in liver metastases was carried out in a subset of 129 patients. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011). When comparing adjuvant treatment with leucovorin/5-FU with or without oxaliplatin in colon cancer, the NSABP C-07 [24.Yothers G.A. O'Connell M.J. Colangelo L. et al.Fluorouracil and leucovorin with or without oxaliplatin for adjuvant treatment of stage II and III colon cancer long-term follow-up of NSABP C-07 with survival analysis.American Society for Clinical Oncology Gastrointestinal Cancers Symposium; Orlando FL USA. 2010; Google Scholar] and MOSAIC trial [25.André T. Boni C. Navarro M. et al.Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.J Clin Oncol. 2009; 27: 3109-3116Crossref PubMed Scopus (1714) Google Scholar] suggested that adjuvant oxaliplatin reduces post-relapse survival, e.g. from 24 to 21 months [25.André T. Boni C. Navarro M. et al.Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.J Clin Oncol. 2009; 27: 3109-3116Crossref PubMed Scopus (1714) Google Scholar]. However, in a pooled analysis of four similar studies, Schmoll et al. [26.Schmoll H.J. Twelves C. Sun W. et al.Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials.Lancet Oncol. 2014; 15: 1481-1492Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar] were not able to reproduce this assumption. But they mentioned that differences in post-relapse therapy could not be excluded, and a more frequent use of bevacizumab and EGFR-inhibitors in the oxaliplatin groups seems possible. Thus, in colon cancer, a reduction of postmetastatic survival after adjuvant oxaliplatin is also probable. Cytostatic pretreatment is also harmful before radiotherapy. Klement et al. reported that previous chemotherapy reduced the effect of stereotactic irradiation of lung [27.Klement R.J. Allgäuer M. Andratschke N. et al.Bayesian cure rate modeling of local tumor control: evaluation in stereotactic body radiation therapy for pulmonary metastases.Int J Radiat Oncol Biol Phys. 2016; 94: 841-849Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] and liver metastases [28.Klement R.J. Guckenberger M. Alheid H. et al.Stereotactic body radiotherapy for oligo-metastatic liver disease—influence of pre-treatment chemotherapy and histology on local tumor control.Radiother Oncol. 2017; 123: 227-233Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] from different primaries. A summary of these findings is given in Table 1.Table 1Adjuvant therapies change characteristics of metastases and postmetastatic courseTumorType of adjuvant therapyEffect on metastasesEffect on therapy after disseminationBreast cancerChemotherapy (general)Percentage of metastases higher in liver and CNS, but lower in bone [4.Valagussa P. Tess J.D. Rossi A. et al.Adjuvant CMF effect on site of first recurrence, and appropriate follow-up intervals, in operable breast cancer with positive axillary nodes.Breast Cancer Res Treat. 1981; 1: 349-356Crossref PubMed Scopus (36) Google Scholar, 5.Hölzel D. Eckel R. Bauerfeind I. et al.Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry.J Cancer Res Clin Oncol. 2017; 143: 1701-1712Crossref PubMed Scopus (26) Google Scholar]Reduced response rateReduced time to treatment failureReduced postmetastatic survivalBreast cancerChemotherapy including taxanesFurther shortened postmetastatic survivalBreast cancerHormonal therapyLoss of estrogen receptor in ∼30%Shorter postmetastatic survivalBreast cancerImmunotherapy with trastuzumabHigher rate of cerebral metastasesReduced effect of trastuzumabColon cancer5FU-based chemotherapyShorter postmetastatic survivalColon cancerChemotherapy including oxaliplatinMore mutations in liver metastasesFurther shortened disease free and overall survival [23.Andreou A. Kopetz S. Maru D.M. et al.Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases.Ann Surg. 2012; 256: 642-650Crossref PubMed Scopus (57) Google Scholar, 24.Yothers G.A. O'Connell M.J. Colangelo L. et al.Fluorouracil and leucovorin with or without oxaliplatin for adjuvant treatment of stage II and III colon cancer long-term follow-up of NSABP C-07 with survival analysis.American Society for Clinical Oncology Gastrointestinal Cancers Symposium; Orlando FL USA. 2010; Google Scholar, 25.André T. Boni C. Navarro M. et al.Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.J Clin Oncol. 2009; 27: 3109-3116Crossref PubMed Scopus (1714) Google Scholar]Different primariesPrevious chemotherapy (not specific adjuvant)Reduced effect of stereotactic radiotherapyIf statements are controvers among the cited authors, the supporting references are given in brackets. Open table in a new tab If statements are controvers among the cited authors, the supporting references are given in brackets. The data given in this article must not be misunderstood as a critique of adjuvant therapy. It has been shown that the gain in years of life due to adjuvant treatment of breast cancer is ∼20× greater than the loss of survival in the subgroup of patients who develop metastases [29.Fink M.K. Kleeberg U.R. Bartels S. Adjuvant therapy reduces rate of dissemination but shortens survival thereafter.Oncologist. 2015; 20: e23.Crossref PubMed Scopus (2) Google Scholar]. But there are several reasons why we should further study this effect: it reduces survival in a subgroup of patients, it is underreported in the literature, and it is difficult to search in public data bases because an adequate search term is lacking. Consequently, we suggest the acronym ATRESS for 'Adjuvant Therapy-RElated Shortening of Survival', which particularly includes survival after overt metastases [30.Fink M.K. Kleeberg U.R. Bartels S. Adjuvant therapy-related shortening of survival (ATRESS): an underrated phenomenon.Oncologist. 2015; 20: 88.Crossref PubMed Scopus (11) Google Scholar]. This effect arises in a pivotal situation of malignant growth: adjuvant therapy has already demonstrated that cancer cells are vulnerable in this phase. Now we should try to understand how cancer cells become resistant and grow despite adjuvant treatment. Studies of postmetastatic survival as well as examinations of surgical specimens after neoadjuvant therapy [15.Karagiannis G.S. Pastoriza J.M. Wang Y. et al.Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism.Sci Transl Med. 2017; 9Crossref PubMed Scopus (275) Google Scholar] are a good approach for this learning process and could eventually help us to circumvent these resistance mechanisms and to increase cure rate. I thank Prof. Hölzel, Munich, Dr Klement, Schweinfurt, and Inge Durre, Asheville, for helpful discussions. None declared.