Καρκίνος μαστού Ο πιο συχνά εμφανιζόμενος καρκίνος στις γυναίκες διεθνώς. Οι πρόσφατες διαγνωστικές και θεραπευτικές προσεγγίσεις επιτρέπουν την περισσότερο εξατομικευμένη αντιμετώπιση, οδηγώντας έτσι στην μείωση της θνητότητας Ο πρώιμος καρκίνος του μαστού είναι μια χρόνια νόσος που χαρακτηρίζεται από ετερογένεια Ο κίνδυνος υποτροπής είναι διαρκής –ακόμα και 20 χρόνια μετά την διάγνωση μπορεί να εμφανιστεί υποτροπή, ειδικά σε ορμονοευαίσθητες ασθενείς Breast cancer is the most frequently diagnosed cancer in Canadian women, accounting for about 30% of all new cancer cases each year.1 Although there have been substantial improvements in the management of early disease, the risk of breast cancer recurrence lingers beyond the initial 2 years following diagnosis and treatment. Breast cancer is considered to have one of the most heterogeneous natural histories of all human cancers. The disease can have a short onset and a fatal outcome within months, or initially it can be appropriately diagnosed and treated, but reappear as metastatic disease more than two decades later. References: 1. Public Health Agency of Canada. http://www.phac-aspc.gc.ca/publicat/updates/breast-99_e.html. Accessed July 27, 2006. 2. Smigal C, Jemal A, Ward E, et al. Trends in Breast Cancer by Race and Ethnicity: Update 2006. CA Cancer J Clin 2006;56:168-183. 3. Fisher et al. In: Cancer Medicine. 4th ed, Williams & Wilkins,1997:2349. 4. Hellman and Harris. In: Diseases of the Breast. 2nd ed, Lippincott Williams & Wilkins, 2000:407. 5. Weiss RB, Woolf SH, Demakos E, et al. Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B. J Clin Oncol. 2003;21:1825-1835. Smigal C. et al. CA Cancer J Clin 2006; 56:168. Fisher et al. In: Cancer Medicine. 4th ed, Williams & Wilkins,1997:2349. Hellman and Harris. In: Diseases of the Breast. 2nd ed, Lippincott Williams & Wilkins, 2000:407. Weiss et al. J Clin Oncol. 2003;21:1825.

Κίνδυνος υποτροπής

Το 50% των υποτροπών εμφανίζονται εντός των πρώτων 5 ετών από το χειρουργείο Recurrences Breast Cancer Deaths 15% 17% 9% 18% 100 100 91.4 85.2 80 68.2 80 87.8 73.0 73.7 60 60 64.0 % of patients 54.9 % of patients 40 40 Tamoxifen Control Tamoxifen Control 20 20 5 10 15 5 10 15 Years Years Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2005;365:1687. 1. Adapted from Oxford overview 2000 meta-analysis. 2. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2005;365:1687.

Recurrence hazard rate Ο κίνδυνος υποτροπής από καρκίνο μαστού είναι πολύ σημαντικός τα πρώτα 5 χρόνια μετά την διάγνωση και κυρίως τα έτη 1-3 0.3 0.2 N=3585 Recurrence hazard rate 0.1 1 2 3 4 5 6 7 8 9 10 11 12 Years Αυξημένος αριθμός υποτροπών τα πρώτα 3 έτη για όλες τις ασθενείς Saphner et al. J Clin Oncol. 1996;14:2738.

Annual recurrence rate (%) Όλοι οι ασθενείς (Ν+ & Ν-) αντιμετωπίζουν αυξημένο κίνδυνο πρώιμης υποτροπής (τα πρώτα 2-3 χρόνια μετά το χειρουργείο) Early Breast Cancer Trialists’ Collaborative Group 1998 meta-analysis control data1, graphed to show prominent early peak of recurrences2 Node-positive Node-negative 16 12 Annual recurrence rate (%) 8 4 Analysis of annual hazard rates (HR) of breast cancer recurrence combining hormone receptor positive and negative disease reveals a continuous risk that peaks 1-3 years post surgery. Although early recurrences are most commonly seen in hormone receptor negative disease, the hazard rate of recurrence is consistently higher with increasing involvement of lymph nodes in hormone receptor positive disease as well. This increased risk extends out to at least 10 years or more following initial diagnosis. Other predictors for early risk of recurrence are overexpression of HER-2/neu, low expression of estrogen receptor, involvement of lymph nodes, and high tumor grade. 2 4 6 8 10 Years 1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451. 2. Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582.

Τύποι υποτροπών

Απομακρυσμένες υποτροπές Οι απομακρυσμένες μεταστάσεις αντιπροσωπεύουν την πλειονότητα των συνολικών υποτροπών Υποτροπές υπό επικουρική θεραπεία με ταμοξιφαίνη (data from ATAC and BIG 1-98 trials) Ετερόπλευρος μαστός (9%-11%) τοποπεριοχικές (16%-28%) Απομακρυσμένες υποτροπές (61%-75%) BIG = Breast International Group. Baum et al. Lancet. 2002;359:2131. Thürlimann et al. N Engl J Med. 2005;363:2747.

Οι απομακρυσμένες μεταστάσεις είναι υπεύθυνες για την έξαρση των υποτροπών στα 2-3 πρώτα χρόνια Overall Distant Locoregional Contralateral 0.05 0.04 Annual Recurrence 0.03 0.02 0.01 Dr. Mansell and co-workers tried to identify factors that predict early recurrence in postmenopausal women with early stage breast cancer. Data from 5589 consecutive postmenopausal patients from 5 UK centres, diagnosed with operable breast cancer between 1995 and 2004, were examined. 85% of the patients received adjuvant hormonal therapy. ER- patients were excluded As seen in the figure, when the annual risk of recurrence was plotted against the time from diagnosis, the pattern of recurrence of breast cancer shows a peak hazard early on. Increasing age, tumour size, grade, nodal status, lymphovascular invasion, unknown ER status and symptomatic presentation were independently significant predictors of early recurrence on multivariate analysis (p<0.01) in this large cohort. Increasing age (odds ratio (OR) 1.027, 95% CI 1.009-1.045, p=0.003), tumour size (OR 1.016, 95% CI 1.005-1.026, p=0.003) and unknown ER status (OR 1.57, 95% CI 1.04-2.37, p=0.03) were the only variables that discriminated between early and later recurrence. the BIG 1-98 Collaborative and the International Breast Cancer Study Group presented their evaluation of predictors of early recurrence in the BIG 1-98 trial at EBCC 5 and showed node positivity to be a predictor of early recurrence as did a study by McArthur et al at SABCS 2005. Together, these data suggest that some patients are particularly susceptible to early recurrence and may benefit from upfront AI therapy. The authors conclude that all patients with grade 3 node-positive cancers plus older patients and patients with larger cancers should be considered for upfront AI therapy. Of all the aromatase inhibitors, letrozole is unique in that it has shown the best efficacy in these patients at increased risk of recurrence. A significant improvement in disease-free survival was demonstrated in the BIG 1-98 trial, and a survival advantage was seen in patients with node-positive disease in the MA.17 trial. It is also evident from the figure that the risk of distant metastases is consistently much higher than the risks of locoregional or contralateral breast cancer throughout the 5 years and is particularly high early on between years two and three. Thus, therapies that reduce the risk of distant metastases may have significant impact on patient outcomes because distant recurrences are an extremely important end point; the development of distant metastases directly translates into decreased survival. The ATAC trial demonstrated that the use of anastrozole reduced the rate of recurrence within this time period compared with the use of tamoxifen. However, the ATAC data do not show that initial adjuvant anastrozole treatment prevents the risk of early distant metastases. A study by Mauriac et al, evaluating the “Predictors of early relapse in postmenopausal women with hormone receptor positive breast cancer,” shows that letrozole is very active at preventing distant recurrences early on. At 2 years, there were 27% fewer distant recurrences with letrozole than with tamoxifen. Distant metastases are a well recognized predictor of death. This greater reduction seen with letrozole, compared with the 7% reduction seen with anastrozole, may suggest that letrozole is the more appropriate aromatase inhibitor to give upfront. 1 2 3 4 5 Years From Diagnosis Mansell J et al. Presented at: SABCS 2006, San Antonio, Tex. Abstract 2091.

Απομακρυσμένες μεταστάσεις: επίδραση στην συνολική επιβίωση

Οι απομακρυσμένες μεταστάσεις συνδέονται με μεγαλύτερο κίνδυνο θανάτου Όλες οι υποτροπές από καρκίνο μαστού συνδέονται με αυξημένο κίνδυνο θανάτου1 Αλλά… Ο κίνδυνος θανάτου αυξάνεται σημαντικά με την εμφάνιση απομακρυσμένων μεταστάσεων συγκρινόμενος με τις τοποπεριοχικές και τις υποτροπές στον ετερόπλευρο μαστό1 1. Lamerato et al. J Clin Oncol. 2005;23(16S):62s. Abstract 738. 2. Lawrence et al. Breast Cancer Res Treat. 2005;94(suppl 1):S211. Abstract 5019.

Οι απομακρυσμένες μεταστάσεις συνδέονται με μεγαλύτερο κίνδυνο θανάτου 2 4 6 8 10 12 14 16 P<0.001 Relative risk of death (HR)* P<0.001 P=0.01 However, a retrospective cohort study among a mid-western health system population with early-stage breast cancer (n=1616, median follow-up 44.5 months) associated distant recurrences with the highest risk of death (HR 13.6, p<0.001 vs. patients without recurrences). Loco-regional and contralateral recurrences were associated with a lower, but still significant risk of death (HR 4.5, p<0.001 and HR 3.0, p=0.01, respectively). Contra- lateral Loco- regional Distant * Hazard ratio (and P value) relative to patients with no recurrence. Lamerato et al. J Clin Oncol. 2005;23(16S):62s. Abstract 738.

Συνολικό ποσοστό θανάτου από τοπική και απομακρυσμένη υποτροπή 100% 5-year survival 76% 80% 10-year survival 56% 60% Overall survival probability (%) 40% 22% 20% Breast cancer recurrence, regardless of recurrence type, is associated with increased mortality in women with early disease, but the effect on mortality is heightened in those with distant recurrence. Isolated local recurrence as the first tumor event (n = 105) was associated with a moderately good prognosis and better than that seen with distant metastasis as the first event (n = 355). Ten-year survival in women with local recurrence was 56% (95% confidence interval [CI], 45%-65), compared with 9% (95% CI, 7%-13%) in those with distant recurrence; median survival was 12.9 ± 5.4 years and 2.2 ± 0.3 years, respectively. Reference Lê MG, Arriagada R, Spielmann M, Guinebretiére J-M & Rochard F. Prognostic factors for death after an isolated local recurrence in patients with early-stage breast carcinoma. Cancer 2002; 94: 2813-2820. 9% 0% Local recurrence* Distant recurrence* * As a first event Lê MG, et al. Cancer 2002; 94: 2813.

Thürlimann B et al. N Engl J Med. 2005;353:2747-2757 BIG 1-98: Πρώτη Κύρια Ανάλυση (Διάμεσος Χρόνος Παρακολούθησης 26 Μήνες) Thürlimann B et al. N Engl J Med. 2005;353:2747-2757

BIG 1-98: Πρώτη Κύρια Ανάλυση- Σχεδιασμός R A N D O M I Z E A TAM n = 2459 B LET n = 2463 8010 patients C TAM LET n = 1548 D LET TAM n = 1540 This slides depicts the BIG 1-98 primary core analysis trial design. The BIG 1-98 protocol-specified primary core analysis compared the two arms that received LET upfront with the two groups assigned to receive TAM initially: TAM: arms A and C LET: arms B and D Events and follow-up in the sequential arms that occurred up to 30 days after treatment switch were combined with events and follow-up in the monotherapy arms and events after the switch in arms C and D were excluded. The primary end point was DFS. Thürlimann B et al. N Engl J Med. 2005;353:2747-2757. 2 5 Years Η Πρώτη Κύρια Ανάλυση συγκρίνει την μονοθεραπεία με Λετροζόλη έναντι της μονοθεραπείας με Ταμοξιφαίνη TAM: Σκέλη A και C LET: Σκέλη B και D Εξαιρούνται οι υποτροπές μετά την αλλαγή της θεραπείας στα σκέλη C και D Κύριο Καταληκτικό Σημείο:DFS Thürlimann B et al. N Engl J Med. 2005;353:2747-2757.

Το Femara αυξάνει σημαντικά την επιβίωση χωρίς νόσο Thurlimann B. et al. N Engl J Med. 2005;353:2747-2757

Το Femara προσφέρει στις ασθενείς μείωση των απομακρυσμένων μεταστάσεων από νωρίς Thurlimann B. et al. N Engl J Med. 2005;353:2747-2757

Mauriac L et al. Ann Oncol. 2007;18:859-867. Επίδραση Λετροζόλης στον Συνολικό Κίνδυνο Πρώιμων Υποτροπών και Πρώιμων Απομακρυσμένων Μεταστάσεων (πρώτα 2 έτη μετά το χειρουργείο) Mauriac L et al. Ann Oncol. 2007;18:859-867.

Η Λετροζόλη Μείωσε τις Συνολικές Πρώιμες Υποτροπές και τις Πρώιμες Απομακρυσμένες Μεταστάσεις Κατά 30 % BIG 1-98 No. of events at 2 years -30% Distant recurrences Recurrences 168 117 125 87 Η λετροζόλη μείωσε σε μεγαλύτερο βαθμό τις πρώιμες απομακρυσμένες μεταστάσεις έναντι της ταμοξιφαίνης Επίπτωση απομακρυσμένων μεταστάσεων στα 2 πρώτα έτη: TAM: 3.3% LET: 2.2% The BIG 1-98 Predictor of Early Recurrence analysis by Mauriac et al showed that LET is superior to TAM in effectively reducing early recurrence risk in the first 2 years after surgery. In the Mauriac retrospective analysis, initial adjuvant LET therapy reduced overall early recurrences by 30% and early DM by 30% in the first 2 years after surgery. The incidence of early DM at 2 years between the treatment arms was as follows: 3.3% in the TAM arm 2.2% in the LET arm 125 early DM events occurred in the TAM arm (n = 3844) at 2 years, so 31 DM events occurred every 6 months in the TAM arm in the BIG 1-98 trial in the first 2 years. In comparison, in the ATAC trial, 143 DM events occurred in the TAM arm at 2.5 years, which is about 29 DM events per 6 months. Also, recall that initial adjuvant LET therapy has also demonstrated the greatest significant reduction of early DM in the upfront setting in the HR+ patient population. (In ATAC at 68 months of follow-up, there was only a 16% significant reduction in DM, while in BIG 1-98 at 25.8 months’ median follow-up, a 27% significant reduction in DM was demonstrated.) Mauriac L et al. Ann Oncol. 2007;18:859-867. Houghton J et al. Ann Oncol. 2006;17(suppl 9):ix94. Abstract 243PD. Mauriac L et al. Ann Oncol. 2007;18:859-867. Rugo H et al. Eur J Cancer Suppl.. 2008;6:118. Abstract 236

“Late Breaking News” στο SABCS το Δεκέμβριο του 2008* Το Femara προσφέρει στις ασθενείς μείωση των απομακρυσμένων μεταστάσεων και σε μεγαλύτερο διάμεσο χρόνο παρακολούθησης* “Late Breaking News” στο SABCS το Δεκέμβριο του 2008* *SABCS, Daily newsletter, December 11, 2008 , Mouridsen H.for the BIG1-98 Collaborative Group coordinated by the IBCSG. Oral presentation at SABCS December 11, 2008. Διαφάνειες της παρουσίασης μπορούν να αναζητηθούν στο www.sabcs.org

Η ανάλυση των σκελών μονοθεραπείας με μεγαλύτερο διάμεσο χρόνο παρακολούθησης παρέχει ισχυρές ενδείξεις για βελτίωση της επιβίωσης των ασθενών* *SABCS, Daily newsletter, December 11, 2008 , Mouridsen H.for the BIG1-98 Collaborative Group coordinated by the IBCSG. Oral presentation at SABCS December 11, 2008. Διαφάνειες της παρουσίασης μπορούν να αναζητηθούν στο www.sabcs.org

«Κρατήστε τις απομακρυσμένες μεταστάσεις… Η χορήγηση Femara ως αρχική επικουρική θεραπεία προσφέρει στις ασθενείς μεγαλύτερη πιθανότητα να ζήσουν περισσότερο και χωρίς καρκίνο* Για τις μετεμμηνοπαυσιακές γυναίκες με ορμονοεξαρτώμενο καρκίνο μαστού «Κρατήστε τις απομακρυσμένες μεταστάσεις… έξω από την εικόνα» SABCS, Daily newsletter, December 11, 2008 , Mouridsen H.for the BIG1-98 Collaborative Group coordinated by the IBCSG. Oral presentation at SABCS December 11, 2008. Διαφάνειες της παρουσίασης μπορούν να αναζητηθούν στο www.sabcs.org