Key words
therapy algorithms - evidence-based treatment - breast cancer guidelines
Schlüsselwörter
Behandlungsalgorithmen - evidenzbasierte Therapie - Brustkrebs-Leitlinien
Introduction
The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological
Oncology Group, AGO) provides annual recommendations on prevention, diagnosis and
treatment of early and metastatic breast cancer [1], [2]. The Committee is a multidisciplinary team of national experts.
Since 2020, this group also publishes algorithms to better illustrate the overall
therapeutic concept. These algorithms are based on the current AGO recommendations,
but obviously cannot represent all evidence-based treatment options, since prior therapies,
performance status, comorbidities, patient preference, etc. must be considered for
the actual treatment choice. The recommendations are evidence-based but also reflect
expert opinion, reflected by different grades of recommendation ([Table 1]). In individual cases, other evidence-based treatment options (not listed here)
may also be appropriate and justified. In some situations, e.g. positive Phase III
data or U. S. Food and Drug Administration (FDA) approval, the algorithms also take
into account drugs that are not approved in Germany at the time the algorithm was
last updated. The general structure of the formatting is illustrated in [Fig. 1].
Table 1 Grades of recommendation.
|
++
|
This investigation or therapeutic intervention is highly beneficial for patients,
can be recommended without restrictions and should be performed.
|
|
+
|
This investigation or therapeutic intervention is of limited benefit for patients
and can be performed.
|
|
+/−
|
This investigation or therapeutic intervention has not shown benefit for patients
and may be performed only in individual cases. According to current knowledge a general
recommendation cannot be given.
|
|
–
|
This investigation or therapeutic intervention can be of disadvantage for patients
and might not be performed.
|
|
− −
|
This investigation or therapeutic intervention is of clear disadvantage for patients
and should be avoided or omitted in any case.
|
Fig. 1 Format legend for the AGO agorithms.
Algorithm (Neo)adjuvant Therapy of HER2-positive Breast Cancer ([Fig. 2])
Algorithm (Neo)adjuvant Therapy of HER2-positive Breast Cancer ([Fig. 2])
Fig. 2 Algorithm (Neo)adjuvant Therapy of HER2-positive Breast Cancer. 1 Gianni L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in
women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere):
a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25 – 32.
2 Tolaney SM et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab
Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast
Cancer. J Clin Oncol 2019; 37: 1868 – 1875. 3 Perez EA et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth
factor receptor 2-positive breast cancer: planned joint analysis of overall survival
from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014; 32: 3744 – 3752. 4 Cameron D et al., Herceptin Adjuvant (HERA) Trial Study Team. 11 yearsʼ follow-up
of trastuzumab after adjuvant chemotherapy in HER2-positive
early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.
Lancet 2017; 389: 1195 – 1205. 5 Martin M et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive
breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled,
phase 3 trial. Lancet Oncol 2017; 18: 1688 – 1700. 6 von Minckwitz G et al., APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab
and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377: 122 – 131.
7 Piccart M et al. Interim overall survival analysis of APHINITY (BIG 4 – 11): A randomized
multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab
plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy
in patients with operable HER2-positive early breast cancer. SABCS 2019; Abstr. GS01-04.
8 Gianni L et al. Neoadjuvant and adjuvant trastuzumab in
patients with HER2-positive locally advanced breast cancer (NOAH): follow-up
of a randomised controlled superiority trial with a parallel HER2-negative cohort.
Lancet Oncol 2014; 15: 640. 9 von Minckwitz G et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive
Breast Cancer. N Engl J Med 2019; 380: 617 – 628. 10 Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J,
Kirk S, Cortés J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA
cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant
anthracycline-containing and anthracycline-free chemotherapy regimens in patients
with HER2-positive early breast cancer. Eur J Cancer 2018; 89: 27 – 35.
Patients with HER2-positive cT1 cN0 breast cancer should undergo upfront surgery in
order to confirm the low-risk situation (pT1 pN0), histologically. In this case, systemic
treatment can be deescalated to 12 × paclitaxel qw and trastuzumab monotherapy completed
for one year. In case of pT2 pN0 a taxane based polychemotherapy plus trastuzumab
monotherapy is recommended which might be followed in case of a HR+ tumor by neratinib
monotherapy for up to 1 year. For patients with confirmed positive lymph nodes (pN+)
HER2 targeted therapy should be escalated to trastuzumab and pertuzumab for up to
one year.
Patients with HER2-positive breast cancer ≥ 2 cm and/or clinically positive lymph
nodes should be treated with a taxane based polychemotherapy and dual antibody blockade
in the neoadjuvant setting. Based on therapy response (pCR/non pCR) different postneoadjuvant
therapy options should be offered after surgery. In initially node positive patients
(cN+) with pCR trastuzumab and pertuzumab should be completed for one year. In patients
with a pCR and low risk of recurrence (cN0) a deescalation to trastuzumab monotherapy
is recommended. Patients with non pCR should be treated with 14 cycles T-DM1 q3w as
postneoadjuvant therapy.
Algorithm Adjuvant Endocrine Therapy in Premenopausal Patients ([Fig. 3])
Algorithm Adjuvant Endocrine Therapy in Premenopausal Patients ([Fig. 3])
Fig. 3 Algorithm Adjuvant Endocrine Therapy in Premenopausal Patients. 1 Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Relevance of breast
cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen:
patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771 – 784. 2 Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen
to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive
breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805 – 806. 3 Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following tamoxifen
as extended adjuvant therapy in receptor-positive breast cancer: updated findings
from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97: 1262 – 1271. 4 Francis PA, Regan MM, Fleming GF et al. The SOFT Investigators and the International
Breast Cancer Study Group. Adjuvant Ovarian
Suppression in Premenopausal Breast Cancer. N Engl J Med 2015; 372: 436 – 446.
5 Pagani O, Regan MM, Walley BA et al. TEXT and SOFT Investigators; International Breast
Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal
breast cancer. N Engl J Med 2014; 371: 107 – 118.
Although recruitment was more than 10 years ago SOFT and TEXT trials are the main
evidence for the treatment recommendations for premenopausal patients. However, it
must be noticed that therapy practice and indication for chemotherapy have changed
since the recruitment and generalization of data for the current patient population
might be limited. Therefore, the recommendations and the algorithms were simplified.
Patients with a low risk of recurrence may receive just tamoxifen, patients with a
higher risk of recurrence should be treated with ovarian function suppression (OFS)
in addition to tamoxifen, and patients with a higher risk of recurrence can be considered
for an aromatase inhibitor and OFS (for 5 years). Patients do not need to be treated
with chemotherapy prior to receiving an OFS. In the above-mentioned trials, chemotherapy
can be considered as a surrogate marker for high-risk. In case a patient has a high
risk of recurrence and does not for whatever reason
receive (neo)adjuvant chemotherapy, the use of an AI an OFS is still indicated.
In general, in HR+/HER2− breast cancer, age is an independent risk factor. Patients
being amenorrheic after chemotherapy can start with Tamoxifen. OFS can be added later
when the menstruation/premenopausal status has been regained. An AI should only be
added when the ovarian function is sufficiently and reliably suppressed. Tamoxifen
can be extended for up to 10 years. An extended adjuvant therapy with 5 years of tamoxifen
should also be offered to those patients with ovarian suppression and tamoxifen or
AI for their initial treatment. If the patient is confirmed as being postmenopausal
within the first 5 years, endocrine therapy can be continued after 5 years of tamoxifen
with 2.5 – 5 years or letrozole.
Algorithm Adjuvant Endocrine Therapy in Postmenopausal Patients ([Fig. 4])
Algorithm Adjuvant Endocrine Therapy in Postmenopausal Patients ([Fig. 4])
Fig. 4 Algorithm Adjuvant Endocrine Therapy in Postmenopausal Patients. 1 Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Relevance of breast
cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen:
patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771 – 784. 2 Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen
to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive
breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805 – 806. 3 Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG): Aromatase inhibitors
versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised
trials. Lancet 2015; 386: 1341 – 1352. 4 Gray R (EBCTCG) et al. Extended aromatase inhibitor treatment following 5 or more
years of endocrine therapy: a metaanalysis of 22 192 women in 11 randomised
trials. SABCS 2018; GS3-03.
In postmenopausal women there has been an extensive discussion about the use of tamoxifen
in comparison with an AI or sequential use of tamoxifen and an AI. Two metaanalyses
have been published during the last years and both suggest that AIs should be preferred
to tamoxifen. In the Early Breast Cancer Trialistsʼ Collaborative Group meta-analysis,
either upfront AI or sequential treatment with tamoxifen followed by an AI or vice
versa was superior regarding mortality in postmenopausal patients. In summary, depending
on the individual risk profile an AI should be part of the endocrine treatment in
the first 5 years for at least 2 – 3 years. In patients with low risk of recurrence,
tamoxifen therapy upfront is still an option. After 5 years of tamoxifen, extended
therapy with 5 years of tamoxifen is an option in patients with higher risk of recurrence
– but switching to an AI for 2 – 5 years should be preferred. If patients received
an AI (upfront or switch), patients at
higher risk should be offered 2 – 5 additional years of AI. It is important to
take into consideration the risk benefit and the tolerability of the endocrine therapy.
Treatment can be adapted to individual needs. This is preferred to stopping prematurely.
Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Strategies ([Fig. 5])
Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Strategies ([Fig. 5])
Fig. 5 Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Strategies. 1 Qi WX, Tang LN, He AN et al. Comparison between doublet agents versus single agent
in metastatic breast cancer patients previously treated with an anthracycline and
a taxane: A meta-analysis of four phase III trials. Breast 2013; 22: 314 – 319. 2 Belfiglio M, Fanizza C, Tinari N et al., Consorzio Interuniversitario Nazionale per
la Bio-Oncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or
in combination with chemotherapy in metastatic breast cancer. J Cancer Res Clin Oncol
2012; 138: 221 – 229. 3 Pallis AG, Boukovinas I, Ardavanis A et al. A multicenter randomized phase III trial
of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline-
and taxane-pretreated women with metastatic breast cancer. Ann Oncol 2012; 23: 1164 – 1169.
4 Dear RF, McGeechan K, Jenkins MC et al. Combination versus
sequential single agent chemotherapy for metastatic breast cancer. Cochrane
Database Syst Rev 2013; (12): CD008792. doi:10.1002/14651858.CD008792.pub2. 5 Petrelli F, Ghidini A, Pedersini R et al. Comparative efficacy of palbociclib, ribociclib
and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of
randomized controlled trials. Breast Cancer Res Treat 2019; 174: 597 – 604. doi:810.1007/s10549-019-05133-y.
PMID: 30659432. 6 Rossi V, Berchialla P, Giannarelli D et al. Should All Patients With HR-Positive
HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based
Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA
7, MONARCH 3, FALCON, SWOG and FACT Trials. Cancers (Basel) 2019; 11; pii: E1661.
doi:10.3390/cancers11111661. 7 Robson M et
al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.
N Engl J Med 2017; 377: 523 – 533. 8 Robson ME, Tung N, Conte P et al. OlympiAD final overall survival and tolerability
results: Olaparib versus chemotherapy treatment of physicianʼs choice in patients
with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol
2019; 30: 558 – 566. doi:10.1093/annonc/mdz012. PMID: 30689707. 9 Robson M, Ruddy KJ, Im SA et al. Patient-reported outcomes in patients with a germline
BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus
chemotherapy in the OlympiAD trial. Eur J Cancer 2019; 120: 20 – 30. doi:10.1016/j.ejca.2019.06.023. PMID: 31446213. 10 Litton J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline
BRCA Mutation. N Engl
J Med 2018; 379: 753 – 763. doi:10.1056/NEJMoa180290510. 11 Turner NC, Telli ML, Rugo HS et al., ABRAZO Study Group. A Phase II Study of Talazoparib
after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast
Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res 2019; 25: 2717 – 2724.
doi:10.1158/1078-0432.CCR-18-1891. PMID: 30563931. 12 Ettl J, Quek RGW, Lee KH et al. Quality of life with talazoparib versus physicianʼs
choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2
mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol 2018;
29: 1939 – 1947. doi:10.1093/annonc/mdy257. PMID: 30124753. 13 Hurvitz SA, Gonçalves A, Rugo HS et al. Talazoparib in Patients with a Germline
BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase
III EMBRACA Trial. Oncologist 2020; 25: e439 – e450. doi:10.1634/theoncologist.2019-0493. PMID: 31767793. 14 Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines
for Advanced Breast Cancer (ABC4). Ann Oncol 2018; 29: 1634 – 1657. 15 Kornblum NS et al. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant
plus everolimus or placebo in postmenopausal women with hormone receptor (HR)-positive,
HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI)
therapy. SABCS 2016; #S1-02. 16 André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P,
Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS,
Mills D, Wilke C, Hirawat S, Juric D, SOLAR-1 Study Group. Alpelisib for
PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380:
1929 – 1940.
Recent evidence from previous years has resulted in additional therapeutic options
for treating the advanced or metastasic hormone receptor (HR-)positive and HER2-negative
breast cancer. In order to reach the therapeutic goal of maintaining as high a quality
of life as possible, today the endocrine-based therapy is considered to be the standard
of care first-line treatment. Thus, CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib)
are administered in first line together with an aromatase inhibitor or fulvestrant.
Only if a very rapid remission is required due to severe symptoms or impending organ
failure, cytostatic drugs, if necessary combined with bevacicumab, should be used
as first-line therapy. Second-line therapy options depend on the aggressiveness of
progressive disease and the patientʼs wish for therapy. In case of a germline mutation
(gBRCA1/2mt), therapy with PARP inhibitors should be offered. In addition, depending
on endocrine sensitivity and resistance
further endocrine mono or combination therapies are available. Besides the combination
with everolimus, in case of a somatic PIK3CA mutation the use of alpelisib is a valuable
therapeutic option. In case of endocrine resistance cytostatic drugs should be offered
as further-line therapy.
Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Endocrine-based First
Line Treatment ([Fig. 6])
Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Endocrine-based First
Line Treatment ([Fig. 6])
Fig. 6 Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Endocrine-based First
Line Treatment. 1 Turner N et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer.
N Engl J Med 2015; 373: 209 – 219. 2 Loibl S et al. Palbociclib Combined with Fulvestrant in Premenopausal Women with
Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results.
Oncologist 2017; 22: 1028 – 1038. 3 Layman RM et al. Comparative effectiveness of palbociclib plus letrozole vs. letrozole
for metastatic breast cancer in US-real world clinical practises. ESMO 2019; #329P.
4 Tripathy D et al. First-line ribociclib vs. placebo with goserelin and tamoxifen
or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive,
HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7
trial. SABCS2017; GS-26. 5 Im SA, Lu YS, Bardia A et
al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.
N Engl J Med 2019; 381: 307 – 316. doi:10.1056/NEJMoa1903765. PMID:31166679. 6 Sledge GW jr., Toi M, Neven P et al. The Effect of Abemaciclib Plus Fulvestrant on
Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed
on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2019. doi:10.1001/jamaoncol.2019.4782 [Epub ahead of print]. PMID:31 563 959. 7 Klijn JG, Blamey RW, Boccardo F et al. Combined tamoxifen and luteinizing hormone-releasing
hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast
cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343 – 353.
8 Rugo HS et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast
Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 2016;
34: 3069 – 3103. 9 Forward DP, Cheung KL, Jackson L et al. Clinical and endocrine data for goserelin
plus anastrozole as second-line endocrine therapy for premenopausal advanced breast
cancer. Br J Cancer 2004; 90: 590 – 594. 10 Park IH, Ro J, Lee KS et al. Phase II parallel group study showing comparable efficacy
between premenopausal metastatic breast cancer patients treated with letrozole plus
goserelin and postmenopausal patients treated with letrozole alone as first-line hormone
therapy. J Clin Oncol 2010; 28: 2705 – 2711. 11 Carlson RW et al. Phase II trial of anastrozole plus goserelin in the treatment of
hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women.
J Clin Oncol 2010; 28: 3917 – 3921. 12 Bartsch R, Bago-Horvath Z et al. Ovarian function suppression and fulvestrant as
endocrine therapy in premenopausal
women with metastatic breast cancer. Eur J Cancer 2012; 48: 1932 – 1938. 13 Taylor CW, Green S, Dalton WS et al. Multicenter randomized clinical trial of goserelin
versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic
breast cancer: an intergroup study. J Clin Oncol 1998; 16: 994 – 999. 14 Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339:
1609 – 1618. 15 Crump M, Sawka CA, DeBoer G et al. An individual patient-based meta-analysis of tamoxifen
versus ovarian ablation as first line endocrine therapy for premenopausal women with
metastatic breast cancer. Breast Cancer Res Treat 1997; 44: 201 – 210. 16 Finn RS et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med
2016; 375: 1925 – 1936. 17 Finn RS et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination
with letrozole versus letrozole alone as first-line treatment of
oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18):
a randomised phase 2 study. Lancet Oncol 2015; 16: 25 – 35. 18 Im SA, Mukai H, Park IH et al. Palbociclib Plus Letrozole as First-Line Therapy in
Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III,
Randomized PALOMA-2 Study. J Glob Oncol 2019; 5: 1 – 19. doi:10.1200/JGO.18.00173. PMID: 31125276. 19 Rugo HS, Finn RS, Diéras V et al. Palbociclib plus letrozole as first-line therapy
in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced
breast cancer with extended follow-up. Breast Cancer Res Treat 2019; 174: 719 – 729.
doi:10.1007/s10549-018-05125-4. PMID: 30632023. 20 Hortobagyi GN et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast
Cancer. N Engl J
Med 2016; 375: 1738 – 1748. 21 Yardley DA, Hart L, Favret A et al. Efficacy and Safety of Ribociclib With Letrozole
in US Patients Enrolled in the MONALEESA-2 Study. Clin Breast Cancer 2019; 19: 268 – 277.e1.
doi:10.1016/j.clbc.2019.02.007. 22 Goetz MP et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.
J Clin Oncol 2017; 35: 3638 – 3646. 23 Johnston S, Martin M, Di Leo A et al. MONARCH 3 final PFS: a randomized study of
abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019;
5: 5. doi:10.1038/s41523-018-0097-z. PMID: 30675515. 24 Bonneterre J et al. Anastrozole versus Tamoxifen as First-Line Therapy for Advanced
Breast Cancer in 668 Postmenopausal Women: Results of the Tamoxifen or Arimidex Randomized
Group Efficacy and tolerability Study. J Clin Oncol
2000; 18: 3748 – 3757. 25 Thürlimann B et al. Anastrozole (Arimidex) versus tamoxifen as first-line therapy
in postmenopausal women with advanced breast cancer: results of the double-blind cross-over
SAKK trial 21/95 – a substudy of the TARGET (Tamoxifen or Arimidex Randomized Group
Efficacy and Tolerability) trial. Breast Cancer Res Treat 2004; 85: 247 – 254. 26 Bonneterre J et al. Anastrozole is superior to tamoxifen as first-line therapy in
hormone receptor positive advanced breast carcinoma Cancer 2001; 92: 2247 – 2258.
27 Mouridsen H et al. Phase III study of letrozole versus tamoxifen as first-line therapy
of advanced breast cancer in postmenopausal women: analysis of survival and update
of efficacy from the International Letrozole Breast Cancer Group Journal of Clinical
Oncology. J Clin Oncol 2003; 21: 2101 – 2109. 28 Paridaens R et al., European Organization for the Research and Treatment of Cancer
(EORTC) –
Investigational Drug Branch for Breast Cancer (IDBBC). Mature results of a randomized
phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy
for postmenopausal women with metastatic breast cancer. Ann Oncol 2003; 14: 1391 – 1398.
29 Gibson L, Lawrence D, Dawson C et al. Aromatase inhibitors for treatment of advanced
breast cancer in postmenopausal women. Cochrane Database Syst Rev 2009; (4): CD003370.
30 Fulvestrant 500 mg plus Palbociclib (vs. Fulvestrant alone). 31 Turner NC, Ro J, André F et al., PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive
Advanced Breast Cancer. N Engl J Med 2015; 373: 209 – 219. 32 Turner NC et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast
Cancer. N Engl J Med 2018; 379: 1926 – 1936. doi:10.1056/NEJMoa1810527. 33 Slamon DJ, Neven P, Chia S et al. Phase III
Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive,
Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.
J Clin Oncol 2018; 36: 2465 – 2472. doi:10.1200/JCO.2018.78.9909. PMID: 29860922. 34 Slamon DJ, Neven P, Chia S et al. Overall Survival with Ribociclib plus Fulvestrant
in Advanced Breast Cancer. N Engl J Med 2020; 382: 514 – 524. doi:10.1056/NEJMoa1911149. 35 Sledge GW jr. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women
With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine
Therapy. J Clin Oncol 2017; 35: 2875 – 2884. 36 Sledge GW jr., Toi M, Neven P et al. The Effect of Abemaciclib Plus Fulvestrant on
Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed
on Endocrine
Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020; 6: 116 – 124.
doi:10.1001/jamaoncol.2019.4782. PMID: 31563959. 37 Ellis MJ et al. Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment
of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study.
J Clin Oncol 2015; 33: 3781 – 3787. 38 Robertson JF et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive
advanced breast cancer (FALCON): an international, randomised, double-blind, phase
3 trial. Lancet 2016; 388: 2997 – 3005. 39 Di Leo A et al. Final overall survival: fulvestrant 500 mg vs. 250 mg in the randomized
CONFIRM trial. J Natl Cancer Inst 2014; 106: djt337.
Data from PALOMA-, MONALEESA- and MONARCH-studies showed significant and clinically
relevant improvements of progression-free survival in pre-, peri- and postmenopause
if CDK4/6 inhibitors had been used. Currently, data referring to overall survival
are only available for individual drug combinations in defined situations. If CDK4/6
inhibitors are not administered, the initial treatment strategy in premenopausal patients
is to shutdown the ovarian function (e.g. with GnRH analogues) combined with tamoxifen.
In case of tumor progression or if tamoxifen is contraindicated, a third-generation
aromatase inhibitor plus a GnRH analogue can be administered. Fulvestrant plus GnRH
analogue is a further option. In postmenopausal patients depending on the previous
adjuvant therapy, aromatase inhibitors or tamoxifen can be administered. After a previous
therapy with an aromatase inhibitor fulvestrant should be considered.
Algorithm HER2-positive Metastatic Breast Cancer: 1st–3rd line ([Fig. 7])
Algorithm HER2-positive Metastatic Breast Cancer: 1st–3rd line ([Fig. 7])
Fig. 7 Algorithm HER2-positive Metastatic Breast Cancer: 1st–3rd-line. 1 Swain SM, Baselga J, Kim SB et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab,
and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724 – 734.
2 Perez EA, López-Vega JM, Petit T et al. Safety and efficacy of vinorelbine in combination
with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive
locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast
Cancer Res 2016; 18: 126. 3 Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced
breast cancer. N Engl J Med 2012; 367: 1783 – 1791. 4 Krop IE, Lin NU, Blackwell K et al. Trastuzumab emtansine (T-DM1) versus lapatinib
plus capecitabine in patients with HER2-positive metastatic breast cancer and central
nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann
Oncol 2015; 26: 113 – 119. 5 Murthy RK, Loi S, Okines A et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive
Metastatic Breast Cancer. N Engl J Med 2020; 382: 597 – 609. 6 Lin NU, Borges V, Anders C et al. Intracranial Efficacy and Survival With Tucatinib
Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer
With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol 2020; 38: 2610 – 2619.
7 Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib
plus capecitabine versus capecitabine alone in women with advanced breast cancer that
has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer
Res Treat 2008; 112: 533 – 543. 8 Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive
advanced breast cancer. N Engl J Med 2006; 355: 2733 – 2743. 9 Saura C, Oliveira M, Feng Y-H et al. Neratinib Plus
Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic
Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.
J Clin Oncol 2020; 38: 3138 – 3149. 10 Modi S, Saura C, Yamashita T et al. Trastuzumab-Deruxtecan in previously treated
HER2-positive breast cancer. N Engl J Med 2020. doi:10.1056/NEJMoa1914510. 11 von Minckwitz G, Schwedler K, Schmidt M et al.; GBG 26/BIG 03 – 05 study group and
participating investigators. Trastuzumab beyond progression: overall survival analysis
of the GBG 26/BIG 3 – 05 phase III study in HER2-positive breast cancer. Eur J Cancer
2011; 47: 2273 – 2281. 12 Rimawi M, Ferrero J – M, de La Haba-Rodriguez J et al. First-Line Trastuzumab Plus
an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor
Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced
Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. J Clin Oncol
2018; 36: 2826 – 2828. 13 Blackwell KL, Burstein HJ, Storniolo AM et al. Overall survival benefit with lapatinib
in combination with trastuzumab for patients with human epidermal growth factor receptor
2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin
Oncol 2012; 30: 2585 – 2592. 14 Blackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of Lapatinib alone
or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory
metastatic breast cancer. J Clin Oncol 2010; 28: 1124 – 1130. 15 Giordano SH, Temin S, Kirshner JJ et al. Systemic therapy for patients with advanced
human epidermal growth factor receptor 2-positive breast cancer: American Society
of Clinical Oncology clinical practice guideline. J Clin Oncol 2014; 32: 2078 – 2099.
16 Kaufman B, Mackey JR, Clemens MR et al.
Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal
women with human epidermal growth factor receptor 2-positive, hormone receptor-positive
metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin
Oncol 2009; 27: 5529 – 5537. 17 Huober J, Fasching PA, Barsoum M et al. Higher efficacy of letrozole in combination
with trastuzumab compared to letrozole monotherapy as first-line treatment in patients
with HER2-positive, hormone-receptor-positive metastatic breast cancer – results of
the eLEcTRA trial. Breast 2012; 21: 27 – 33. 18 Johnston S, Pippen J jr., Pivot X et al. Lapatinib combined with letrozole versus
letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive
metastatic breast cancer. J Clin Oncol 2009; 27: 5538 – 5546. 19 Burstein HJ, Cirrincione CT, Barry WT et al. Endocrine Therapy With or Without Inhibition
of Epidermal Growth
Factor Receptor and Human Epidermal Growth Factor Receptor 2: A Randomized,
Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib
for Postmenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer-CALGB
40 302 (Alliance). J Clin Oncol 2014; 32: 3959 – 3966. 20 Rimawi M, Ferrero JM, de la Haba-Rodriguez J et al.; PERTAIN Study Group. First-Line
Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal
Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally
Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. J Clin
Oncol 2018; 36: 2826 – 2835. doi:10.1200/JCO.2017.76.7863. PMID:30106636.
In HER2-positive breast cancer with de novo metastases or a treatment-free interval
(TFI) > 6 months, taxane-based chemotherapy plus dual antibody blockade with trastuzumab
and pertuzumab is recommended as first-line combination. In patients not suitable
for chemotherapy or according to patientʼs preference, combination of endocrine therapy
and anti-HER2 therapy might be an option. In these patients as well as in secondary
metastatic breast cancer with a TFI ≤ 6 months after (neo-)adjuvant anti-HER2 treatment
with dual blockade, T-DM1 is the preferred second-line option. In case of progression
after two prior lines of anti-HER2 therapy, including patients after (neo)adjuvant
therapy with trastuzumab +/− pertuzumab followed by adjuvant T-DM1, tucatinib in combination
with trastuzumab and capecitabine is a new anti-HER2 combination therapy that results
in improved overall survival. There is a plethora of further anti-HER2 treatment options
including trastuzumab deruxtecan
and neratinib in combination with capecitabine representing new therapeutic options
in heavily pretreated patients with HER2-positive advanced breast cancer.
Algorithm Triple-negative Metastatic Breast Cancer ([Fig. 8])
Algorithm Triple-negative Metastatic Breast Cancer ([Fig. 8])
Fig. 8 Algorithm Triple-negative Metastatic Breast Cancer. 1 Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines
for Advanced Breast Cancer (ABC4). Ann Oncol 2018; 29: 1634 – 1657. 2 Condorelli R, Mosele F, Verret B et al. Genomic alterations breast cancer: level
of evidence for actionability according to ESMO Scale for Clinical Actionability of
molecular Targets (ESCAT). Ann Oncol 2019; 30: 365 – 373. 3 Hu XC, Zhang J, Xu BH et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine
as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised,
open-label, multicentre, phase 3 trial. Lancet Oncol 2015; 16: 436 – 446. 4 Litton JK, Rugo HS, Ettl J et al. Talazoparib in Patients with Advanced Breast Cancer
and a Germline BRCA Mutation. N Engl J Med 2018; 379: 753 – 763. 5 Miles DW, Diéras V, Cortés J et al. First-line bevacizumab in
combination with chemotherapy for HER2-negative metastatic breast cancer: pooled
and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24: 2773 – 2780.
6 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 – 2676. 7 Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared
with bevacizumab plus capecitabine in patients with previously treated metastatic
breast cancer. J Clin Oncol 2005; 23: 792 – 799. 8 Robson M, Im S-A, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients
with a Germline BRCA Mutation. N Engl J Med 2017; 377: 523 – 533. 9 Robson M, Tung N, Conte P et al. OlympiAD final overall survival and tolerability
results: Olaparib versus chemotherapy treatment of physicianʼs choice in patients
with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann
Oncol 2019; 30: 558 – 566. 10 Schmid P, Adams S, Rugo HS et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative
Breast Cancer. N Engl J Med 2018; 379: 2108 – 2121. 11 Cortes J, Cescon DW, Rugo HS et al. Pembrolizumab plus chemotherapy versus placebo
plus chemotherapy for previously untreated locally recurrent inoperable or metastatic
triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind,
phase 3 clinical trial. Lancet 2020; 396: 1817 – 1828. 12 Tutt A, Tovey H, Cheang MCU et al. Carboplatin in BRCA1/2-mutated and triple-negative
breast cancer BRCAness subgroups: the TNT Trial. Nat Med 2018; 24: 628 – 637. 13 Twelves C, Cortes J, Vahdat L et al. Efficacy of eribulin in women with metastatic
breast cancer: a pooled analysis of two phase 3 studies [published correction appears
in Breast Cancer Res Treat 2015; 149: 313. Breast Cancer Res Treat 2014; 148: 553 – 561.
14 Yardley DA, Coleman R, Conte P et al. nab-Paclitaxel plus carboplatin or gemcitabine
versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative
metastatic breast cancer: results from the tnAcity trial. Ann Oncol 2018; 29: 1763 – 1770.
15 Zielinski C, Láng I, Inbar M et al., TURANDOT investigators. Bevacizumab plus paclitaxel
versus bevacizumab plus capecitabine as first line treatment for HER2-negative metastatic
breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, noninferiority,
phase 3 trial. Lancet Oncol 2016; 17: 1230 – 1239. 16 Bardia A, Hurvitz SA, Tolaney SM et al. Sacituzumab govitecan in metastatic triple-negative
breast cancer. N Engl J Med 2021; 384: 1529 – 1541. 17 Bardia A, Mayer IA, Vahdat LT et al. Sacituzumab Govitecan-hziy in Refractory Metastatic
Triple-Negative Breast Cancer. N Engl J Med 2019; 380: 741 – 751
In advanced or metastatic triple-negative breast cancer (TNBC) evaluation of PD-L1
status and germline BRCA mutation (gBRCAmt) is needed as a basis for standard-of-care
therapy decision making because the optimal choice of therapies depends on these two
biomarkers. In patients with PDL-1-negative/gBRCAwt, paclitaxel or capecitabine plus
bevacizumab, cisplatin plus gemcitabine or carboplatin +/− nab-paclitaxel are recommended
treatment options. In later lines, the antibody-drug-conjugate sacituzumab govitecan
offers promising activity.
In patients with PDL-1-negative/gBRCAmt, PARP inhibitors should be considered after
anthracycline and taxane pretreatment and chemotherapy +/− bevacizumab in chemotherapy-naïve
patients. For those patients with PD-L1-positive/gBRCAwt metastatic breast cancer,
the combination of nab-paclitaxel and the immune checkpoint-inhibitor (ICI) atezolizumab
is recommended. In addition, a combination of the ICI pembrolizumab and first-line
chemotherapy (i.e. paclitaxel or nab-paclitaxel or carboplatin plus gemcitabine) could
be considered. Finally, in PDL-1-positive/gBRCA mutant patients, either nab-paclitaxel
plus atezolizumab or PARP inhibitors are recommended. The choice of further therapies
after tumor progression depends on PD-L1 and gBRCA status, clinical presentation,
pretreatments and approval status.
Conclusion
The treatment options shown in these algorithms are based on the 2021 AGO recommendations,
but cannot represent all evidence-based treatment options, since prior therapies,
performance status, comorbidities, patient preference, etc. must be considered for
the actual treatment choice. In individual cases, other evidence-based treatment options
(not listed here) may also be appropriate and justified. However, theses treatment
algorithms are intended to intensify structured treatment decision by providing reproducible
and evidence-based treatment paths and may be helpful for a broad treatment landscape.
