Key words St. Gallen Consensus 2021 - early breast cancer - surgery - radiotherapy - (neo)adjuvant
systemic therapy - targeted therapy
Introduction
The motto of this yearʼs 17th St. Gallen (SG) Conference on “Primary Treatment of
Early Breast Cancer” (SG-BCC) was “Customising local and systemic therapies for women
with early breast cancer”. Targeting the treatment of early breast cancer more and
more to the specific disease situation of each patient is a clinical challenge. The
60 breast cancer experts came from 25 countries, including five panel members from
Germany (see [Table 1 ]). The SG-BCC recommendations are based on a majority vote of the panellists aiming
to establish an international consensus for everyday clinical practice. The panellists
come from a number of different countries with different health systems and resources.
It is not surprising that this would also be reflected in the consensus. For some
years now, a German working group has been commenting on the voting results of the
SG-BCC panel and their agreement with the treatment recommendations of the Breast
Commission of the “Arbeitsgemeinschaft Gynäkologische Onkologie e. V.” (AGO Mamma)
[1 ], which updates its recommendations every year.
Table 1 International SG-BCC Panel 2021.
Chair: Eric P. Winer (USA)
Co-Chairs: Harold Burstein (USA), Giuseppe Curigliano (Italy), Michael Gnant (Austria), Meredith
Regan (USA), Beat Thürlimann (Switzerland), Walter Weber (Switzerland)
Stephan Aebi (Switzerland)
Fabrice André (France)
Carlos Barrios (Brazil)
Jonas Bergh (Sweden)
Hervé Bonnefoi (France)
Denisse Bretel Morales (Peru)
Sara Y. Brucker (Germany)
Harold Burstein (USA)
David Cameron (UK)
Fatima Cardoso (Portugal)
Lisa Carey (USA)
Boon Chua (Australia)
Eva Ciruelos (Spain)
Marco Colleoni (Italy)
Giuseppe Curigliano (Italy)
Suzette Delaloge (France)
Carsten Denkert (Germany)
Peter Dubsky (Switzerland)
Bent Ejlertsen (Denmark)
Eun Sook Lee (South Korea)
Florian Fitzal (Austria)
Prudence Francis (Australia)
Viviana Galimberti (Italy)
Heba Gamal (Egypt)
Judy Garber (USA)
Michael Gnant (Austria)
William J. Gradishar (USA)
Bahadir Gulluoglu (Turkey)
Nadia Harbeck (Germany)
Chiun-Sheng Huang (Taiwan)
Jens Huober (Germany)
Andre Ilbawi (WHO Cancer Control Program)
Steven Johnston (UK)
Sibylle Loibl (Germany)
Monica Morrow (USA)
Ann H. Patridge (USA)
Martine Piccart (Belgium)
Philip Poortmans (Belgium)
Aleix Prat (Spain)
Meredith Regan (USA)
Isabella Rubio (Spain)
Hope Rugo (USA)
Emiel J. T. Rutgers (Netherlands)
Felix Sedlmayer (Austria)
Vladimir Semiglazov (Russia)
Zhiming Shao (PR China)
Tanja Spanic (Europa Donna)
Petra Tesarova (Czech Republic)
Beat Thürlimann (Switzerland)
Sergei Tjulandin (Russia)
Masakazu Toi (Japan)
Maureen Trudeau (Canada)
Nicholas Turner (UK)
Inez Vaz Luis (France)
Giuseppe Viale (Italy)
Toru Watanabe (Japan)
Walter Weber (Switzerland)
Eric P. Winer (USA)
Binghe Xu (PR China)
Jiang Zefei (PR China)
Genetic Testing for High-Risk Mutations
Genetic Testing for High-Risk Mutations
General considerations
Genetic testing for mutations in high-risk genes (e.g. BRCA1/2 ) requires appropriate patient information and counselling. The German experts agree
with the majority vote (78%) of the SG-BCC panellists that patients with a calculated
risk of a pathogenic germline mutation > 10% should be offered genetic testing (Level
of Evidence [LoE] 2bB AGO++). For further details, the German experts refer to the
current recommendations of the AGO Mamma [1 ].
Genetic testing of which genes?
In addition to mutations in the known risk genes BRCA1/2 , the SG-BCC panellists (67%) recommend mutation analysis of other genes, such as
ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, RAD51C/RAD51D and TP53 .
The German experts agree [1 ]. The AGO Mamma differentiates between mutations with high and moderate risk of disease.
The clinical benefit of genetic testing is highest for the high-risk BRCA1/2 genes (LoE 1bA AGO++), as it results in effective preventive measures. The AGO has
upgraded PALB2 mutations in terms of cumulative risk of disease (LoE 1bA AGO++). However, the efficacy
of preventive measures is less well established for PALB2 mutations, which is why the recommendation regarding the clinical benefit of PALB2 mutation analysis was rated less strong (LoE 3aB AGO+). The moderately penetrant
genes mentioned (ATM, BARD1, CHEK2, RAD51C, RAD51D) are among the core genes of common panels and will therefore usually be analysed
as well. Clinical consequences should preferably be studied in the context of prospective
trials or clinical registries (LoE 3aB AGO+/−) [1 ].
Prophylactic mastectomy in confirmed PALB2 mutation?
Half of the SG-BCC panellists consider prophylactic mastectomy to be justified in
PALB2 mutation. From the German perspective, the high risk of the disease justifies prophylactic
mastectomy, even though there is currently no data regarding the impact on survival.
Due to the limited data available, competent counselling in a specialised centre should
be pursued.
Testing for adjuvant olaparib?
PARP (poly ADP-ribose polymerase) inhibition is an effective treatment option in metastatic
breast cancer with germline BRCA1/2 mutation (gBRCA1/2) . In early breast cancer, the OlympiA trial [3 ] (NCT02032823) with the PARP inhibitor olaparib has reached its primary endpoint
according to a press release. The scientific data will be presented at the 2021 annual
meeting of the American Society of Clinical Oncology (ASCO). The SG-BCC panellists
(56%) voted in favour of future genetic testing of all patients eligible for adjuvant treatment with olaparib. The
German experts agree in principle with the majority vote.
Procedure in confirmed disease-causing mutation
Drawing on fictitious cases with different clinical scenarios, the SG-BCC panellists
discussed how to counsel patients at genetically increased risk of breast cancer.
If a disease-causing mutation in BRCA1, BRCA2 or PALB2 – high penetrance (odds ratio [OR] > 3) were detected, almost 85% of SG-BCC panellists
would advise a 40-year old woman to undergo risk-reducing bilateral mastectomy. For
60-year old women, barely half the SG-BCC panellists (46%) voted in favour of this
measure. The German experts recommend that the decision-making process include a thorough
counselling. Risk-reducing mastectomy is an effective procedure. Regular radiological
monitoring, including MRI, may be an option. In some older women, prophylactic tamoxifen
may also be an option [1 ].
If a disease-causing mutation of intermediate penetrance (OR 2 – 3) was detected in
the genes BARD1, CHEK2, CDH1, TP53 , two-thirds of the SG-BCC panellists would recommend intensified screening, including
MRI, for the 40-year-old woman, compared with only 42% of the SG-BCC panellists for
the 60-year-old woman. A good third (35%) consider routine monitoring to be adequate
in older women.
If disease-causing mutations were detected in the low-risk genes ATM, BRIP1, NF1, RAD51C, RAD51D, FRANCC, STK11 (low penetrance; OR 1 – 2), 50% of the SG-BCC panellists voted for intensified screening,
including MRI, for the 40-year-old woman, while 40% considered routine monitoring
to be adequate. In the 60-year-old woman, the SG-BCC panellists voted by majority
(62%) for routine breast screening. Only 30% recommended intensified monitoring, including
MRI. The German experts agree with the SG-BCC majority votes on the genes with medium
or low penetrance. The lower the penetrance and the higher the age of the patient,
the less aggressive the screening should be.
Pathology
Relevance of the proliferation index (Ki-67)
For years, the significance and validity of Ki-67 testing for treatment decisions
in early oestrogen receptor-positive (ER+) and HER2-negative (HER2−) breast cancer
have been discussed. Recently, an international working group [4 ] recommended Ki-67 testing, stating that patients with early ER+/HER2− breast cancer
(T1–2 N0–1) and Ki-67 ≤ 5% do not need adjuvant chemotherapy, whereas Ki-67 ≥ 30%
would warrant chemotherapy. Almost two thirds (62%) of SG-BCC panellists agreed with
this statement.
The German experts basically agree with the SG-BCC vote, but points out that the question
involves extreme “cut-off” values with high “inter-observer” concordance [4 ], [5 ], [6 ], [7 ].
For patients with ER+/PR+/HER2− breast cancer without lymph node involvement (N0),
according to the SG-BCC vote (42%), a Ki-67 level of 30% and above indicates a high
risk and thus the need for chemotherapy. The German experts do not agree with this
majority vote, but agrees with those panellists (36%) who state that no definitive
Ki-67 cut-off in this situation exists (N0) indicating chemotherapy per se. For intermediate
Ki-67 levels between 10 and 25%, it is also necessary from the German point of view
to include other criteria for risk assessment.
Ki-67 measurement before and during neoadjuvant endocrine therapy
Almost two thirds of the SG-BCC panellists (61%) and the German expert group agree
that Ki-67 testing should be performed in routine clinical practice for all patients
with early ER+/HER2− breast cancer. Likewise, two thirds (68%) of SG-BCC panellists
recommend Ki-67 testing during or after neoadjuvant endocrine therapy (NET) to assess
treatment response. They also voted by a majority (70%) that the prognosis of patients
with ER+/HER2− ductal breast cancer can be assessed by the change in Ki-67 levels
after a 2-week course of endocrine therapy (NET). The German experts agree that a
2 – 4 week NET to assess endocrine sensitivity, as used for example in the German
ADAPT trial [8 ] and in the POETIC trial [9 ], is an appropriate measure [1 ].
Focus on multigene signatures
In certain circumstances, multigene signatures can support the treatment decision
for/against chemotherapy in early ER+/HER2− breast cancer. Based on various clinical
scenarios, the SG-BCC panellists voted on when multigene signatures would be helpful.
The starting point in each case is a patient with early ER+/HER2− breast cancer (tumour
size 1 – 3 cm) eligible for chemotherapy. The clinical situation of this patient varied
in terms of gender (male/female), menopausal status and age (pre/postmenopausal),
axillary lymph node (LN) involvement (pN0, 1 – 3 LN, ≥ 4 LN), and tumour grading (G1,
G2, G3).
The majority of SG-BCC panellists recommended gene expression analysis in selected patients ([Table 2 ]). A majority of the panellists (79%) rejected multigene signature in patients with
ER+/HER2− primary breast cancer (1 – 3 cm) with four or more affected lymph nodes.
Table 2 In early ER+/PR+/HER2− breast cancer (T 1 – 3 cm), the multigene signature is recommended
by the SG-BCC panel in selected cases. Consent of the German experts.
Patient profile
Gene expression analysis
Never
In selected patients
Routine
* majority vote in each case
Gender
x (56%)*
x (72%)
Menopause status
x (67%)
x (64%)
Nodal status
x (63%)
x (83%)
x (79%)*
Tumour grading
x (60%)
x (72%)
x (61%)
The German experts basically agree and emphasise that because of the available prospective
data gene expression analyses are only indicated in patients with a maximum of three
affected lymph nodes. Moreover, gene expression analyses should only be performed
if the decision for/against chemotherapy cannot be based on the usual clinical and
pathological factors. The voting of the SG-BCC panellists are in line with the AGO
recommendations [1 ]. In addition, the German experts point out the poor data in men, which is why the
argument for them can only be made by analogy. In the context of the SG-BCC recommendation,
it should be noted that in Germany the multigene testing recommended by the AGO is
reimbursed for routine care in N0 patients, but in patients with LN involvement only
under special contract arrangements (e.g., outpatient specialist management) [1 ].
Early TNBC: no PD1/PD-L1 testing
The SG-BCC panellists and the German experts agree that neither PD1/PD-L1 testing
(majority vote: 93%) nor tumour-infiltrating lymphocytes (TILs; majority vote: 61%)
are routinely indicated in patients with early triple-negative breast cancer (TNBC:
ER−/PR−/HER2−) undergoing systemic treatment [1 ].
Neoadjuvant systemic therapy
Neoadjuvant systemic therapy
General considerations
The concept of neoadjuvant therapy is recognised and favoured in Germany as a standard
approach in early breast cancer as soon as adjuvant chemotherapy is indicated under
the same treatment regimen [1 ]. In contrast, the SG-BCC panellists (60%) do not favour the concept of neoadjuvant
therapy (60%). Pathological complete response (pCR) following neoadjuvant systemic
therapy (NAST) may be used as a surrogate endpoint for drug approval in early breast
cancer. With a clear majority (83%), the SG-BCC panellists put this approach into
perspective: Achieving pCR is promising but inadequate when defining standard treatment.
This can only be defined based on survival data. The German experts agree.
NACT or NET?
The SG-BCC panellists voted almost unanimously (98.21%) that in postmenopausal patients
with ER+/HER2− breast cancer and low risk, based on clinical pathological criteria
or gene expression analysis, for whom neoadjuvant treatment is planned, endocrine
therapy should be preferred over chemotherapy. The German experts agree that chemotherapy
is not indicated here. In Germany, neoadjuvant endocrine therapy (NET) is not standard
[1 ].
In early ER+/HER2− breast cancer, 74% of SG-BCC panellists supported gene expression
analysis of core biopsies to decide whether to administer NET or neoadjuvant chemotherapy
(NACT). From the German perspective, the question – NET or NACT – is not significant
clinically, as NET is not a standard regimen in Germany. Multigene signature is only
reasonable in those patients where the indication for chemotherapy is questionable.
Neoadjuvant systemic therapy in HER2+ breast cancer
With a clear majority (85%), the SG-BCC panellists saw no need for anthracyclines
in addition to neoadjuvant taxane/anti-HER2-based regimens in stage II breast cancer
patients without LN involvement (cN0). In contrast, in LN involvement (c/pN+), 54%
of SG-BCC panellists advocated neoadjuvant anthracycline/taxane-based chemotherapy
plus anti-HER2 therapy.
In the modified case of a stage II/III cN0 patient with neoadjuvant taxane/trastuzumab
therapy, 35% of the panellists voted to administer an anthracycline plus pertuzumab in addition to the neoadjuvant taxane/trastuzumab regimen. Just under
30% (27%) chose pertuzumab/platinum and 24% opted to add pertuzumab only.
The AGO Mamma [1 ] rates anthracycline-free and anthracycline-containing standard regimens in combination
with trastuzumab plus pertuzumab as equally effective. However, various long-term
sequelae have been described, and this needs to be discussed with the patient. The
German experts therefore agree with the SG-BCC vote that cN0 patients can receive
a standard anthracycline-free regimen. This is also true for patients with LN involvement
regardless of the stage (for example: six cycles of TCbH [docetaxel, carboplatin,
trastuzumab] or six cycles of TCbHP [TCbH + pertuzumab]). Some German experts, however,
prefer treatment with anthracyclines in cases of higher risk, e.g., with lymph node
involvement.
Neoadjuvant therapy in TNBC
In early TNBC, carboplatin is an effective treatment option alongside anthracyclines
and taxanes. About 60% of SG-BCC panellists rejected neoadjuvant carboplatin in addition
to anthracycline/cyclophosphamide/taxane-based treatment. The German experts see a
difference to the German recommendations. According to the AGO Mamma [1 ], neoadjuvant platinum-containing chemotherapy can be used in early TNBC depending
on patient risk profile and possible side effects (LoE 1aA AGO+). In Germany, carboplatin
is usually combined with a taxane.
No checkpoint inhibition in early TNBC
The German experts agree with the SG-BCC panellists (90%) that at present checkpoint
inhibitors should not be given in early TNBC outside of clinical trials.[1 ] Trial participation (GeparDouze, Alexandra, Neo Mono) is recommended [10 ], [11 ], [12 ].
Local Treatment Following NAST
Local Treatment Following NAST
Residual axillary tumour
The SG-BCC panellists (73%) and the German experts agreed that axillary lymph node
dissection (ALND) is indicated if a macrometastasis (> 2 mm) was confirmed in the
sentinel LN (SLN) or target LN (= biopsied and labelled LN; TLN) following NAST.
The majority of SG-BCC panellists see no indication for ALND if following NAST micrometastases
(≤ 2 mm) (majority vote: 60%) and isolated tumour cells (ypN0[i+]) are detected only
in the SLN (majority vote: 89%). 72% of SG-BCC panellists recommend ALND if 1/3 of
the SLN is affected. The German experts agree in principle, but refers to the differentiated
recommendations of the AGO Mamma [1 ] ([Fig. 1 ]). If a SLN or the TLN is “positive” following NAST, ALND is indicated irrespective
of the number of LN examined and the size of the detected metastasis. There is agreement
that axillary dissection is not justified when only isolated tumour cells are detected
(ypN0[i+]).
Fig. 1 Recommendations of the AGO Mamma on the surgical approach in the axilla following
neoadjuvant chemotherapy, from: [1 ].(Source: Courtesy of AGO Mamma)
The German experts criticise that the issues voted on do not contain any information
on the axillary status before NAST. They add that ALND, just like SLND or TAD (“targeted axillary dissection”,
i.e., TLN plus SLN excision [SLNE]), also serve diagnostic objectives. At present,
however, there is no evidence for superiority of a regional therapy option (ALND vs.
radiotherapy) in patients with ycN0 or ypN1 status. Basically, according to the German
experts, the evidence is limited and partly based on empirical data. The AXSANA/EUBREAST
3 trial [13 ] undertaken by the AGO Breast study group and the AWOgyn (Arbeitsgemeinschaft für
ästhetische, plastische und wiederherstellende Verfahren in der Gynäkologie e.V.)
will close these gaps in knowledge.
Is it possible to omit ALND?
There was no consensus SG-BCC vote on the question of whether ALND can be avoided
in patients with positive nodal status (cN1) before treatment and marked, histologically
positive TLN who convert to ycN0 status and whose lymphatic drainage areas (LDA) must
be irradiated. 41% of SG-BCC panellists agreed to omit ALND when 3/3 SLNs were tumour-free
and 37% of panellists agreed when 1/1 SLN was tumour-free.
From the German perspective, the question cannot be answered because it is unclear
whether the TLN had been removed. The evidence on this is sparse. Although the German
experts emphasise that the AGO recommends both: TAD and ALND in the situation of ycN0.
If the TLN corresponds to the SLN, a negative SLN suffices [14 ], [15 ]. More than 80% of SG-BCC panellists (82%) recommend ALND when a patient with cN1
status (biopsy confirmed) has not responded or has only responded marginally to NAST
(ypN1). For this situation (ypN+), the AGO Mamma recommends ALND ([Fig. 1 ]) [1 ].
Patient with unsuspicious nodes at presentation (cN0) with positive SLN following
NAST
The SG-BCC panellists voted on whether radiotherapy of the axilla can replace ALND
in selected patients with initial cN0 but positive SLN (ypN1).
The majority of SG-BCC panellists (62%) recommend ANLD instead of radiotherapy in
patients with 2/3 “positive” SLN, if there was at least one macrometastasis (> 2 mm).
If only 1/3 SLN demonstrates macrometastasis (> 2 mm), 48% of SG-BCC panellists voted
for axillary radiotherapy; 52% voted for ALND.
When ypN1mic (> 0.2 – 2 mm) or ypN0(i+) (≤ 0.2 mm) was detected in 1/3 SLN, the majority
of SG-BCC panellists (72% and 88%, respectively) favoured axillary radiotherapy over
ALND.
The more residual tumour following NAST, the more SG-BCC panellists felt that level
I/II radiotherapy alone did not have an adequate therapeutic effect, and therefore
ALND should be performed. The German experts agree in principle, but refer to the
markedly more differentiated AGO recommendations ([Fig. 1 ]) [1 ]. Due to the limited evidence, the AGO Mamma still recommends ALND. There is an increased
risk of additional lymph node involvement following NAST and that – unlike in primary
surgery [16 ], [17 ] – these are treatment-resistant cells with questionable response to radiotherapy.
Due to the poor data in general, new recommendations must be postponed until the ongoing
trials [13 ], [16 ], [18 ] have been completed. Overall, the SG-BCC questions on LN
staging following NAST do not reflect the complexity of the situation.
Axillary intervention regardless of subtype
Neither the tumour subtype nor the respective available post-neoadjuvant treatment
options in patients with positive LN following NAST affect the need for ALND. The
majority of SG-BCC panellists rejected omitting ALND in favour of SLNE plus radiotherapy.
The German experts agree, as there is no data that the decision for ALND following
NAST depends on morphology or intrinsic subtype.
TAD following NAST?
The surgical approach in the axilla following NAST does not depend on tumour biology.
The German experts agree with the respective majority vote of the SG-BCC panellists
on the TAD indication – assuming optimised and standardised technique [13 ].
TAD is an adequate alternative to standard ALND (60%).
TAD is an option in c/pN1 patients with conversion to ycN0 (90%).
TAD is an option regardless of breast cancer subtype (85%).
Beside that “no surgery” is not an option in cases of presumed pathological complete
remission, no new statement on breast surgery following NAST was presented at the
SG-BCC this year. From the German perspective, however, it should be noted that surgery
in the new, shrunken tumour volume remains standard according to the AGO Mamma, thus
facilitating a very high breast conserving surgery rate [1 ].
Surgery, Radiotherapy and Breast Reconstruction
Surgery, Radiotherapy and Breast Reconstruction
Management following mastectomy
On the question of how and when patients should undergo post-mastectomy radiotherapy
(PMRT), 32% of SG-BCC panellists voted for an expander during PMRT (before planned
reconstruction), while 20% would irradiate first and reconstruct later. The remainder
favoured immediate reconstruction with autologous tissue (25%) or an implant (single-
or two-stage procedure; 23%).
From the German perspective, all other options are also possible and should be discussed
by the tumour board and with the patient (AGO ++) [1 ]. Delayed autologous reconstruction is preferred, with temporary expander or implant
if needed. [Fig. 2 ] illustrates the breast reconstruction algorithm recommended by the AGO Mamma [1 ]. The decision for breast reconstruction, especially delayed reconstruction, must
be discussed with each patient individually. The German experts note an increased
risk of complications (e.g., risk of capsular fibrosis) if radiotherapy is performed
after implant reconstruction.
Fig. 2 AGO Mamma algorithm for breast reconstruction following mastectomy, from: [1 ].(Source: Courtesy of AGO Mamma)
Hypofractionated radiotherapy following reconstruction?
If a patient with immediate breast reconstruction requires PMRT, the SG-BCC panellists
(64%) without restrictions consider moderate hypofractionated radiotherapy a suitable
option. The German experts note the clearly limited data available. The AGO Mamma
has not commented on hypofractionated PMRT [1 ].
Radiotherapy Following Breast-Conserving Surgery
Radiotherapy Following Breast-Conserving Surgery
Hypofractionated radiotherapy as standard?
In stage I/II ER+/HER2− breast cancer following breast-conserving surgery (BCS) with
negative resection margins, the majority of SG-BCC panellists (72%) voted for moderately
hypofractionated whole-breast radiotherapy (WBRT; 15 – 16 fractions) as the preferred
fractionation regimen, regardless of patient age. This is consistent with the S3 guideline
and the recommendation of the AGO Mamma [1 ], [2 ]. 9% of the SG-BCC panellists favoured ultra-short course WBRT, in line with the
FAST and FAST-Forward trials [19 ], [20 ]. The AGO Mamma defines ultra-short course WBRT as an alternative in selected cases
(LoE 1bB AGO+/−) when standard hypofractionated WBRT is not an option [1 ]. This is supported by a statement of the German Society of Radiation Oncology (DEGRO)
[21 ]. Ultra-short course
radiotherapy may become the treatment of the future.
Focus on partial breast irradiation
For partial breast irradiation (PBI) in stage I/II ER+/HER2− breast cancer without
LN involvement, the majority of SG-BCC panellists saw no PBI indication in patients with lobular breast cancer (80%), or lymphovascular invasion
(87%), or germline mutation (85%), and/or in patients < 40 years (92%). The German
experts agree in principle, but notes the limited data available, especially on germline
mutations, which is why there is no guideline recommendation [1 ], [22 ]. However, the increased risk of ipsilateral secondary cancer due to genetic predisposition
and the protective effect of WBRT support the recommendation [23 ].
Importance of multigene signatures in radiotherapy
According to the SG-BCC majority vote, commercially available multigene signatures
do not provide a basis for deciding whether regional nodal irradiation (RNI: 92%)
or chest wall irradiation (89%) is indicated. This also applies to the decision to
forego radiotherapy in invasive breast cancer following breast-conserving surgery
(84%). The German experts agree in each case. The AGO Mamma [1 ] and DEGRO [24 ] advise against the use of multigene signatures in these situations.
Post-neoadjuvant Systemic Therapy
Post-neoadjuvant Systemic Therapy
General consideration
The prognostic significance of pathological complete response (pCR: ypT0/is pN0) following
neoadjuvant chemotherapy (NACT) is undisputed. The question of whether the tumour
stage at initial diagnosis or the intrinsic tumour subtype also affect the future
outcome of a patient with pCR was supported by two-thirds of the SG-BCC panellists
(65%). The German experts agree and add that the prognosis following NACT can be estimated
with different models [25 ], [26 ], [27 ].
Post-neoadjuvant therapy in HER2 positive breast cancer
For patients with HER2+ breast cancer and clinically suspect lymph nodes at initial
diagnosis (cN+) who achieve pCR with neoadjuvant chemotherapy plus trastuzumab and
pertuzumab, the SG-BCC panellists (56%) recommend continuing post-neoadjuvant treatment
with trastuzumab and pertuzumab. If the patient was cN0 at initial diagnosis, the
SG-BCC panellists (70%) recommend that additional administration of pertuzumab is
not needed in the post-neoadjuvant setting. The German experts agree with both majority
votes. The AGO Mamma recommends post-neoadjuvant trastuzumab (LoE 2aC AGO++) in low
risk of recurrence patients and additional pertuzumab in high risk patients (cN+:
LoE 2bC AGO+) [1 ].
If a patient does not achieve pCR after standard NAST, further post-neoadjuvant treatment with trastuzumab
emtansine (T-DM1) is the therapy of choice for almost all SG-BCC panellists (89%).
This corresponds to the AGO recommendation (LoE 1bB AGO+). According to the SG-BCC
majority vote (77%) and the German experts, post-neoadjuvant T-DM1 is also indicated
in small tumour residuals (< 5 mm) [28 ].
Post-neoadjuvant therapy in TNBC
In patients with early TNBC and pCR following NACT plus immunotherapy, the SG-BCC
panellists (85%) see no indication for post-neoadjuvant checkpoint inhibitors. The
German experts agree. No survival data from clinical trials are available yet.
If patients who do not achieve pCR, continued treatment with capecitabine is a post-neoadjuvant
option. The German experts agree with the majority vote of the SG-BCC panellists (88%).
The AGO-Mamma recommends up to eight cycles of capecitabine (LoE 1bB AGO+). Trial
enrollment is recommended (LoE 5D AGO+) [1 ], for example, in the SASCIA trial [29 ].
Post-neoadjuvant therapy in ER+/HER2− breast cancer
The SG-BCC panellists stated unanimous (100%) that patients with early, hormone-sensitive
(ER+/HER2−) breast cancer who have not achieved pCR in the breast but a good response
in the axilla (pN0) after NET should receive post-neoadjuvant chemotherapy. The German
experts agree with the statement, with the comment that conventional (4 – 6 months)
NET is rarely used in Germany and is primarily reserved for older patients or those
with significant comorbidities.
No pCR following NET
Further SG-BCC questions on post-neoadjuvant chemotherapy in patients (ER+/HER2−)
without pCR following NET rarely arise in Germany, as NET is not a standard treatment regimen
in Germany. Moreover, the probability of pCR following NET is very low (5%).
Ductal Carcinoma in Situ (DCIS)
Ductal Carcinoma in Situ (DCIS)
Postoperative radiotherapy in ER+ DCIS?
According to the SG-BCC panellists (majority vote: 58%), omitting postoperative radiotherapy
following BCS of ER+ DCIS with adequate resection margin is justified in all patients
over 70 years of age, and in principle (no age limit in the question) in patients
at low biological (“luminal-like”) or genomic (multigene testing) risk (70%) as well
as in low grade tumours (G1, 74%). Two-thirds of the SG-BCC panellists (67%) recommend
omitting postoperative radiotherapy only in older patients (> 70 years) with at least
one of the low-risk factors noted above. A simple majority (53%), on the other hand,
saw an indication for postoperative radiotherapy in unifocal DCIS (≤ 2 cm) without
necrosis.
The German experts point out that postoperative radiotherapy following BCS of ER+
DCIS with adequate free resection margin reduces the recurrence rate in the affected
breast, but has no effect on overall survival [30 ]. This should be discussed with each patient individually. In the view of the Germans
group, the voting results reflect that the overall risk profile should be taken into
account when deciding for or against radiotherapy following BCS in DCIS.
Endocrine therapy following BCS and R0 situation
Various options are available if a patient with ER+ DCIS and postoperative radiotherapy
also desires endocrine therapy as recurrence prophylaxis [1 ]. The vast majority of the panel favoured endocrine therapy (83%) with standard-dose
(20 mg/day) or lower-dose (5 mg/day) tamoxifen or an aromatase inhibitor (AI).
The AGO Mamma recommends endocrine therapy in addition to adjuvant radiotherapy as
an option in individual cases (AGO+/−). All the choices listed (tamoxifen 20 mg, tamoxifen
5 mg, AI [only in postmenopausal patients]) are an option [1 ]. The German experts emphasise that the indication for endocrine therapy depends
on possible risk factors, potential side effects and the patientʼs wishes. The patient
should be informed that endocrine therapy is not associated with an overall survival
benefit, but may in particular reduce the risk of secondary cancer in the other breast
(LoE 1a) [1 ].
Radiotherapy
Importance of the boost
The SG-BCC panel heterogeneously discussed the issue of routine boost irradiation
following BCS and WBRT in patients with early invasive breast cancer. Nearly half
(47%) would boost the tumour bed only in younger patients (18% in < 40 years, 29%
in < 50 years), 31% would base their indication on tumour biology alone (G3, extensive
intraductal component, HER2-positive, TNBC), while 20% regard the boost as indicated
in every patient. From the German perspective, the heterogeneous vote is also reflected
in the recommendations of the AGO Mamma ([Fig. 3 ]) [1 ]. The AGO Mamma clearly recommends the boost in premenopausal patients (LoE 1bB AGO++).
In postmenopausal patients, boost is only indicated in patients at increased risk
(LoE 2bB AGO+) [1 ].
Fig. 3 Recommendations of the AGO Mamma on “boost” irradiation following BCS in invasive
breast cancer, from: [1 ].(Source: Courtesy of AGO Mamma)
Boost in DCIS?
The SG-BCC panellists reject routine radiation boost both generally in DCIS (89%)
and also in low-risk DCIS patients (96%). A slight majority (55%) rejects routine
radiation boost in DCIS patients < 50 years of age. In contrast, two-thirds of SG-BCC
panellists (65%) recommend routine radiation boost in DCIS patients at increased risk,
for example, due to necrosis, close resection margins (< 2 mm), and large lesions.
The AGO Mamma recommends radiation boost in DCIS patients only in special cases at
increased risk (LoE 1bB AGO+/−). According to the AGO, this includes patients < 50
years of age or those ≥ 50 years if additional risk factors are present (e.g., symptoms,
G2/3, central necrosis, close resection margins, multifocal tumour, etc.) [1 ]. The German experts point out that this is an individual decision that should be
discussed in the multispecialty tumour board and with the patient. Data from a randomised
trial [31 ] on this question was presented for the first time at the San Antonio Breast Cancer
Symposium 2020 showing no difference between hypofractionated radiotherapy and conventional
radiotherapy and a moderate advantage of adding the boost.
Moderate hypofractionation in invasive cancer
The SG-BCC panellists regard hypofractionation as adequate radiotherapy modality following
mastectomy (90%) and in regional nodal irradiation (RNI) (76%). – The AGO Mamma has
not issued a statement regarding fractionation in PMRT without RNI. For combined irradiation
of the chest wall with RNI, the German experts recommend conventional fractionation
due to the limited data available on hypofractionation.
The AGO Mamma regards hypofractionated RNI as an option in selected cases (LoE 2bB
AGO+/−). The publication by Wang et al. [32 ] is based solely on patients with locally advanced breast cancer with a short follow-up
period. In Germany, the standard is conventional fractionation over a period of five
weeks (LoE 1aA AGO++). Current ongoing trials will clarify this question [33 ], [34 ], [35 ], [36 ].
The majority of SG-BCC panellists (59%) voted in favour of hypofractionated radiotherapy
as the standard option for the chest, thoracic wall and regional lymph nodes – only
rare circumstances such as repeat (second) radiotherapy were excluded. Due to the
limited data on hypofractionation, the AGO Mamma recommends conventional fractionated
radiotherapy in this indication, but considers hypofractionated irradiation an option
(LoE 2bB AGO+/−). Only 21% of SG-BCC panellists considered hypofractionated radiotherapy
a standard option only following BCS, regardless of the patientʼs age. This vote corresponds
to the recommendations of the AGO Mamma [1 ]. Regardless of this, it was pointed out at the SG-BCC that obstacles to the implementation
of hypofractionation, for example, billing models based on the number of radiation
fractions, should be reduced [37 ], [38 ].
Regional node irradiation (RNI) following NAST
Another focus of the SG-BCC vote was the importance of RNI following NAST in TNBC
or HER2+ breast cancer stage II and above. In clinically unsuspicious LN before NACT (cN0), a clear majority of SG-BCC panellists saw no indication for RNI in pCR
of the primary tumour (TNBC: 86%; HER2+: 90%). In contrast, in patients with stage
II/III, pCR and clinically suspect LN (cN1) prior to NACT, 70% (TNBC) and 65% (HER2+) routinely recommended RNI despite pCR. Only 26%
(TNBC) and 30% (HER2+) restricted this to stage III patients.
With reference to the recommendation of the AGO Mamma, the German expert group emphasises
that the indication for RNI should be risk-adapted ([Fig. 4 ]) [1 ]. They therefore fully agree with the SG-BCC vote in the cN0 patient. In contrast,
RNI is indicated in cN1 patients with initial stage III despite pCR. In stage II,
the indication for RNI should be discussed with the patient depending on other risk
factors.
Fig. 4 Recommendations of the AGO Mamma on radiotherapy following neoadjuvant systemic chemotherapy,
from: [1 ].(Source: Courtesy of AGO Mamma)
Elderly patients with life expectancy > 10 years
According to the AGO Mamma, adjuvant radiotherapy can be omitted in patients with
small invasive ER+/HER2− breast cancer (pT1pN0) who have undergone breast-conserving
surgery and have a life expectancy of less than 10 years, after individual consultation
and accepting an increased risk of intramammary recurrence. This requires that the
cancer has been resected completely (R0) and that the patient receives adjuvant endocrine
therapy (LoE 1aB AGO+) [1 ].
The SG-BCC also discussed the question of adjuvant radiotherapy in older patients
(> 70 years) with breast-conserving surgery in ER+/HER2− breast cancer and a life
expectancy of more than 10 years. The majority of SG-BCC panellists did not recommend this option in general
(90%). The SG-BCC panellists (88%) consider to omit additional radiotherapy, especially
in patients with small ER+/HER2− breast cancers (< 2.5 cm) and low clinical or genomic
risk. According to the SG-BCC majority vote, radiotherapy should not be omitted in
larger tumours (> 2.5 cm/N0; majority vote: 80%), in the case of a positive SLN (90%)
and in the case of unfavourable clinical/biological factors or high genomic risk (92%).
From the German perspective, the decision for or against adjuvant radiotherapy in
older women with low-risk breast cancer requires an individual risk-benefit analysis.
Trial data are so far only available with a follow-up period of up to about ten years
[39 ]. Important options in older patients, which may affect the risk-benefit analysis
in the future, are partial-breast radiotherapy and, potentially ultra-hypofractionated
irradiation [1 ].
Intraoperative radiotherapy
Overall, 61% of SG-BCC panellists agreed that there are patients eligible for intraoperative
radiotherapy (IORT) as sole modality. The German experts agree. The AGO Mamma considers
intraoperative radiation alone to be a therapeutic option in patients > 70 years of
age with a low risk of recurrence (LoE 1bA AGO+) and in specific cases in patients
> 50 years of age (LoE 1bA AGO+/−) [1 ]. Due to the methodical limitations of the TARGIT-A trial [40 ], [41 ], no general recommendation favouring IORT as sole modality can be given [22 ].
Adjuvant Systemic Therapy in ER+ Breast Cancer
Adjuvant Systemic Therapy in ER+ Breast Cancer
General considerations
Half of the SG-BCC panellists defined the threshold of ER-positive cells detected
by immunohistochemistry at ≥ 1% and ≥ 10% respectively. From the German perspective,
the cut-off ≥ 1% is adequate for adjuvant endocrine therapy, although knowing that
1 – 10% ER-positive cells are considered as “questionably endocrine sensitive”. Adjuvant
endocrine therapy may be offered to these patients (LoE 3bD AGO+). With ER-positive cells > 10%, there
is a clear indication for treatment (LoE 1A AGO++) [1 ].
Patients with “questionably endocrine sensitive” ER+/HER2− breast cancer must be informed
accordingly. The German experts add that nowadays more sensitive antibodies are used
in the detection of ER-positive cells and that it can be assumed that patients with
ER-low expression (“low expressers”) may have more biologically aggressive “basal-like”
breast cancer.
The German experts and the SG-BCC panellists agree that patients with luminal A- or
luminal B-like breast cancer without lymph node involvement (pN0) may benefit from
adjuvant endocrine therapy regardless of tumour size – even in the case of microinvasion
in the sentinel node (SG majority vote: 59 and 58%, respectively).
In case of ER+/HER2+ breast cancer (pN0), the majority of SG-BCC panellists (51%)
voted in favour of adjuvant anti-HER2-based therapy if the tumour size was 5 mm or
larger. A minority of 15% would administer adjuvant anti-HER2-based therapy regardless
of tumour size. – The AGO Mamma recommends the use of trastuzumab (LoE 2bB AGO+) in
pN0 patients and a tumour size > 5 mm and for tumour sizes > 10 mm (LoE 1aA AGO++).
In tumours ≤ 5 mm in diameter, adjuvant trastuzumab is possible on an individual risk-adapted
decision (LoE 2bB AGO+/−) [1 ].
Duration of endocrine therapy in the premenopausal patient
If a premenopausal patient with ER+/HER2− breast cancer and high risk of recurrence
received adjuvant tamoxifen plus OFS (ovarian function suppression) for five years,
almost 90% of SG-BCC panellists recommend continuing endocrine therapy for another
five years. A slight majority (45%) favour monotherapy with tamoxifen, 41% want to
switch to an AI (plus OFS, if the patient remained premenopausal). Only four percent
would continue tamoxifen/OFS.
The German experts emphasize that there is no valid data for extended adjuvant endocrine
therapy (EAT) after five years of tamoxifen/OFS. From the German perspective, continued
treatment with tamoxifen is an option. The AGO Mamma recommends continued treatment
with tamoxifen (years 6 – 10) (LoE 1aA AGO++) after initial five years of tamoxifen
and regards continued treatment with tamoxifen alone as a “possible” option (LoE 5D
AGO+) after initial five years of endocrine therapy plus OFS [1 ].
Duration of endocrine therapy in lymph node involvement
According to the recommendation of the AGO Mamma, the standard is adjuvant endocrine
therapy for five years (AGO++) [1 ]. For patients with lymph node involvement at initial diagnosis, the majority of
SG-BCC panellists vote for endocrine therapy beyond five years: 34% recommend 7 – 8
years and 53% would treat for a total of ten years. The AGO Mamma recommends treatment
duration beyond five years after individual risk-benefit analysis (AGO++). Duration
and choice of treatment and, if necessary, the sequence (AI or tamoxifen) depend,
among other things, on patient menopausal status, treatment tolerance, risk of recurrence,
and the patientʼs wishes [1 ].
Adjuvant therapy with CDK4/6 inhibitors?
CDK4/6 inhibitors have not yet been approved in Germany for adjuvant therapy in ER+/HER2−
breast cancer. The only positive trial data currently available – albeit with a still
short follow-up period (< 20 months) – is for adjuvant abemaciclib from the monarchE
trial [42 ]. In the SG-BCC vote, 54% of panellists favour abemaciclib in addition to adjuvant
endocrine therapy in patients with at least four involved lymph nodes. In patients
with 1 – 3 involved LN and additional risk factors (e.g. G3 and/or T3 or high Ki-67),
an equally narrow majority of SG-BCC panellists (54%) reject adjuvant abemaciclib.
About 60% of the SG-BCC panellists do not see additional Ki-67 testing (in addition
to other prognostic markers) as an option to allow patients the adjuvant treatment
with a CDK4/6 inhibitor.
The AGO Mamma considers adjuvant abemaciclib over two years in addition to standard
endocrine therapy to be an option in patients with an increased risk of recurrence
and if the inclusion criteria of the monarchE study are met (LoE 2bC AGO+/−) [1 ].
Use of gene expression signatures
The majority of SG-BCC panellists (79%) reject the indication for chemotherapy in
postmenopausal patients if their genomic risk according to the clinical criteria of
the MINDACT [43 ], TAILORx [44 ] or RxPonder [45 ] or similar trials is low and/or their recurrence score (RS) is ≤ 25.
The German experts agree in principle. Gene expression analysis should only be used
if the traditional clinical-pathological factors (tumour size, nodal involvement,
grading, Ki-67, ER/PR as well as HER2) do not allow decision-making for or against
chemotherapy followed by endocrine therapy (vs. endocrine therapy alone). If gene
expression analysis is indicated, the recommendation resulting from the analysis should
be followed. In addition, the German experts refer to the current data of the ADAPT
trial [8 ] as well as to the ADAPTlate [46 ] and ADAPTcycle [47 ] trials on this issue, which are currently recruiting patients with intermediate
and higher clinical risk.
Focus on OFS
Standard adjuvant endocrine therapy in premenopausal patients (ER+/HER2−) is tamoxifen
for 5 years (AGO 1aA ++) if the risk of recurrence is low, plus OFS (LoE 2bC AGO++)
in higher risk of recurrence. Tamoxifen/OFS treatment should only be given as long
as it is tolerated by the patient and she is clearly premenopausal. According to the
AGO recommendation, tamoxifen/OFS or AI/OFS is an option following chemotherapy once
ovarian function returns within 24 months [1 ].
The German experts do not agree with the majority vote of the SG-BCC panellists recommending in principle an
OFS in premenopausal patients with clinical stage II (71%). In patients < 40 years
of age, as many as 94% would expand treatment with OFS. From a German perspective,
the issue is not differentiated enough. The indication for OFS is based on the risk
of recurrence.
If a patient with stage II ER+/HER2 breast cancer is premenopausal after initial chemotherapy,
the question of further endocrine therapy was adressed. 43% of SG-BCC panellists see
the indication for OFS (plus tamoxifen) in all patients, while 52% rely on supplementary
OFS only in “high risk” cases (age < 40 years, lymph node involvement [N+], high Ki-67
and/or luminal B carcinoma, or intermediate or high risk according to gene expression
analysis). In a separate vote, 94% of the SG-BCC panellists favour OFS in principle
as part of endocrine therapy in patients with a risk of recurrence that justifies
the indication for chemotherapy, as long as the patient remains premenopausal.
From the perspective of the German experts, the voting results reflect that, regardless
of the stage, it must be differentiated between patients with low and high risk of
recurrence and that an OFS is only indicated with increased risk [1 ]. The previous chemotherapy is a surrogate marker for high risk.
Role of multigene signatures in endocrine therapy
In premenopausal patients with ER+/HER2− breast cancer without lymph node involvement
and with low/intermediate genomic risk, e.g. RS 16 – 25, the majority of SG-BCC panellists
(53%) agree on OFS in addition to tamoxifen or an AI. Almost a quarter recommended
only tamoxifen (22%) or endocrine therapy plus chemotherapy (24%).
The German experts cannot completely agree with the majority vote. According to the
AGO Mamma [1 ], chemotherapy plus endocrine therapy can be useful in this group with individually
increased risk of recurrence [44 ]. This must be discussed with the informed patient and decided individually.
In patients with 1 – 3 positive LN and low genomic risk (e.g., RS ≤ 25), 30% of SG-BCC
panellists recommend chemotherapy followed by oral endocrine therapy, while 17% refuse
oral endocrine therapy plus OFS. About one quarter consider both treatment options
to be adequate, and 26% would prefer chemotherapy or endocrine monotherapy.
With regard to the indication for OFS, the German experts add that this should be
independent of the genomic risk. So far, there is no data clearly proving a correlation
between OFS indication and multigene test result.
Oestradiol level during OFS?
For patients under OFS, 53% of SG-BCC panellists recommend routine measurement of
oestradiol levels, while 47% reject this step. From the German perspective, there
is no reason for routine testing. This corresponds to the 50 : 50 vote of the panellists.
Testing should be done after hysterectomy to determine menopausal status and may also
be useful during endocrine therapy with an AI plus GnRH analogue to verify endocrine
suppression.
Chemotherapy effect in premenopausal patients
Chemotherapy efficacy in premenopausal patients is based not only on the cytotoxic
effect but also on the ovarian suppression induced by chemotherapy – especially in
patients with favourable biological factors (positive ER/PR status, well-differentiated
cancer, low Ki-67 score, low genomic risk). The extent of an endocrine effect of the
chemotherapy itself is under discussion. The voting result of the SG-BCC panellists
was quite heterogeneous. From the German perspective, it is impossible to differentiate
between cytotoxic and chemotherapy-induced endocrine effects.
Effective chemotherapy regimens
In patients with stage I/II ER+/HER2 breast cancer without LN involvement and chemotherapy
indication, the majority of SG-BCC panellists (34%) recommend an anthracycline/cyclophosphamide/taxane-based
regimen, plus 6% who chose a dose-dense anthracycline-containing regimen. An anthracycline-free
regimen with either four (32%) or six cycles (12%) of taxane/cyclophosphamide (TC)
was favoured by 44% of panellists. The broad vote is in line with the recommendations
of the AGO Mamma [1 ]. The German experts refer to the standard treatments recommended by the AGO Mamma
[1 ]. The chemotherapy regimen to be used must be decided individually with the patient
taking into account potential adverse events. In patients with low volume LN involvement,
anthracycline-free standard chemotherapy regimens are generally considered to be equivalent
to anthracycline-containing standard regimens. Equal efficacy with the standard
anthracycline-taxane sequences has been demonstrated for the TC regimen only
if six cycles (6× docetaxel/cyclophosphamide) are administered.
Focus on the postmenopausal patient
Trials such as ADAPT [8 ], MINDACT [43 ], TAILORx [44 ] and RxPONDER [45 ] have studied the impact of endocrine therapy ± chemotherapy in ER+/HER2− breast
cancer. Based on the trial outcomes, the SG-BCC panellists see the indication for
chemotherapy in addition to endocrine treatment (vs. endocrine treatment alone) in
the majority of postmenopausal stage III patients, regardless of biomarkers (68%)
and in the case of large tumour volume, for example, N3 (≥ 10 affected lymph nodes)
or T3N2 (96%). The German experts agree in each case here, since in the high-risk
clinical situation there is the basic indication for chemotherapy.
When asked whether chemotherapy is indicated in the same patient – postmenopausal,
stage III – with G1/2 cancer and lobular histology, 48% SG-BCC panellists agree, while
52% reject this recommendation. In case of low-risk G1 cancer with Ki-67 < 10%, 63%
do not recommend chemotherapy. In terms of the RS, 61% of SG-BCC panellists reject
chemotherapy for RS < 11, while 58% see an indication for chemotherapy for RS < 25.
From the German perspective it is impossible to comment on the indication for chemotherapy
due to the limited information in the question. This is also reflected in the ambivalent
outcome of the voting. The German experts add that the decision on chemotherapy does
not depend on histology (NST or lobular), but on the known clinical-pathological factors
and, if needed, on gene expression analysis.
Chemotherapy for high tumour burden
If chemotherapy is indicated in ER+/HER2 negative breast cancer with locally advanced
stage or with a high tumour burden, the German experts refer to the standard chemotherapies
as recommended by the AGO Mamma [1 ].
Adjuvant Systemic Therapy in Estrogen Receptor-negative (ER−) Breast Cancer
Adjuvant Systemic Therapy in Estrogen Receptor-negative (ER−) Breast Cancer
TNBC and ER−/HER2+ breast cancer
In pN0 patients with ER-negative (ER−) and HER2+ breast cancer and tumour size of
5 – 6 mm and larger, a majority of SG-BCC panellists (52%) recommend adjuvant anti-HER2-based
systemic therapy. Almost as many (46%) would also start adjuvant anti-HER2 therapy
in smaller lesions (including 12% even in microinvasion). The German experts add that
the prognostic data of this patient group reveals a significant risk of recurrence
regardless of tumour size [48 ], [49 ], [50 ]. Recent retrospective data [51 ] suggests an effective effect of adjuvant anti-HER2 therapy even in very small HER2+
breast cancers (pT1a).
In case of TNBC without LN involvement (pN0), the majority of SG-BCC panellists (46%)
favour adjuvant systemic therapy if the tumour size is 5 mm or larger. The German
expert group agrees with reference to the AGO Mamma [1 ].
Adjuvant Systemic Therapy in HER2-positive Breast Cancer
Adjuvant Systemic Therapy in HER2-positive Breast Cancer
Trastuzumab ± Pertuzumab
Patients with HER2+ breast cancer usually also require adjuvant anti-HER2 targeted
treatment if chemotherapy is indicated. The AGO Mamma recommends trastuzumab-based
adjuvant therapy in patients without LN involvement and tumour size larger than 5 mm
(6 – 10 mm: LoE 2bB AGO+; > 10 mm: LoE 1aA AGO++). This decision must be re-evaluated
on a case-by-case basis in HER2+ breast cancer ≤ 5 mm (LoE 2bB AGO+/−). Adjuvant trastuzumab
plus pertuzumab is recommended in patients with lymph node involvement (pN+) (LoE
1bB AGO+) and is an option only in some patients without lymph node involvement (LoE
1bB AGO+/−) but at increased risk [1 ]. The German experts therefore agree with the majority vote of the SG-BCC panellists
(94%) that patients with HER2+ breast cancer without LN involvement should not receive
adjuvant pertuzumab in addition to trastuzumab.
Adjuvant use of neratinib?
The adjuvant use of neratinib in patients with prior (neo)adjuvant trastuzumab/pertuzumab
and/or trastuzumab emtansine (T-DM1) regimen is supported by 63% of the SG-BCC panellists
in the positive ER (ER+) and high risk of recurrence (for example, ≥ 4 involved LN).
The AGO Mamma recommends that patients with ER+/HER2+ breast cancer who have already
received one year of trastuzumab should continue treatment with neratinib for one
year in combination with standard endocrine therapy as an option (LoE 1bB AGO+), and
in the post-neoadjuvant setting on an individual basis in non-pCR patients (LoE 2bB
AGO+/−) [1 ]. Due to a lack of data, there is no recommendation on the use of neratinib following
trastuzumab/pertuzumab and T-DM1 treatment.
The German experts agree with the majority vote of the SG-BCC panellists, as the AGO
Mamma sees a possible indication in ER-positive cases at increased risk. The German
experts note the potential adverse events of neratinib, which must be discussed with
the patient.
Anthracyclines and anti-HER2 therapy
A clear majority (76%) of SG-BCC panellists agree that there are patients with HER2+
breast cancer who can receive an anthracycline sequentially in addition to anti-HER2
therapy combined with anthracycline-free chemotherapy. The German experts agree with
this vote. Sequential anthracycline administration is an option depending on individual
risk and individual (in particular cardiac) comorbidities.
T-DM1 instead of trastuzumab/paclitaxel?
Two-thirds of SG-BCC panellists (69%) see no indication for T-DM1 in the adjuvant
setting in patients with HER2+ stage I breast cancer, while 31% would consider adjuvant
T-DM1 in special circumstances. The German experts agree and add that T-DM1 is not
approved for this situation because there are no study data for such an approach.
Adjuvant Systemic Therapy in TNBC
Adjuvant Systemic Therapy in TNBC
Adjuvant PD1-/PD-L1-targeted therapy in TNBC?
About 90% of SG-BCC panellists see no indication for PD/PD L1-targeted immune checkpoint
inhibitors in addition to adjuvant chemotherapy in patients with stage II/III TNBC.
The German experts agree with the SG-BCC majority vote and note the insufficient data
and lack of approval of immune checkpoint inhibitors in early TNBC. In terms of adjuvant
treatment, reference is made to the currently ongoing Alexandra trial [10 ]. They add that patients with early TNBC and chemotherapy indication should primarily
receive neoadjuvant treatment [1 ].
Adjuvant use of PARP inhibition?
One hopeful therapeutic perspective in early BRCA1/2-associated breast cancer is the
use of PARP inhibitors. In terms of the future outcomes of the OlympiA trial [3 ], 48% of SG-BCC panellists would support adjuvant olaparib in BRCA1/2-associated
breast cancer if after three years of follow-up the OlympiA trial will show an absolute
benefit in invasive disease-free survival (iDFS) of > 5% in the olaparib arm versus
the control arm. From the German perspective, we should wait for the presentation
of the outcome data at the ASCO meeting in June 2021.
Surgical Issues
BCS plus radiotherapy in locally recurrent breast cancer
If a patient is diagnosed with intramammary recurrence and/or ipsilateral second breast
cancer more than five years after surgery for the primary tumour followed by radiotherapy,
63% of the SG-BCC panellists see BCS plus radiotherapy as a suitable alternative to
mastectomy. The German experts agree in principle, but still recommend as primary
option mastectomy (LoE 3b AGO++). According to the AGO Mamma, BCS is an option if
subsequent (partial) irradiation of breast is possible (LoE 2bB AGO+) [1 ].
BCS for patients with recurrence?
The majority of SG-BCC panellists see BCS as an option in patients with intramammary
recurrence if it is a low-risk situation (small cancer of the luminal A type) (majority
vote: 81%) or if the initial diagnosis occurred at least five years previously (majority
vote: 64%). The German experts agree that BCS is justifiable in small cancers and/or
luminal A type. Moreover, a time limit cannot be defined. The longer since the initial
diagnosis, the less likely is a local recurrence, but rather a second cancer. In everyday
clinical practice, however, the distinction is not allways possible.
If repeat radiotherapy is not possible in a patient with intramammary recurrence,
the question arises as to whether BCS is appropriate. The SG-BCC vote was 50 : 50,
reflecting the complexity of decision-making. If radiotherapy following BCS is not
an option, the German experts recommend the discussion with the patient should primarily
focus on mastectomy with possible reconstruction (LoE 3bB AGO++) [1 ].
No axillary intervention?
The majority (83%) of the SG-BCC panellists feel that no axillary intervention is
needed in patients over the age of 70 if there are no clinically suspect lymph nodes
(cN0). The German experts point out that the decision does not depend solely on the
age of the patient, but that comorbidities, the risk of recurrence and possible therapeutic
consequences must be considered and discussed with the patient. The decision for or
against axillary surgery should only be taken after detailed information. This is
also reflected in the recommendations of the AGO Mamma [1 ]. The German experts also refer to the INSEMA trial [52 ].
No surgery following NAST?
With a clear majority (86.00%), the SG-BCC panellists reject omitting that surgery
in patients with early breast cancer and clinical as well as radiological complete
response with NAST. The German experts agree with this vote (majority vote: 84%).
Surgical approach in the axilla
The SG-BCC panellists did not agree on the question of whether to remove more than
ten LN in high axillary tumour burden (> 5 LN involved). The German experts point
out that ALND is defined in terms of its anatomical boundaries and is not based on
the number of removed lymph nodes. The goal is to clear the axilla of all tumour manifestation.
The SG-BCC panellists also failed to reach a consensus on the question of surgical
approach in the axilla in patients who, after BCS and in an N0 situation (“sentinel
node mapping”), currently present with ipsilateral recurrence without LN involvement
on imaging. About one third of the SG-BCC panellists recommend SLNE with or without
frozen section and 12% favour ALND, while 20% are against axillary surgery. The German
experts do not agree with the interventions in the axilla. According to AGO Mamma recommendations,
SLNE in cN0 patients after primary SLNE (LoE 2aB AGO−) is not indicated [1 ].
Oligometastasis
Curative intent in isolated metastasis
In patients with clinical stage T2N1 breast cancer and isolated bone metastasis, the
SG-BCC panellists (85%) recommend a curative therapeutic approach with optimal systemic
therapy and radiotherapy of the isolated metastasis. The German experts agree with
the maximum curative approach whenever there is a chance of cure or long-term survival.
Intensive treatment even in case of 3 – 5 metastases
If a patient (cT2N1) is diagnosed with multiple (> 3) bone metastases confirmed by
fine-needle biopsy and the tumour is no longer clinically detectable in the breast
and axilla after 6 months of systemic therapy with excellent clinical response in
the bone, the SG-BCC panellists (69%) recommend a palliative concept with regard to
local and loco-regional control. The German experts do not agree with the SG-BCC majority
vote for a palliative loco-regional concept, but recommend at least considering the
continuation of a multimodal approach with curative intent.
Follow-up Care and Quality of Life in Breast Cancer Patients
Follow-up Care and Quality of Life in Breast Cancer Patients
Intravaginal oestrogens for mucosal dryness
If a patient on adjuvant AI therapy experiences mucosal or vaginal dryness that cannot
be adequately relieved with moisturisers or lubricants, SG-BCC panellists (73%) recommend
intravaginal oestrogens for symptomatic relief. The German experts agree in principle,
but caution that only topical vaginal oestriol containing oestrogens may be used.
These are also considered safe for patients with ER+ breast cancer and do not negatively
affect treatment success [53 ]. The issue should be addressed proactively. It is important to maintain compliance
with the systemic therapy.
Scalp cooling to prevent alopecia
SG-BCC panellists (69%) recommend that patients receiving chemotherapy associated
with a risk of alopecia be routinely offered scalp cooling. The German experts agree
in principle [54 ]. This prevents higher-grade alopecia in 40 – 50% of patients [55 ], [56 ]. The patients must be informed that side effects, especially headaches, may occur
as a result of the strong cooling of the scalp. However, coverage by health insurance
is still limited in Germany at present.
Aiming for physical activity
The SG-BCC panellists particularly recommend physical activity and exercise (44%)
as well as acupuncture (20%) and normalisation of body weight (20%) to alleviate disease-
and treatment-related secondary symptoms of breast cancer. From the German perspective,
all the above proposals are important options and should be pursued according to individual
needs and preferences. The best data is on 3 – 5 hours of physical activity per week
(LoE 1bA AGO++). Other measures can be found in the recommendations of the AGO Mamma
[1 ].
Reducing alcohol consumption
Reduced alcohol consumption can help reduce the risk of recurrence in breast cancer
patients. The majority of SG-BCC panellists (57%) recommend a maximum of one alcoholic
drink per day. The AGO Mamma recommends limiting daily alcohol consumption to a maximum
of 6 g/day (LoE 2bB AGO+) [1 ]. Regardless of this recommendation, it is important to set realistic goals. The
general rule is that the less alcohol the better.
Comments
The post-St. Gallen meeting was organised and conducted by Aurikamed Institute GmbH
and made possible by a non-restricted grant from AstraZeneca GmbH, Daiichi Sankyo
Deutschland GmbH, Exact Sciences Deutschland GmbH, Lilly Deutschland GmbH, Mylan Germany
GmbH, Pierre Fabre Pharma GmbH, Veracyte, Inc. The responsibility for preparing the
manuscript rested solely with the authors of the “writing committee”. The authors
would like to thank Ms. Birgit-Kristin Pohlmann, Nordkirchen, for her editorial support
during the preparation of the manuscript.
