Key words St. Gallen Consensus 2023 - early-onset breast cancer - genetics - pathology - surgery
- radiotherapy - (neo)adjuvant systemic therapy
Introduction
This yearʼs 18th St. Gallen (SG) consensus conference on the treatment of patients
with early breast cancer (SGBCC: St. Gallen International Breast Cancer Conference)
focused on
practice-oriented questions and, in particular, on clinical situations that are controversial
and difficult zu decide. One focus was to highlight the importance of individual treatment
decisions and to clarify their clinical relevance using case studies with different
clinical scenarios. This yearʼs SGBCC panel consisted of 71 breast cancer experts
from 27 countries,
including five panel members from Germany (cf. [Table 1 ]). The SGBCC recommendations are based on a majority vote by the SGBCC panel. The
aim is to establish
an international consensus for everyday clinical practice. In parallel, we shall also
work out which areas still have a low level of consensus in order to devise new study
concepts.
Table 1 International SGBCC Panel 2023.
Stephan Aebi (Switzerland)
Meteb Al-Foheidi (Kingdom of Saudi Arabia)
Fabrice André (France)
Mikola Anikusko (Ukraine)
Rajendra Badwe (India)
Andrea V. Barrio (USA)
Carlos Barrios (Brazil)
Jonas Bergh (Sweden)
Hervé Bonnefoi (France)
Denisse Bretel Morales (Peru)
Sara Y. Brucker (Germany)
Harold J. Burstein (USA)
Carlos Caldas (GB)
David Cameron (GB)
Fatima Cardoso (Portugal)
Maria Joao Cardoso (Portugal)
Lisa Carey (USA)
Steven Chia (Canada)
Charlotte Coles (GB)
Javier Cortes (Spain)
Giuseppe Curigliano (Italy)
Jana de Boniface (Sweden)
Suzette Delaloge (France)
Angela DeMichele (USA)
Carsten Denkert (Germany)
Gerd Fastner (Austria)
Florian Fitzal (Austria)
Prudence Francis (Australia)
Heba Gamal (Egypt)
Oreste Gentilini (Italy)
Michael Gnant (Austria)
William J. Gradishar (USA)
Bahadir Gulluoglu (Turkey)
Nadia Harbeck (Germany)
Jörg Heil (Germany)
Chiun-Sheng Huang (Taiwan)
Jens Huober (Switzerland)
Zefei Jiang (China)
Orit Kaidar-Person (Israel)
Marleen Kok (Netherlands)
Eun-Sook Lee (Korea)
Sherene Loi (Australia)
Sibylle Loibl (Germany)
Miguel Martin (Spain)
Icro Meattini (Italy)
Kathy D. Miller (USA)
Monica Morrow (USA)
Ann Patridge (USA)
Frederique Penault-Llorca (France)
Martine Piccart (Belgium)
Lori Pierce (USA)
Philip Poortmans (Belgium)
Meredith Regan (USA)
Jorge Reis-Filho (USA)
Isabella Rubio (Spain)
Hope Rugo (USA)
Emiel J. T. Rutgers (Netherlands)
Cristina Saura (Spain)
Elzbieta Senkus (Poland)
Zhiming Shao (VR China)
Christian Singer (Austria)
Beat Thürlimann (Switzerland)
Masakazu Toi (Japan)
Sara Tolaney (USA)
Nicholas Turner (GB)
Andrew Tutt (GB)
Marie-Jeanne Vrancken-Peeters (Netherlands)
Toru Watanabe (Japan)
Walter Weber (Switzerland)
Hans Wildiers (Belgium)
Binghe Xu (VR China)
The SGBCC panel consists of experts from different disciplines, coming from different
countries with different health systems and resources. Thatʼs why a working group
of German breast cancer
experts has been commenting on the voting results of the SGBCC panel for several years.
The German experts refer to the current treatment recommendations of the Mamma [breast]
Commission of
the Working Group for Gynecological Oncology e. V. (AGO) [1 ], that are updated every year and therefore are based on a high level of evidence
and have a high
degree of accuracy. In this manuscript we refer to the recommendations of AGO version
2023.1D [1 ], [2 ].
Follow-up Care in Early Breast Cancer
Follow-up Care in Early Breast Cancer
High body mass index
Patients with early invasive breast cancer have a chance of cure or long-term survival.
The patient may support the long-term benefit of therapeutic interventions by additional
measures,
that affect lifestyle for example. It has been discussed whether a specific diet can
help reduce the risk of recurrence in patients with a body mass index > 25 (BMI > 25).
German
experts agree with the majority vote of the SGBCC panel (73.21%) that there is no
specific diet to reduce the risk of recurrence. However, AGO recommends that patients should
be
informed about modifiable risk factors, such as weight loss for high BMI (AGO chapter
16, slide 8: LoE [level of evidence] 2a, GR [grade] B, recommendation +) [1 ], [2 ].
Accordingly, we agree with the majority vote of the SGBCC panel (83.33%) to motivate
severely overweight patients (BMI > 30) to lose weight in order to reduce the risk
of recurrence
[1 ], [2 ].
The importance of acupuncture
According to the SGBCC panel, acupuncture is a standard method to relieve arthralgia-related
symptoms during aromatase inhibitor (AI) therapy or chemotherapy-induced neuropathy
and should
be reimbursed by each healthcare system (majority vote: 69.64%).
AGO recommends acupuncture as a complementary intervention not only for AI-induced
arthralgias and chemotherapy-induced polyneuropathy (chapter 23, slide 10), but for
a whole range of
symptoms, including nausea/vomiting, depression, hot flashes, and sleep disorders
(chapter 23, slides 6 + 10; chapter 24, slide 6). Reimbursement of costs is justified
in these cases in the
view of the German experts.
Interruption of endocrine treatment for pregnancy?
The first results of the POSITIVE study [3 ] indicate that young women with early hormone receptor-positive (HR+) breast cancer
can temporarily pause therapy
under certain conditions in order to conceive – after at least 18 months of adjuvant
endocrine treatment. The SGBCC panel advises against interrupting endocrine treatment
in women with HR+
breast cancer who have at least four positive axillary lymph nodes and who have been
receiving tamoxifen plus OFS (ovarian functional suppression) for two years (majority
vote: 78.57%).
German experts point out the high risk of relapse in this scenario, with initially
at least four positive lymph nodes, and agree with the SGBCC majority vote. In addition,
the POSITIVE
study [3 ] enrolled predominantly low-risk patients with only 6% of patients (n = 31/516)
that had stage III breast cancer. The situation mentioned above is
not (adequately) reflected by the study results.
Due to the short follow-up of the POSITIVE trial the German experts do not advise
to interrupt endocrine therapy after two years in patients with high risk. According
to a meta-analysis by
the “Early Breast Cancer Trialistsʼ Collaborative Group” (EBCTCG), the annual recurrence
and metastasis rates are up to 6% in HR+ breast cancer over a period of up to 20 years
– depending on
the primary risk of the patient [4 ], [5 ]. The short follow-up of the POSITIVE study (median 41 months) does not yet allow
evidence-based statements on the long-term course. However, this is an individual
decision that must be discussed with the patient.
This also applies to young patients, who have time to become pregnant later. Here,
again the German experts agree with the SGBCC majority vote (77.78%).
Intravaginal estrogen administration
A postmenopausal woman receiving adjuvant AI for estrogen receptor (ER) positive (ER+)
breast cancer may be treated intravaginally (topically) with estrogens if required
for example in case
of mucosal or vaginal dryness (majority vote: 57.58%). German experts add that vaginal
estrogens are very likely safe in patients with ER+ breast cancer. There are no data
to indicate that
slightly elevated systemic estrogen levels negatively impact the efficacy of adjuvant
AI treatment. It is important to use estriol instead of estradiol [1 ], [2 ].
AGO recommends topical treatment with estriol on a case-by-case basis (2b B +/−),
especially if non-hormonal interventions are insufficient (chapter 24, slide 3; chapter
24, slide 13) [1 ], [2 ]. Whether vaginal dryness is a problem should be addressed proactively. German experts
prefer intermittent administration of
estriol.
Pathology
The role of tumor-infiltrating lymphocytes?
According to the SGBCC panel, detection of tumor-infiltrating lymphocytes in the stroma
(sTILs) can be used as a criterion in favor of adjuvant chemotherapy in triple-negative
breast cancer
(TNBC). In a 43-year-old female patient with TNBC (primary tumor 1.6 cm; N0, grade
3, sTIL score 75%), the majority of SGBCC panel members voted for the use of adjuvant
chemotherapy after
tumor excision (87.93%). For a smaller primary tumor (T1b, 0.8 cm, sTIL score > 50%),
58.18% voted in favour of adjuvant chemotherapy.
According to the German experts, both votes are acceptable. According to AGO, chemotherapy
should be considered for TNBC with a primary tumor with a size of at least 0.5 cm
(chapter 11,
slide 6) [1 ], [2 ]. German experts point out that a high TIL score is not the sole criterion to avoid
chemotherapy in TNBC
(chapter 5, slide 15: 2b B +/−) [1 ], [2 ]. The detection of TILs in the stroma can provide a prognostic information for therapy
planning in individual cases. The predictive therapeutic significance, for example
for immunotherapy or a de-escalating strategy, has not yet been evaluated in randomized
trials. An
important prerequisite is that there are standardized histological methods to determine
and to measure TILs.
Genetics
Genetic counseling and testing
German experts agree with the SGBCC panel that patients with breast cancer must have
access to genetic counseling (majority vote: 98.48%). The SGBCC panel voted on various
clinical
scenarios to determine if and when genetic testing is indicated in routine clinical
practice. In each case, the results did not provide a clear recommendation for or
against genetic testing
in routine clinical practice. After all, almost 40% voted for all patients to be tested,
i.e., also those without family predisposition. Almost 48% voted in favor of routine
testing in
everyday clinical practice for the therapy-relevant mutations in the BRCA1/2 and the PALB2 genes. This voting result reflects the diversity of international opinion on this
topic. Therefore, without commenting on the individual voting results, German experts
refer to the recommendations of AGO, which set out in detail the diagnostic and therapeutic
indications
for genetic testing (“companion diagnostic”) (chapter 2, slides 4 + 6; chapter 2,
slide 5) [1 ], [2 ].
Genetic mutations
Based on different gene mutations (BRCA1/2, PALB2, ATM, CHEK2) and taking into account the menopausal status, the SGBCC panel voted whether prophylactic
or risk-reducing
contralateral mastectomy (CRRM) or intensified follow-up (mammography and MRI [magnetic
resonance imaging]-based) should be recommended for patients with early breast cancer
and evidence of
a pathogenic mutation that increases the risk of breast cancer.
Two thirds of the panelists voted for CRRM if BRCA1 mutations were detected in pre- or postmenopause and in a premenopausal patient.
if BRCA2 mutations were detected. Fewer
panel members – about 42% – voted for CRRM when the BRCA2 mutation is diagnosed in postmenopausal patients. Differences depending on menopausal
status were also seen when a
PALB2 mutation was detected: If the PALB2 mutation was diagnosed in premenopause, 42% of panel members voted for CRRM. If the
patient was postmenopausal, 19% voted for CRRM.
The remaining panelists voted in favor of intensified diagnostic imaging ([Table 2 ]).
Table 2 Risk-reducing mastectomy or intensified follow-up care – voting results of the SGBCC
panel (2023) depending on the menopausal status and different gene
mutations.
Surgery
Intensive screening
Abstain
Gene: BRCA1, Menopausal Status: Pre
66.67%
13.63%
19.70%
Gene: BRCA1, Menopausal Status: Post
60.61%
16.67%
22.72%
Gene: BRCA2, Menopausal Status: Pre
63.64%
13.64%
22.72%
Gene: BRCA2, Menopausal Status: Post
42.42%
31.82%
25.76%
Gene: PALB2, Menopausal Status: Pre
42.42%
31.82%
25.76%
Gene: PALB2, Menopausal Status: Post
19.70%
53.03%
27.27%
Gene: ATM, Menopausal Status: Pre
9.09%
72.73%
18.18%
Gene: ATM, Menopausal Status: Post
1.52%
78.78%
19.70%
Gene: CHEK2, Menopausal Status: Pre
7.58%
71.21%
21.21%
Gene: CHEK2, Menopausal Status: Post
1.52%
78.78%
19.70%
The voting results and different recommendations were intensively discussed in the
German expert group. They reflect the known risks for contralateral breast cancer.
In Germany, too, this
topic is discussed intensively and controversially. The decision should be made in
a “shared decision” process (participatory decision making). The patient should get
detailed information on
the current data, taking into account advantages and disadvantages (AGO: chapter 2,
slide 25) [1 ], [2 ].
The risk of contralateral breast cancer (CBC) is significantly increased in the presence
of a pathogenic variant (PV) in BRCA1, BRCA2 , and CHEK2 . For a PV in PALB2 , an
increased risk is only considered for the ER-negative patients. In contrast, the ATM -PV carriers did not show a significantly increased risk of contralateral breast cancer
[6 ], [7 ].
We refer to current data: In premenopausal women, the cumulative 10-year incidence
of CBC was estimated to be 33% for BRCA1- , 27% for BRCA2- , 13% for CHEK2 -PV carriers
with breast cancer, and 35% for PALB2 -PV carriers with ER-negative breast cancer. The cumulative 10-year incidence of CBC
among postmenopausal PV carriers was 12% for BRCA1 , 9%
for BRCA2 , and 4% for CHEK2
[7 ]. With the exception of BRCA1/2 mutations, there are only limited data for other pathogenetic gene variants
and therefore insufficient evidence in favor of CRRM for a risk reduction.
According to the German experts, a CRRM is plausible if a BRCA1/2 mutation is demonstrated. In the case of pathogenic mutations in the ATM and CHEK2 gene, intensified
imaging during follow-up care is currently recommended. As part of participatory decision
making, it is recommended that patients be informed of the potential benefits and
respective risks,
and that both options – prophylactic mastectomy or intensified follow-up – be discussed.
Our patient representative on the German expert committee points out that, in these
cases, CRRM
should be covered by the statutory health insurance if the patient requests it.
Olaparib in patients with a PALB2 mutation?
Opinion was also divided on whether patients with early breast cancer and PALB2 mutations should be treated with olaparib in the adjuvant setting – in accordance
with the criteria
for adjuvant use of olaparib in patients with germline BRCA1/2 mutation (gBRCA1/2 mut). This is against the background that corresponding study data on PALB2 are missing.
A slight majority of panel members (53.45%) voted against, while 37.93% were in favor.
German experts point out the lack of data. Data on olaparib efficacy in PALB2 mutations are only available for metastatic TNBC [8 ] with a “plus/minus”
recommendation from AGO for the metastatic settting (chapter 2, slide 27) [1 ], [2 ]. There are no adjuvant data on this question.
Since this is a rare mutation, a randomized trial is unlikely to be done. The majority
of German experts would draw an analogy in favor of adjuvant olaparib. There is agreement
that this is
an individual decision, taking into account the overall risk and the treatment alternatives.
Unlike in the metastatic setting, a claim for reimbursement is required in the adjuvant
setting.
Olaparib in patients with somatic BRCA mutation?
Controversy also surrounded the question of whether olaparib should be used in the
adjuvant setting when a somatic mutation is detected in the BRCA1 gene (sBRCA1 mutation):
Almost half of the panel members (48.28%) favor it, while almost as many (46.55%)
are against.
The German experts also have different opinions. They point out that a germline BRCA -negative (gBRCA) but sBRCA1 -positive breast cancer is very rare. Because the
approval of olaparib relates to gBRCA1/2 mutations, there is no formal indication for adjuvant olaparib use. It is not known
whether a conclusion based on “biological criteria” is
justifiable. There is agreement that a special testing for sBRCA mutations in breast cancer is currently not recommended. However, it may be useful
to include sBRCA mutations
in the context of comprehensive analyses in molecular tumor boards.
BRCA2 mutation in ER+ and HER2-positive (HER2+) breast cancer is also rare. If the inclusion
criteria of the OlympiA study [9 ], [10 ] are met with regard to the tumor stage, a slight majority of panel members (45.61%
vs. 43.86%) would use olaparib in addition to standard adjuvant therapy.
According to the German experts, this is not evidence-based. The adjuvant approval of olaparib does not include HER2+ breast cancer,
but refers to HR+/HER2-negative (HER2−) breast
cancer, taking into account the inclusion criteria of the OlympiA pivotal study [9 ], [10 ].
Ductal Carcinoma in Situ (DCIS)
Ductal Carcinoma in Situ (DCIS)
Vote for hypofractionation
The questions regarding ductal carcinoma in situ (DCIS) focused on adjuvant radiotherapy
after breast-conserving surgery.
For low-risk patients with DCIS who undergo breast-conserving surgery, the SGBCC panel
gave a clear vote in favor of moderate hypofractionated radiation regardless of menopausal
status. For
premenopausal women, the vote was even clearer than for postmenopausal women (majority
vote: 50% and 33.85%), respectively). This may be a consequence of the fact that in
postmenopause,
radiotherapy indication in this constellation is rather rare, and 20% of SGBCC panel
members recommend radiation therapy of the partial breast (5 fractions) for postmenopausal
patients after
breast-conserving surgery, but only for almost 5% of premenopausal patients. Regardless
of menopausal status, no panel member voted for conventional fractionated radiation.
The German experts welcome the clear vote in favor of moderate hypofractionation.
To date, AGO gives a “plus” recommendation (1a A + each) for both moderately hypofractionated
and
conventionally fractionated radiation therapy for those patients. Partial breast irradiation
is also an alternative in Germany for postmenopausal patients with low-risk DCIS (AGO:
chapter 7,
slide 13) [1 ], [2 ].
Indication for adjuvant radiotherapy
Using different clinical scenarios – depending on the age of onset (< 50 years, 50 – 65
years, > 70 years), tumor diameter (</>2 cm), and/or evidence of comedonecroses (yes/no)
– the SGBCC panel voted on which DCIS patients should receive adjuvant radiotherapy
after breast-conserving surgery with a clear incision margin (> 2 mm).
German experts refrain from commenting on the individual – very detailed – scenarios
and point out that postoperative radiation after breast-conserving surgery reduces
the risk of
ipsilateral local recurrence but has no effect on overall survival. It is therefore
indicated when local control is the primary concern (AGO: chapter 7, slide 12). Fixed
criteria for or
against adjuvant radiotherapy do not exist, so the decision should be made individually
in discussion with the patient. This also applies to patients receiving adjuvant endocrine
therapy
postoperatively because of ER+ DCIS – the reason being that the adjuvant radiation
time window will have passed should adjuvant endocrine therapy be discontinued due
to side effects.
The decision for or against radiation therapy after breast-conserving surgery cannot
be broken down to one factor, but should take into account the overall constellation
(benefit-risk). As
a general rule, the following applies: According to the German experts, the more favorable
the risk constellation and the lower the estimated life expectancy, the more likely
it is that
postoperative radiotherapy after breast-conserving surgery can be forgone.
A healthy postmenopausal woman who has received adjuvant radiotherapy after being
diagnosed with ER+ DCIS and undergoing a breast-conserving operation is considering
additional adjuvant
endocrine therapy to reduce the risk of an “in-breast” relapse. Considering potential
side effects and low effect of endocrine therapy, almost 40% (39.29%) of SGBCC panel
members recommended
low-dose tamoxifen (5 mg/day). Almost 30% (28.57%) would advise against endocrine
therapy.
According to AGO, endocrine therapy is an option on a case-by-case basis as an addition
to the adjuvant radiation therapy (chapter 7, slide 15) [1 ], [2 ]. For postmenopausal women with ER+ DCIS, tamoxifen (tamoxifen 20 mg/day, tamoxifen
5 mg/day) or the application of an AI are possible options [1 ]. The indication for endocrine therapy should be based on possible risk factors,
potential side effects, and patient preference. Patients should be informed that
additional endocrine therapy is not associated with an overall survival benefit and
that the effect on local control in the ipsilateral breast is small [1 ].
The preventive effect concerns the contralateral side. There is no approval for this
in Germany. The evidence for the benefit of low-dose tamoxifen (5 mg/day) is limited
from the German
point of view. However, low-dose tamoxifen appears to be better tolerated than standard-dose
tamoxifen 20 mg/day [11 ].
Male Breast Cancer
A man with early invasive breast cancer without evidence of a gBRCA1/2 mutation should undergo a conventional mastectomy according to the majority of SGBCC
panel members (41.82%).
36.36% of the panel members expressed their support for breast-conserving surgery
plus radiation therapy. Since men can undergo breast-conserving surgery in the same
way as women, from the
German point of view the majority vote (mastectomy) is not acceptable. The same surgical
guidelines apply to men with early breast cancer as they do to women, in each case
respecting the
aesthetic/cosmetic considerations. The possibility of breast-conserving surgery exists
regardless of gBRCA1/2 status.
The preferred endocrine therapy in early male breast cancer, regardless of stage (I – III),
is tamoxifen [1 ], [2 ]. The German
experts agree with the majority vote of the SGBCC panel (stage I: 80%; stage III:
50.77%) for tamoxifen. Loss of libido can occur during endocrine therapy [12 ].
If AI is used, it must always be combined with a gonadotropin-releasing hormone agonist
(GnRHa) in males. Nearly 30% of SGBCC panel members would use the AI/GnRHa combination
in stage III.
Adjuvant Radiotherapy
Vote for moderate hypofractionation
Regarding the use of adjuvant radiotherapy in early invasive breast cancer, the SGBCC
panel agreed on various clinical scenarios. A clear majority of participants was in
favor of moderate
hypofractionated radiotherapy (15 – 16 fractions over three weeks). Ultra-hypofractionated
radiation therapy (5 fractions in one week) was not successful:
Thoracic wall irradiation after mastectomy independent of radiation of the axillary
lymph nodes: Moderate hypofractionation 64.06% (vs. 10.94% for ultra-hypofractionated
radiotherapy [5
sessions/week])
Whole-breast radiotherapy (WBRT) after breast-conserving surgery regardless of radiotherapy
of the axillary lymph nodes: 60.94% (vs. 15.65% for ultra-hypofractionated radiotherapy
[5 sessions/week])
The voting results are in line with the recommendations of AGO [1 ], [2 ]: Moderate hypofractionation is clearly the standard in
Germany after breast-conserving surgery, whereas ultra-hypofractionation is currently
an option in individual cases (AGO 1b B +/−). German experts point out that this year
AGO has given a
“plus” recommendation for the first time to moderate hypofractionation for locoregional
irradiation of axillary lymph nodes (1b B +) (chapter 13, slide 26). However, conventional
fractionation is still recommended (AGO 1a A ++) [1 ], [2 ]. The reason is that the evidence for moderate hypofractionation for
the axillary nodes is somewhat weaker since relevant study data are not yet available
as a full-length publication [13 ]. It is currently unclear whether tumor
biology should influence the decision on fractionation.
Indication for “boost” radiotherapy
German experts agree with the majority vote (35.94%) of the SGBCC panel (with 34.38%
abstentions) that, following a breast-conserving surgery of primary invasive breast
cancer, there is an
indication for “boost” radiotherapy to the primary tumor bed if one of the following
prognostic factors is present: A poorly differentiated tumor (G 3), extensive intraductal
component
(EIC), TNBC or HER2+ subtype, and age < 50 years. The above mentioned “boost” criteria
largely correspond to the German recommendations of AGO [1 ], [2 ].
German experts recommend intraoperative clip marking of the tumor bed if “boost” radiotherapy
is indicated [1 ], [2 ]. They point
out that in Germany, “boost” radiotherapy is used very often in international comparison.
The increased rate of side effects and increased risk of fibrosis should be considered
when making
treatment decisions [14 ], [15 ].
“Boost” radiotherapy after neoadjuvant systemic therapy?
There was a mixed vote on the question of whether “boost” radiotherapy could be waived
if pathological complete remission (pCR) was achieved after neoadjuvant systemic therapy
(NAST) with
breast-conserving surgery. German experts point out that no data are available for
this situation. This may be reflected in the fact that many SGBCC panel members (38.10%)
did not vote.
German experts position themselves as follows: If there is an indication for “boost”
radiotherapy based on prognostic factors, it is also recommended for patients with
pCR, regardless of
the underlying tumor biology.
Indication for whole-breast radiotherapy
The indication for adjuvant WBRT (after breast-conserving surgery) in a healthy postmenopausal
woman with early luminal A-breast cancer (1.3 cm) without axillary lymph node involvement
would be decided by the majority (41.30%) of SGBCC panel members based on life expectancy
and the patientʼs age. The SGBCC panel members consider an indication for WBRT at
a life expectancy
of more than 15 years. An almost identical result emerged from the on-site vote among
the audience (majority vote: 39%).
German experts agree with this. The focus on life expectancy corresponds to the recommendation
of AGO, which, however, applies a life expectancy of 10 years [1 ], [2 ]. In the PRIME-II study, forgoing WBRT (after breast-conserving surgery) was associated
with a significantly increased local ipsilateral risk of
recurrence at 10 years (p < 0.001), but had no effect on overall survival (OS; p = 0.68)
[16 ], [17 ]. The study included
elderly patients (≥ 65 years) with HR+ early invasive breast cancer and low risk (pT1–2
< 3 cm, pN0, M0), who underwent breast-conserving surgery and adjuvant ET ± WBRT [16 ], [17 ]. The voting result of the SGBCC panel members suggests that the reduction of the
local recurrence rate may be a good
reason for WBRT – especially in the context of decreasing therapy duration as a consequence
of hypofractionation and good tolerability.
The following vote substantiates this: Two thirds (63.46%) of SGBCC panel members
considered the most important clinical outcome of the PRIME-II study to be the reduction
of the “in-breast”
recurrence rate, and only 26.92% would forgo adjuvant WBRT because of the lack of
survival benefit. According to the German experts, the results of the PRIME-II study
[16 ], [17 ] should be discussed with the patients in the sense of a “shared decision”.
Indication for post-mastectomy radiation therapy
SGBCC panel members voted on the indication for post-mastectomy radiation therapy
(PMRT) in postmenopausal patients based on several clinical scenarios – including
lymph node involvement,
tumor stage, tumor biology, and whether the type of reconstruction changes the indication
(skin-sparing vs. conventional mastectomy). It seems worth mentioning that 25% of
panel members
recommended thoracic wall irradiation in a postmenopausal patient with an HR+ T2 tumor
and a mastectomy with one positive lymph node. In contrast, with two positive lymph
nodes, it was 54%,
and with three positive lymph nodes, 94% suggested this intervention. German experts
refer to the current recommendations of AGO ([Fig. 1 ]) [1 ], [2 ].
Fig. 1 Current recommendations of AGO for post-mastectomy radiation therapy (PMRT) in the
axilla with 1 – 3 affected lymph nodes [1 ]. (Source: The
Breast Cancer Commission of the Gynecological Oncology e. V. working group).
According to the German experts, the decision for or against PMRT should be discussed
in the interdisciplinary tumor board. The type of reconstruction does not affect the
oncologic
treatment decision. Surgical technique alone is not a reason for more extensive radiotherapy
if the indication for nipple or skin-sparing mastectomy is correctly done. Conversely,
if there
is an indication for radiotherapy for oncological reasons, this should not be forgone
– irrespective of any implant-based reconstruction that has already taken place.
Detection of a heterozygous ATM mutation
Detection of a heterozygous pathogenic mutation in the ATM gene is not a contraindication to adjuvant radiotherapy after breast-conserving surgery
(SGBCC majority vote: 73.58%).
These patients can undergo breast-conserving surgery and receive radiotherapy postoperatively.
German experts agree with this. German experts add that this does not apply to patients
with
homozygous mutation in the ATM gene or when a TP53 mutation is detected. In these two cases, radiotherapy should be viewed critically
because of the increased risk of secondary
malignancy, and ablative procedures should be considered first.
Breast and Axillary Surgery
Breast and Axillary Surgery
Axilla surgery
Surgery in the axilla after NAST has been debated for years. If the axilla is not
tumor-free after NAST, the question arises about how patients are further treated
in that area. In patients
with TNBC and a residual tumor in the axilla (macrometastasis in 1/3 sentinel lymph
nodes [SLN]) after anthracycline/taxane-based NAST, the majority (46.94%) of SGBCC
panel members voted to
complete axillary lymph node dissection (ALND). Just over 20% (20.41%) voted for radiation
of the axilla and 28.57% would recommend ALND plus radiation. The audience vote yielded
almost
identical results.
The majority vote for ALND is in line with the AGO recommendation [1 ], [2 ]. German experts emphasize that in the case of
macrometastatic SLN after NAST, the probability of other non-SLNs being affected is
over 60% [18 ]. In Germany, no full-dose axilla radiation is recommended
after ALND, as the risk of lymphedema increases significantly. There are currently
insufficient data for axillary radiation alone. Here, the results of the AXSANA [19 ] and the TAXIS studies (NCT03513614) should be awaited.
According to the German experts, it seems important that AGO recommends a “targeted
axillary dissection” (TAD) as an equivalent alternative to ALND in patients with clinical
complete
remission (ycN0) who initially had a nodal-positive disease prior to NAST, so that
many patients with a good response to NAST can be spared ALND and its long-term effects.
German experts add that the decision for axillary treatment after NAST should be made
in the interdisciplinary tumor board – depending, among other things, on the extent
of axillary lymph
node involvement. In addition, there may be implications for subsequent systemic therapy,
such as adjuvant use of olaparib [9 ], [10 ]. This applies not only to TNBC, but also to patients with HR+ breast cancer and
a CPS-EG score ≥ 3.
Multifocal breast cancer
In light of the recent data from the ACOSOG-Z11 102 study [20 ] on the surgical approach to multifocal breast cancer, the SGBCC panel recommended
two tumor
resections as the standard of care for two tumor lesions in the ipsilateral breast
in low-risk patients, if technically feasible (majority vote: 68.18%). The vote was
based on the example of
a postmenopausal patient with HR+/HER2− breast cancer without lymph node involvement
and two ipsilateral tumors in two adjacent quadrants. German experts agree with this.
In the
ACOSOG-Z11 102 study, previously published as an “abstract” and presented at the San
Antonio Breast Cancer Symposium (SABCS) in December 2022, patients had up to three
ipsilateral tumors
with a distance of ≥ 2 cm in a maximum of two affected quadrants. Patients with or
without clinically abnormal axillary lymph nodes (cN0/cN1) were eligible for inclusion
in the study. The
cumulative incidence of local recurrence after five years was 3.1% (95% confidence
interval [CI]: 1.3 – 6.4) [20 ].
Locoregional Recurrence
Indication for repeat radiotherapy
German experts agree with the majority vote of the SGBCC panel (58.18%) to recommend
breast-conserving surgery with adjuvant radiotherapy to a postmenopausal patient with
ipsilateral
recurrence (ER+/HER2−; cN0; lesion < 2 cm) again after nine years. At initial diagnosis,
stage II was present without LN involvement. Radiotherapy was administered after lumpectomy.
This
was followed by adjuvant systemic therapy. German experts would like to add that it
is necessary to clarify whether further radiotherapy is possible before the surgical
intervention. This is
the prerequisite for the indication of breast-conserving surgery. Partial breast radiotherapy
(PBR) is preferable.
If the recurrence in the ipsilateral breast occurs after three years and adjuvant
endocrine therapy was discontinued two years ago (for example, at the patientʼs request
or due to side
effects), a mastectomy is indicated according to the SGBCC panel (majority vote: 74.07%).
German experts also agree with this. Although there is no strict threshold for the
relapse-free
interval, the shorter it is, the less favorable the prognosis usually is, and the
higher the cumulative toxicity risk under re-irradiation. In addition, if the recurrence
interval is short,
it is important to question how effective the initial radiotherapy was.
From the German expert opinion, the interval of three years is not an absolute contraindication
to do another breast-conserving surgery plus radiotherapy, but the decision should
be made
with caution. Mastectomy is a safe alternative to breast-conserving surgery plus radiotherapy.
Isolated local recurrence under endocrine treatment
If there is an isolated local recurrence during adjuvant AI therapy, which has been
completely resected and submitted to definitive local therapy, the SGBCC panel members
gave a
heterogeneous opinion to continue endocrine treatment. Some (23.64%) chose to switch
to tamoxifen. As many as 20% of SGBCC panel members had advocated for switching to
fulvestrant plus
CDK4/6 inhibitor, and 5.45% would combine a CDK4/inhibitor with an AI.
German experts believe that only switching to tamoxifen or switching from a non-steroidal
AI to exemestane or vice versa is possible; both options are approved. There is no
indication for
switching to a CDK4/6 inhibitor plus fulvestrant or AI or to fulvestrant alone, neither
of which has been studied or approved for this situation. German experts would recommend
a
preoperative therapy – taking into account the tumor size – to monitor the treatment
response and to be able to adjust the therapy if necessary.
If the isolated local recurrence under AI therapy in the situation described above
has a high ER expression (ER+/HER2−) and no adjuvant chemotherapy was initially given,
the majority
(62.94%) of SGBCC panel members would not recommend adjuvant chemotherapy even not
in the case of a recurrence. German experts agree with this and recommend changing
the endocrine therapy
[1 ], [2 ].
In case of relapse under ongoing adjuvant ET, the decision for or against adjuvant
chemotherapy cannot be made based on gene expression analysis. The majority (52.73%)
of SGBCC panel
members rightly point out that the clinical decision is made based on other factors
such as grading, Ki67 expression, HR status, or patient age. The gene signature thresholds have
only been validated for the primary tumor, and not for the relapsed disease or the
situation while ongoing adjuvant therapy [1 ], [2 ].
Adjuvant Endocrine Therapy
Adjuvant Endocrine Therapy
Uncertain endocrine sensitivity
Breast cancer with estrogen receptor (ER) expression of 1 – 10% is generally considered
endocrine-positive (ER-low), but the endocrine sensitivity is uncertain. According
to AGO
recommendation, endocrine therapy is an option when endocrine sensitivity is questionable
[1 ], [2 ]. Nevertheless, with very low
ER expression and additional aggressive tumor biology, it cannot be ruled out that
biologically and functionally the tumor behaves like TNBC and does not respond to
endocrine therapy. In
analogy to TNBC, chemotherapy – eventually with pembrolizumab – might be discussed.
This should be considered in this special group of patients as part of an individualized
therapy.
Therefore, German experts cannot fully agree with the voting of the SGBCC panel members,
since 57.38% recommend endocrine therapy at an ER expression of 1%. German experts
add that in the
abovementioned scenario – low ER expression – there is no evidence-based data using
pembrolizumab.
Endocrine therapy duration
It is undisputed that patients with ER+/HER2− invasive stage I breast cancer should
receive endocrine therapy for five years (majority vote: 88.24%). This is also true
for stage II patients
without axillary lymph node involvement (N0) (vote: 44.90%).
As many as 36.73% of SGBCC panel members would extend the endocrine therapy duration
to 7 – 8 years in this situation (stage II, N0). German experts do not agree with
this. Prolonged
adjuvant ET in the sense of an extended endocrine adjuvant therapy (EAT) is indicated,
according to the recommendation of AGO [1 ], [2 ], among other things, in nodal involvement (N+).
According to German experts, the duration of EAT depends not only on the initial tumor
extent (nodal status, tumor size), but also on the initial ET. Recommended for the
majority of
patients is 7 – 8 years with AI therapy [21 ] and 10 years with tamoxifen [22 ], [23 ], [24 ]. In individual cases, a 10-year therapy can also be considered as an individual
decision for patients with a very extensive primary tumor load, if the
treatment is well tolerated and there are no osseous complications. The German experts
agree with the other votes of the SGBCC panel members, well over 90% of whom recommend
EAT in patients
with ER+/HER2− invasive breast cancer stage II/N+ and III.
There is also consent that the decision in favor of EAT from stage II should be made
taking into account established risk factors, such as stage, grading, treatment tolerability,
and
patient preference (majority vote: 96.97%). The German experts recommend a risk-benefit
assessment. Individual deviations are reasonable and possible in individual cases
(AGO chapter 10,
slide 19) [1 ], [2 ].
The SGBCC panel members (majority vote: 60.61%) reject the use of gene expression
analyses to determine the duration of endocrine therapy. The German experts agree,
since the endocrine
therapy duration can be reliably determined using established clinical criteria.
Adjuvant use of abemaciclib
The decision to treat patients with ER+/HER2− invasive breast cancer in the adjuvant
setting additionally with abemaciclib is based on tumor stage and histology, and is
independent of
Ki67 expression (majority vote: 77.27%). This is in line with the approval in Germany
and the USA, which is based on the data from cohort 1 of the monarchE pivotal study
[25 ], [26 ], [27 ].
Following this, the case of a patient with ER+/HER2− invasive stage II breast cancer
(primary tumor 2.3 cm) and macrometastatic sentinel lymph nodes (SLN) was presented
to the panel members
for voting. The majority vote (44.44%) was that adjuvant chemotherapy plus endocrine
therapy is adequate in this situation. Just over 35% would perform ALND to determine
if additional lymph
nodes are positive, and adjuvant treatment with abemaciclib is indicated. The audience
vote yielded an almost identical result. According to German experts, it should be
discussed in an
interdisciplinary tumor board whether the number of positive lymph nodes should influence
the decision on adjuvant systemic therapy. If this is the case and the likelihood
of further lymph
nodes being affected is high, ALND should be discussed considering the potential morbidity
associated with ALND.
Neoadjuvant endocrine therapy
A simple majority (37.88%) of SGBCC panel members would treat a 70-year-old patient
with ER+/PR+ and HER2− invasive breast cancer (cT3N1) and a low risk – defined by
gene expression and
clinical criteria – with neoadjuvant endocrine therapy for approximately six months,
followed by breast-conserving surgery. Another 34.85% would give neoadjuvant ET until
maximum
response.
Neoadjuvant ET is very rarely performed in Germany – possibly as an option for elderly
and comorbid patients, but not per se due to advanced age. However, it is generally an
option
when there is an indication for breast-conserving surgery for ER+ invasive breast
cancer. If a neoadjuvant ET is used, German experts agree to administer the ET for
a relatively long time.
AGO recommends AI treatment for at least six months (“plus” recommendation) [1 ], [2 ].
Chemotherapy in ER-positive Breast Cancer
Chemotherapy in ER-positive Breast Cancer
Therapy of choice in HR+/HER2− invasive breast cancer is endocrine treatment [1 ], [2 ]. If the risk of relapse is high, adjuvant
chemotherapy is also indicated. The benefit in patients with genomic intermediate
risk is questionable. SGBCC panel members voted on various clinical scenarios when
chemotherapy should be
recommended.
Short preoperative endocrine therapy
With a majority vote (69.70%), SGBCC panel members recommend a short 2 – 4 week ET
preoperatively to potentially identify those who do not require chemotherapy in addition
to endocrine
therapy in patients with HR+/HER2− early breast cancer and genomic intermediate risk.
This procedure, which is based on the POETIC study [28 ] and the German
ADAPT concept [29 ], got a “plus” rating from AGO [1 ], [2 ]. However, there is a lack of long-term
data.
If endocrine sensitivity is checked preoperatively, German experts add that postmenopausal
women should receive at least 2 weeks of treatment with an AI preoperatively, and
premenopausal
women should receive 4 weeks of ET plus OFS. The Ki67 reduction is most effective when OFS and AI are combined. However, the opinion in
the German expert panel is heterogeneous
regarding the clinical consequences. Long-term data are lacking in premenopausal patients
to determine whether this approach ensures that adjuvant chemotherapy is not needed.
It should be
noted that the gene expression test from the punch can be performed on the therapy-naive tumor.
Adjuvant therapy and multigene expression testing
According to subanalyses of the MINDACT, TAILORx, and RxPONDER studies [30 ], [31 ], [32 ],
premenopausal patients with LN involvement benefit from chemotherapy and are not candidates
for ET alone. However, the SGBCC panel rejected the question of whether gene expression
testing
can be omitted in premenopausal patients in stage I or II (majority vote: 76.60%).
German experts agree with this. The multigene expression test allows pre-selection
of premenopausal women with ER+ invasive stage I or II breast cancer for whom it may
be appropriate to
test for endocrine sensitivity (dynamic Ki67 ) preoperatively to omit additional chemotherapy. It should be noted that the clinical
relevance of “dynamic Ki67 ” in premenopausal
patients with intermediate genomic risk and 1 – 3 positive axillary LN has been intensively
discussed in the German expert group. For some experts, further follow-up of the ADAPT
study
should be awaited.
Premenopausal women have the highest endocrine response probability with AI/GnRHa
(~ 70 – 80%). With tamoxifen, it is only about 40% [29 ], [33 ]. If chemotherapy is not required, German experts refer to the recommendations of
AGO on the risk-adapted application of adjuvant ET: For high-risk patients,
AGO recommends the use of AI plus GnRHa (if chemotherapy is omitted), and for low-risk
patients, tamoxifen plus GnRHa (chapter 10, slide 8) [1 ], [2 ].
Subsequent SGBCC panel votes addressed different clinical scenarios in pre- and postmenopausal
patients with ER+/PR+ and HER2− invasive breast cancer and varying genomic risk. The
question
was, which adjuvant systemic therapy should be recommended.
German experts refrain from commenting on every single vote. According to German experts,
it is important to note that tumor stage, tumor biology, Ki67 score, possibly the endocrine
response, and if indicated, gene expression testing in the context of menopausal status,
are important factors for optimal adjuvant therapy in HR+/HER2− invasive breast cancer.
According to German experts, gene expression testing (independent of menopausal status)
supports decision making in patients (HR+/HER2−) with intermediate clinical risk.
High score values
on gene expression tests increase the likelihood of chemotherapy being beneficial.
For premenopausal patients (≤ 50 years), it should be noted that analogous to the
data of the TAILORx and
MINDACT studies, the benefit of chemotherapy is minimal with low genomic risk and
high clinical risk at 12 and eight years (TAILORx and MINDACT, respectively). In contrast,
the benefit of
chemotherapy is clinically relevant in these patients with intermediate genomic risk
[30 ], [32 ], [34 ]. Ongoing studies should clarify whether adjuvant therapy may be optimized in this
patient group (chemotherapy “yes/no”, CDK4/6 inhibitor plus endocrine therapy “yes/no”).
Lobular cancer
The histology of breast cancer has no influence on chemotherapy indication. Therefore,
even in patients with invasive lobular breast cancer (stage I – III, grade 1 or 2,
clearly ER+ and
HER2−, no pleomorphic features), chemotherapy may be indicated depending on individual
risk. German experts agree with the majority vote of the SGBCC panel (60.0%).
If a classic invasive lobular breast cancer (grade 1 or 2, clearly ER+/PR+, Ki67 < 10%, HER2-negative, no pleomorphic features) is present, and gene expression determination
confirms low risk, the majority (63.46%) of SGBCC panel members recommend no (neo)adjuvant
chemotherapy for stages I – III. According to German experts, this can only be approved
for stages
I/II (patients with up to three positive LN). From stage III (≥ 4 positive LN), German
experts recommend chemotherapy. In premenopausal patients with 1 – 3 positive LN,
the tumor size and
the Ki67 expression and a multigene assay should be considered for treatment decision.
Side effects of AI/GnRHa
If a 38-year-old amenorrheic patient with invasive ER+ stage II breast cancer develops
menopausal symptoms under AI/GnRHa treatment, the SGBCC panel members (44.23%) recommend
measuring
estradiol levels every six months. The German experts only partially agree: Although
menopausal symptoms may be a consequence of estrogen deprivation, elevated E2 levels
may be present
despite amenorrhea. Elevated E2 levels indicate that GnRHa therapy is not adequately
downregulating ovarian function. This would have the consequence of taking another
GnRHa and switching
from a 3-monthly to a monthly administration or switching from AI to tamoxifen. Thus,
controlling peripheral hormones may have therapeutic consequences for oncological
therapy [35 ].
SGBCC panel members recommend switching to monthly GnRHa administration (majority
vote: 64.62%) for a 39-year-old patient (stage II, ER+/HER2−) who had breakthrough
bleeding under AI plus
3-monthly administration of GnRHa. More stringent monthly dosing may avoid escape
phenomena that may occur under 3-monthly dosing. German experts share this opinion.
According to the majority vote of the SGBCC panel (35.38%), a premenopausal patient
over the age of 40 with invasive ER+ stage III breast cancer after 5 years of treatment
with AI/GnRHa
should receive extended adjuvant endocrine therapy (EAT) and switch to tamoxifen.
The patient developed not insignificant arthralgias under the treatment. German experts
agree in both cases.
Stage III warrants EAT because of the increased risk of recurrence. In the absence
of data on AI/GnRHa therapy beyond five years, switching to tamoxifen is also warranted
by indirect
analogy.
Triple-negative Breast Cancer
Triple-negative Breast Cancer
Neoadjuvant use of platinum
Carboplatin is an integral component of neoadjuvant chemotherapy (NACT) with taxane/anthracycline
and cyclophosphamide in early TNBC (stage II/III) when pembrolizumab is used in addition
to
chemotherapy. This is consistent with the KEYNOTE-(KN-)522 pivotal study of pembrolizumab
(majority vote: 78.0%) [36 ], [37 ].
Pembrolizumab had been used in the neoadjuvant setting simultaneously to carboplatin/paclitaxel
followed by doxorubicin/cyclophosphamide (AC), and was continued postoperatively as
monotherapy.
In this situation, the SGBCC panel members recommend using carboplatin in addition
to neoadjuvant taxane/anthracycline-based chemotherapy even if patients do not receive
pembrolizumab
(majority vote: 72.0%). This is in line with the “Plus” recommendation of AGO (chapter
12, slide 12) [1 ], [2 ].
Dose-dense chemotherapy plus pembrolizumab under discussion
In the KN-522 study [37 ], the AC regimen was administered every three weeks (q3W) as was pembrolizumab. Due
to the lack of data, the majority of SGBCC panel
members (38.46%) is unsure whether chemotherapy with AC can also be given 2-weekly
(q2W) when pembrolizumab is used additionally. Just under 30% (29.23%) were in favor.
German experts discussed this issue intensively. In Germany, dose-dense chemotherapy
is generally preferred for TNBC [1 ], [2 ].
Reference is made to the GeparNuevo and GeparDouze studies, both of which used dose-dense
regimens together with immunotherapy [38 ], [39 ].
It is unclear whether the 2-weekly administration has unfavorable effects on the efficacy
of immunotherapy. Despite the open questions, the German experts agree that dose-dense
administration of the AC regimen in combination with pembrolizumab can be considered
depending on risk and tolerability. But, it is important that pembrolizumab continues
to be administered
every three weeks, even in combination with the dose-dense AC regimen.
(Neo)adjuvant use of pembrolizumab
A premenopausal patient with TNBC who achieves pathological complete remission (pCR)
under neoadjuvant chemotherapy with taxane/carboplatin followed by AC, plus additional
pembrolizumab,
should continue treatment with pembrolizumab (monotherapy) in the adjuvant setting
despite pCR (majority vote: 58.49%). This is consistent with the pivotal study [37 ]. Only in individual cases, for example if pembrolizumab is very poorly tolerated,
should adjuvant administration of pembrolizumab be omitted according to German experts.
The
absolute benefit in event-free survival (EFS) at three years was 2% in the pembrolizumab
group compared with the control group [36 ].
German experts agree with the majority vote of the SGBCC panel that a 60-year-old
patient with TNBC (cT2N0; 2 – 3 cm), who can undergo breast-conserving surgery, should
be treated
neoadjuvantly with chemotherapy plus pembrolizumab. The neoadjuvant approach is preferred
in Germany and the neoadjuvant use of pembrolizumab is in accordance with the AGO
recommendation
[1 ], [2 ].
In contrast, neoadjuvant use of pembrolizumab-based chemotherapy in stage I TNBC (TNBC
< 2 cm; cT1 cN0) [37 ] does not meet the approval. German experts
support the SGBCC majority vote (46.15%) to forgo pembrolizumab in this situation.
Also not covered by the approval is the adjuvant use of pembrolizumab in a patient
with primary surgery for stage II TNBC and positive lymph nodes (majority vote: 62.0%).
The postoperative
use of pembrolizumab is only approved together with neoadjuvant administration (plus
chemotherapy). German experts point out once again that the neoadjuvant treatment
is preferred for TNBC
patients with a tumor size larger than 1 cm [1 ], [2 ].
HER2-positive Breast Cancer
HER2-positive Breast Cancer
Adjuvant trastuzumab administration
The preferred adjuvant regimen for patients with HER2-positive (HER2+) stage I breast
cancer is the combination of paclitaxel/trastuzumab (TH) (majority vote: 84.62%).
This is supported by
the 10-year data from the APT study published this year [40 ], and the 5-year data from the ATEMPT study in the TH study arm [41 ].
Adjuvant administration of trastuzumab is the therapy of choice for patients with
HER2+ breast cancer without clinically suspicious lymph nodes (cN0) who achieved pCR
with neoadjuvant
treatment with docetaxel/carboplatin plus trastuzumab/pertuzumab (TCHP) (majority
vote: 63.27%). German experts agree. The 8-year data from the APHINITY study [42 ] showed no efficacy benefit for dual antibody blockade with trastuzumab/pertuzumab
versus adjuvant trastuzumab administration in pN0 patients.
If residual tumor remains after neoadjuvant TCHP therapy and is HER2-negative by immunohistochemistry
(IHC) and FISH analysis, the majority of SGBCC panel members recommend adjuvant
treatment with trastuzumab emtansine (T-DM1) [43 ]. The German experts agree. However, it should be noted that retesting of the HER2
status on the residual
tumor is not recommended by AGO; it is a decision made on a case-by-case basis [1 ], [2 ]. Currently, there is no evidence for
retesting the receptor status on the residual tumor.
BRCA-associated Breast Cancer
BRCA-associated Breast Cancer
Use PARP inhibition and checkpoint inhibition?
A 43-year-old female patient with a gBRCA1 mutation and a stage II TNBC with lymph node involvement still had a residual tumor
after neoadjuvant treatment according to the KN522
study (carboplatin/paclitaxel followed by AC, each plus pembrolizumab) [37 ]. In this situation, the majority (62.0%) of the SGBCC panel recommends using
pembrolizumab and olaparib postoperatively. Just under a quarter of SGBCC panel members
(24.0%) would administer both agents in sequence.
The German experts agree because PARP inhibition in this high-risk situation is an
additional therapeutic approach with a potential efficacy benefit. However, this approach
has not been
evaluated in either pivotal study. Nevertheless, study data on the combination of
checkpoint and PARP inhibition indicate that there are no safety concerns [44 ], [45 ], [46 ]. The potential benefit of additional olaparib administration should not be withheld
from high-risk
patients, as this therapy has a survival advantage. This is why the SGBCC majority
vote is understandable from a German perspective. The current recommendations of AGO
is in-line.
PARP inhibition and CDK4/6 inhibition?
For a gBRCA2 -mutated patient with ER+/HER2− invasive stage III breast cancer, the SGBCC panel
recommends olaparib and abemaciclib in sequence in the postneoadjuvant setting. This
is
in addition to standard endocrine therapy after neoadjuvant dose-dense therapy with
AC/paclitaxel (majority vote: 48.02%). 37.25% would only use olaparib in addition
to ET.
The post-neoadjuvant use of olaparib and abemaciclib is understandable in this patient
as this is a high-risk scenario. Due to overlapping side effects, both substances
should be given
sequentially. The approval of both substances does not prevent sequential administration.
German experts point out that the monarchE study [25 ] also had some
patients who were included in the study only twelve months after primary diagnosis.
TNBC: Platinum or olaparib?
Detection of a gBRCA1/2 mutation is not predictive of the benefit of platinum as part of (neo)adjuvant chemotherapy;
therefore, all patients with gBRCA1/2 -mutated
invasive breast cancer should also receive platinum-based chemotherapy. This applies
regardless of the availability of olaparib (majority vote: 50% and 60.87%, respectively
[olaparib
available]). German experts agree. The indication for platinum-based chemotherapy
in TNBC is independent of the detection of a gBRCA1/2 mutation (AGO chapter 12, slide 11) [1 ], [2 ]. In HR+ breast cancer, there is no indication for the use of platinum due to the
absence of adequate study data.
Osteoprotective Therapy
According to AGO, adjuvant (osteoprotective) bisphosphonate use should be recommended
for all postmenopausal patients [1 ], [2 ].
As with any treatment, a risk-benefit assessment is necessary. The majority vote of
the SGBCC panel members (32.0%) that the use is an option only in postmenopausal women
with ER+ invasive
stage II/III breast cancer is not accepted. German experts point out that bisphosphonates
act independently of receptor status. For denosumab, there are adjuvant study data
showing benefit
only for postmenopausal patients undergoing AI therapy [47 ].
Oligometastatic Disease
Chance of long-term survival?
Patients with oligometastatic disease may still have a chance of cure or long-term
survival. Against this background, the SGBCC panel members (majority vote: 68.0%)
recommend to resect and
subsequently irradiate a patient with ER-negative/HER2-positive breast cancer (primary
tumor 4 cm) plus axillary lymph node involvement (N+) and with isolated pulmonary
metastases who
achieved pCR during induction therapy with THP (taxane, trastuzumab, pertuzumab).
The vote from the audience was almost identical. The SGBCC panel recommended this
approach for said patient
(4 cm, N+, isolated lung metastasis) regardless of tumor biology.
German experts agree that a curative treatment is sought. There are no study data
for this clinical situation. Data on surgery for the primary tumor in the metastatic
setting do not support
this approach. According to German experts, these are individual decisions [1 ], [2 ].
If a patient with stage II invasive breast cancer in the contralateral axilla has
isolated lymph node metastases, the SGBCC panel members (majority vote: 75.0%) recommend
curative therapy
with ALND on the contralateral side, plus radiation and adjuvant systemic standard
therapy. The multidisciplinary approach is in line with the recommendation of AGO
(chapter 21, slide 15)
[1 ], [2 ]. Breast cancer patients with contralateral axilla metastasis usually have a good
prognosis with the chance of long-term
survival [48 ].
Molecular Diagnostics
Circulating tumor DNA is not yet standard
Molecular diagnostic methods are becoming increasingly common in oncology. They are
accompanied by the hope of detecting recurrences earlier and improving prognosis through
more targeted
intervention. Numerous studies are investigating testing for circulating tumor cell
DNA in the blood (ctDNA) to better predict the risk of recurrence in tumor patients.
Currently, ctDNA
testing is not a standard method and is reserved for clinical trials because it does
not yet entail therapeutic consequences (majority vote: 89.3%).
Accordingly, the SGBCC panel members (majority vote: 86.0%) reject postoperative ctDNA
testing in patients with early breast cancer in clinical practice. The German experts
agree. In
Germany, the SURVIVE study (Standard Surveillance versus Intensive Surveillance in
Early Breast Cancer) is currently underway, the results of which are awaited (https://www.survive-studie.de/fuer-fachpersonal.html ).
ctDNA without clinical consequences
SGBCC panel members disagreed on whether the result of a ctDNA testing performed as
part of a translational research project of a study should be shared with the treating
physician and/or
the patient. According to German experts, there is no need to communicate the results
– neither to the physician nor to the patient – as no therapeutic consequences can
be derived from them.
If the result is reported to the physician, it must also be reported to the patient.
With this in mind, a treatment switch should also be rejected if a patient achieves
pCR in a clinical trial using neoadjuvant systemic therapy, and postoperative ctDNA
testing in the trial
detects ctDNA in the blood. German experts agree with the SGBCC panel (majority vote:
69.23%).
Study concept under discussion
A postmenopausal patient with ER+/HER2− stage III invasive breast cancer who has been
successfully treated with standard endocrine therapy for five years will be enrolled
in a clinical
trial in which ctDNA testing will be used to determine further treatment. Patients
whose ctDNA findings indicate an ESR1 mutation are randomized and alternatively treated with AI or
switched to fulvestrant. The question of whether this is a fair study was affirmed
by a simple majority of SGBCC panel members (43.08% vs. 38.46% and 18.46% abstentions).
German experts do not have a uniform opinion either. There was consensus that stage
III represents a high risk of recurrence, which is why further adjuvant treatment
is reasonable. It is
unclear whether the data on endocrine resistance, when an ESR1 mutation is detected, originating from the metastatic situation can be transferred
to the adjuvant situation. Since
fulvestrant is only approved in the metastatic setting, some German experts support
study participation to give patients the chance of adjuvant fulvestrant. Other German
experts rejected the
study concept to avoid the possibility of a patient with ESR1 mutation being further treated with AI, and preferred a reimbursement claim for fulvestrant.
