Key words advanced breast cancer - biomarkers - therapy - prognosis
Introduction
This review summarises the latest data on the treatment of patients with advanced
breast cancer and on new biomarkers. It also reports a large pooled analysis of fertility
and pregnancy after breast cancer treatment. This type of therapeutic impact on quality
of life plays a special role in the ever-improving therapies established in recent
years [1 ], [2 ], [3 ], [4 ], [5 ], [6 ]. This paper considers full publications and presentations at the current major cancer
and breast cancer meetings such as ESMO (European Society for Medical Oncology) 2020
and SABCS (San Antonio Breast Cancer Symposium) 2020.
Treatment of Patients with Metastatic Breast Cancer
Treatment of Patients with Metastatic Breast Cancer
Chemotherapy agents partnered with immune checkpoint inhibitors (KEYNOTE-355)
Publication of the IMpassion131 [7 ] and IMpassion130 trial [8 ] raises the question of which chemotherapy agents would best be partnered with anti-PD-1/PD-L1
therapy. More data to clarify this issue are of particular interest here. The IMpassion130
trial compared first-line therapy with nab-paclitaxel and atezolizumab to nab-paclitaxel
monotherapy in patients with advanced TNBC. Both progression-free survival and overall
survival in PD-L1-positive patients improved [9 ]. The IMpassion131 trial employed paclitaxel dissolved with Cremophor as a combination
agent rather than Nab-paclitaxel and failed to meet its primary endpoint (i.e., improvement
in PFS [Progression Free Survival]). Atezolizumab thus failed to provide any further
benefit in this trial compared with paclitaxel therapy alone [7 ]. This even led to a warning from the US Food and Drug
Administration (FDA) against combining atezolizumab with paclitaxel. However,
both studies need to be studied in more detail. In the IMpassion130 study, almost
40% of patients did not receive adjuvant or neoadjuvant treatment, i.e., they were
treatment-naïve patients. Moreover, no patients were enrolled in the trial who metastasised
within 12 months following adjuvant or neoadjuvant treatment. The number of patients
with PD-L1-positive tumour in the IMpassion131 trial was relatively low, with 100
patients in each arm. In addition, 30% of the patients in this study showed de novo
metastases, i.e., they were also treatment-naïve, while 70% of the patients had undergone
prior treatment. Since about half of the patients had received taxanes or anthracyclines,
the question arises as to what the remaining 20 patients were treated with. This data
can only be extracted from the final publications.
Recently, data from the KEYNOTE-355 trial was presented, which was able to provide
further insight into this issue. The KEYNOTE-355 trial compared a combination therapy
of chemotherapy plus pembrolizumab with chemotherapy alone. Chemotherapy comprised
either nab-paclitaxel (31.6%), paclitaxel (13.5%) or gemcitabine/carboplatin (54.9%),
as preferred by the physician. In the overall study, adding pembrolizumab to chemotherapy
benefited progression-free survival in the group of patients with a CPS score for
PD-L1 of ≥ 10, with a hazard ratio (HR) of 0.65 (95% CI: 0.49 – 0.86) [10 ]. In the chemotherapy partner subgroups, the HR was 0.57 (95% CI: 0.34 – 0.95) for
nab-paclitaxel, 0.33 (95% CI: 0.14 – 0.76) for paxlitaxel and 0.77 (95% CI: 0.53 – 1.11)
for gemcitabine/carboplatin [11 ]. Similar results were seen for patients with a CPS score of ≥ 1 and in the overall
trial population. Thus, KEYNOTE-355 did not
demonstrate that the combination partner nab-paclitaxel vs. paclitaxel made a
difference in the efficacy of pembrolizumab.
Whether the three trials (IMpassion130/131 and KEYNOTE-355) can generally be compared
with each other with regard to this question will only become clear once sufficient
follow-up time for overall survival is available from all trials. It should be noted
that the effect of the immune checkpoint inhibitors was only shown with a treatment-free
interval of more than 12 months; in the KEYNOTE-355 trial, no effect was shown with
a treatment-free interval of less than 12 months, and the IMpassion130 and -131 trials,
too, only enrolled patients who had not undergone treatment for at least 12 months
since the end of adjuvant chemotherapy.
Oral taxanes
A new oral formulation of paclitaxel was reported at SABCS 2019 a year ago [12 ]. Only small amounts of paclitaxel are absorbed orally because it is removed from
the cell by the P-glycoprotein pump (P-gp) [13 ]. Specific inhibition of P-gp with the agent encequidar increases the absorption
of oral paclitaxel. In the phase III KX-ORAX-001 trial, 360 patients were randomised
2 : 1 to treatment with oral paclitaxel plus encequidar or to treatment with intravenous
paclitaxel. Eligible were patients with advanced breast cancer who had not been treated
with a taxane within the last year [14 ]. In both groups, most patients had ER+/HER− breast cancer (56%/49%). The primary
endpoint of the trial was to demonstrate an improvement in overall response rate with
the encequidar combination. In the treatment arm with oral taxane, a response was
seen in 40.4% of cases, whereas in the group with
parenteral taxane this was true in only 25.6% of patients (p = 0.005). This difference
was statistically significant (p = 0.005). A 2019 analysis revealed no difference
in PFS with an HR of 0.76 (95% CI: 0.551 – 1.049). However, an HR of 0.684 (95% CI:
0.475 – 0.985) demonstrated a benefit in terms of overall survival for the oral taxane.
In terms of side effects, neuropathies ≥ grade 2 in particular occurred less frequently
with the oral taxane at 7.6 vs. 31.1% with the intravenous taxane. Alopecia was also
observed less frequently. Diarrhoea, nausea and vomiting occurred more frequently
[14 ]. Analyses of this trial conducted in Central and South America with a longer follow-up
period have now been presented [14 ]. The analysis regarding PFS now reached statistical significance (HR: 0.739; 95%
CI: 0.561 – 0.974). Overall survival also yielded results similar to those of the
primary analysis (HR: 0.735; 95%
CI: 0.556 – 0.972). The combination of oral taxane and encequidar is currently
(March 2021) under review by the US Food and Drug Administration (FDA).
Another oral taxane is tesetaxel. It is a modified taxane that is not eliminated from
the cell by the P-gp and can therefore also be administered orally. The oral bioavailability
is 56%. In addition, tesetaxel is markedly more soluble than paclitaxel and docetaxel
[15 ]. Dosed at 27 mg/m2 , it is taken once every 3 weeks without premedication. Recently, the outcomes of
the phase III CONTESSA trial were reported. This trial had enrolled ER+/HER2− patients
who had received no or just one line of chemotherapy in the metastatic setting. In
addition, the (neo)adjuvant situation called for treatment with a taxane. Any number
of prior endocrine treatments were accepted. Patients were randomised 1 : 1 to receive
treatment with tesetaxel plus capecitabine or capecitabine alone. The primary endpoint
of the trial was PFS. Secondary endpoints of the trial included overall survival and
overall response rate. Most of the patients enrolled had
not received any prior treatment in the metastatic setting (93%). Thus, the study
population comprised mainly patients who received their first treatment in the metastatic
setting.
The primary endpoint of the trial was met. With a median follow-up of 13.9 months,
the addition of tesetaxel improved median progression-free survival from 6.9 (95%
CI: 5.6 – 8.3) to 9.8 (95% CI: 8.4 – 12.0) months. The HR was 0.716 (95% CI: 0.573 – 0.895;
p = 0.003) in favour of tesetaxel plus capecitabine [15 ]. It is not surprising that combined treatment is superior to monotherapy in terms
of response rate and progression-free survival. Whether these promising results become
relevant for clinical practice depends on the data on overall survival, which have
not been analysed so far because the number of events is too low. Neuropathy grade
III – IV developed in 5.9% of patients treated with tesetaxel [15 ].
According to a press release, however, further approval of the agent tesetaxel is
not being pursued. Reasons were not initially given [16 ].
Some new substances in the treatment of advanced breast cancer have not been convincing
Even though significant progress has been made with numerous agents in recent years,
there are still prominent examples of trials in which the compounds studied failed
to achieve any improvement in efficacy.
One such example is the HDAC (histone deacetylase) inhibitor entinostat.
Following promising data from a randomised phase II trial for patients with advanced
HR+/HER2− breast cancer, which demonstrated that both PFS and OS improved with the
addition of entinostat to exemestane [17 ], a phase III E2112 trial was conducted for confirmation. Eligible for enrolment
were patients with HR+/HER2− advanced breast cancer who had progressed on a non-steroidal
aromatase inhibitor and who had not received more than one prior chemotherapy. 608
patients received either exemestane plus placebo or exemestane plus entinostat. About
one third of the patients had been treated with a CDK4/6 inhibitor before enrolment.
The trial was negative. No difference in either PFS or OS was seen between the treatment
arms with relatively short median PFS times of 3.3 and 3.1 months. Median overall
survival was 23.4 versus 21.7 months.
The other trial, which also followed a positive randomised phase II trial for patients
with advanced TNBC, was the IPATunity130 phase III trial [18 ]. This trial studied the Akt inhibitor ipatasertib. The Akt kinase signalling pathway
is one of the main signal transduction pathways from the cell surface to the nucleus.
It can be activated by a variety of molecular changes such as PTEN loss, PI3K mutations,
or AKT1 mutations. Since approximately 35% of all TNBC tumours exhibit one of these
molecular alterations, targeted therapy may be important for a clinically significant
group of patients. The phase II LOTUS trial published previously reported an HR of
0.60 (95% CI: 0.37 – 0.98) [19 ] for PFS in the overall population (N = 93). In the group of patients with PTEN/AKT1/PIK3CA
alteration (n = 33), the HR was 0.44 (95% CI: 0.20 – 0.99) [19 ]. The IPATunity130 trial now attempted to
replicate the outcomes through a randomised phase III trial. It studied 255 patients
with advanced TNBC and a PIK3CA/AKT1/PTEN alteration in the first line of therapy,
i.e., without prior treatment of the advanced breast cancer. Patients were treated
with either paclitaxel weekly 80 mg/m2 or paclitaxel weekly plus 400 mg ipatasertib per day for 21 days followed by a week
off. With regard to the primary endpoint PFS at a median follow-up time of 8.3 months,
no difference was seen between both treatment arms. Median PFS times were short at
6.1 (95% CI: 5.5 – 9.0) months in the paclitaxel arm and 7.4 months (95% CI: 5.6 – 8.5)
in the ipatasertib plus paclitaxel arm (HR: 1.02; 95% CI: 0.71 – 1.45).
Both trials emphasise the importance of validating initially good efficacy signals
in larger phase III trials.
Biomarker
PAM50 in treatment with CDK4/6 inhibitors in the metastatic setting (ML2,3,7).
Combining endocrine treatment with CDK4/6 inhibitors is the standard of care for first
line therapy in patients with advanced ER+/HER2− breast cancer. So far, there are
no known prognostic or predictive markers, except for hormone receptor status, that
could predict a greater or lesser benefit of endocrine monotherapy or combined treatment
with CDK4/6 inhibitors plus endocrine therapy. It is known that the histopathological
determination of the oestrogen receptor, progesterone receptor, HER2 status, and the
grading can roughly classify the patients into intrinsic subtypes. However, in over
20% of cases, this assessment does not match the molecular subtype [20 ]. Since CDK4/6 inhibitors have demonstrated their efficacy, particularly in molecular
luminal and HER2-amplified cell lines [21 ], one can reasonably pose this question in clinical populations as well. This has
now been undertaken through a pooled
analysis of the MONALEESA trials (MONALEESA-2 [22 ], MONALEESA-3 [23 ], [24 ], MONALEESA-7 [25 ], [26 ]) [27 ]. In1160 of the total population of 2066 patients, it was possible to analyse a tumour
sample with the PAM50 classifier with regard to the molecular subtype. Of these 1160
patients, 47% had subtype luminal A, 24% had subtype luminal B, 13% had subtype HER2,
3% had subtype Basal-like and 14% had subtype Normal-like. The HR for these groups
are listed in [Table 1 ]. The 13% of patients in the HER2 subgroup benefited most from treatment with ribociclib
(HR: 0.39; p < 0.001). The few patients with the Basal-like subtype (3%) did not benefit
from treatment with ribociclib (HR: 1.15; p = 0.7672) [27 ]. Thus, these
results confirm the preclinical data on CDK4/6 inhibitors [21 ]. Although interesting data was generated by this analysis, it is unlikely that it
will affect clinical practice. However, the outcomes could be used to identify suitable
patient populations for treatment once CDK4/6 inhibitors are introduced into adjuvant
therapy.
Table 1 Impact of molecular subtypes on the effect of ribociclib and the effect on prognosis
in the treatment groups regarding progression-free survival.
Comparison of ribociclib+ER vs. ET monotherapy*
Comparison of molecular subtype vs. Luminal A group in patients treated with ribociclib + endocrine
therapy
Comparison of molecular subtype vs. Luminal A group in patients treated with endocrine
monotherapy
Hazard Ratio
p-value
Hazard Ratio
p-value
Hazard Ratio
p-value
* The hazard ratio differences were tested with an interaction variable. The differences
were statistically significant (p = 0.045).
Luminal A
0.63
< 0.001
Reference
Reference
Luminal B
0.52
< 0.001
1.17
0.35
1.68
0.00055
HER2 enriched
0.39
< 0.001
1.76
0.00082
1.47
< 0.0001
Basal-like
1.15
0.7672
5.1
< 0.0001
3.05
0.004
Normal-like
not shown
0.98
0.93
1.69
0.0025
Biomarker analysis of the ASCENT trial in HER2-positive metastatic breast cancer
One class of substances that has significantly enhanced the therapeutic landscape
since its approval for advanced HER2-positive breast cancer and for patients without
complete response after neoadjuvant anti-HER2 chemotherapy are the so-called antibody
drug conjugates (ADCs). A linker binds cytotoxic substances to antibodies. This allows
not only target molecules driving the prognosis of cancer to be a treatment target,
but also molecules only found on the cell surface as “anchors”. This was shown, for
example, with the ADC trastuzumab-deruxtecan (T-DXd), which also demonstrated its
efficacy in patients with low HER2 expression [28 ]. In patients with triple-negative breast cancer, the ADC sacituzumab govitecan (SG)
represents a new therapy with high efficacy even after some prior therapies [29 ], [30 ]. It binds to the target molecule Trop-2, which has been detected in patients
with breast cancer. Compared with chemotherapy as preferred by the physician,
sacituzumab govitecan significantly improved both PFS (HR: 0.41) and overall survival
(HR: 0.48), as shown in the ASCENT trial [29 ]. In this context, it is interesting to ask whether the expression levels of Trop-2
might affect the efficacy of the ADC. Hypothetically, any effect on efficacy should
not be significant. A biomarker analysis of the ASCENT trial addressed precisely this
question. In addition, the TNBC patient population was also tested for BRCA1/2 mutations
[31 ]. Trop-2 expression was determined by immunohistochemistry and patients were classified
into high, medium and low Trop-2 expression groups. The analysis included 468 patients
altogether. Trop-2 expression was assessed in 290 patients, of whom 54.1% showed high
expression, 25.5% medium expression and 20.3% low expression. Of the 292 patients
screened for BRCA1/2
mutations, 11.6% presented with a mutation. In the group of patients who had
been treated with chemotherapy, Trop-2 expression did not impact prognosis (median
PFS times: 2.5 months [high expression]; 2.2 months [medium expression]; 1.6 months
[low expression]). In the sacituzumab govitecan arm, the difference between the medium
and high Trop-2 expression groups was also small. In patients with high Trop-2 expression,
the median PFS was 6.9 months (95% CI: 5.8 – 7.4) and in those with intermediate expression
5.6 months (95% CI: 2.9 – 8.2). However, low expression correlated with a median PFS
of only 2.7 months (95% CI: 1.4 – 5.8) [31 ] ([Fig. 1 ]). Nevertheless, PFS improved significantly in all groups. BRCA1/2 status did not
affect the efficacy of sacituzumab govitecan [31 ]. This analysis thus illustrates that principle treatment with an appropriate ADC
may also be effective
in tumours with lower target molecule expression.
Fig. 1 Progression-free survival in the ASCENT trial by Trop-2 expression [31 ].
Biomarkers as selection criterion in patients undergoing endocrine therapy
Many of the (adjuvant) trials on multigene tests or other biomarkers published in
recent years employed a trial design investigating whether different characteristics
in a patient population resulted in similar prognoses, rather than comparing different
treatment regimens, including the endocrine part of the ADAPT trial [32 ]. The ADAPT trial on HR+/HER− early breast cancer with 0 – 3 affected lymph nodes
compared the following patients:
Patients with an Oncotype DX® Recurrence Score of 0 – 11 at initial diagnosis (n = 868)
Patients with an Oncotype DX Recurrence Score of 12 – 25 at initial diagnosis and
a decline in Ki-67 to ≤ 10% at re-biopsy after 3 weeks of preoperative endocrine treatment
(n = 1422)
Due to the difference in patient selection, both groups differed in most characteristics.
The authors emphasised that this was not a comparison of groups in a randomised trial.
Both groups had a comparable probability of relapse-free survival. In group A, the
probability of disease-free survival at 5 years was 93.9% (95% CI: 91.8 – 95.4), whereas
in group B it was 92.6% (95% CI: 90.8 – 94.0). It was ruled out that the difference
with a one-tailed 95% confidence interval was greater than the prespecified 3.3%.
Similar outcomes were obtained for the overall survival analysis, the distant metastasis-free
survival analysis, and for patients under the age of 50 years and those over the age
of 50 years. The non-inferiority of group B, independent of menopausal status, demonstrated
that dynamic Ki-67 assessment can close a prognostic gap in premenopausal breast cancer
patients with limited lymph node involvement and an RS of 12 – 25 (see RxPONDER trial).
The only variables of prognostic significance in the group of patients analysed were
lymph node status (0 – 2 malignant lymph nodes vs. 3 lymph nodes), tumour stage (pT2 – 4
vs. pT0 – 1) and progesterone receptor expression (ordinal variable with 10% increments)
[32 ]. Thus, it can be stated that in the heterogeneous group recruited in the ADAPT trial,
only lymph node status, tumour size and progesterone receptor expression were independent
predictors of prognosis.
CTC as a marker for monitoring treatment in metastatic breast cancer
One biomarker that has been studied for decades is circulating tumour cells in the
blood (CTCs) [33 ], [34 ]. In both patients with early breast cancer and those with advanced disease, the
presence of CTCs correlates with unfavourable prognosis. One question arising from
this observation is whether the presence of CTCs in the course of the disease may
be tapped as a monitoring marker for treatment. An international pooled analysis with
4079 patients addressing this issue has now been presented [35 ]. The paper focused on trials in which CTC measurements were available prior to as
well as during the treatment. This international analysis included a total of 14 trials.
For the overall population and for the molecular subtypes, groups of patients who
continued to have detectable CTCs both at baseline and during follow-up were compared
with patients who were also CTC-positive at
baseline but for whom CTCs were no longer detected during follow-up. [Table 2 ] summarises the findings. Both in the overall population and the subgroups (HR-positive,
HER2-positive, TNBC), the elimination of CTCs during the treatment roughly doubled
median overall survival. This illustrates that CTC levels during the treatment course
can provide a very good indication of the response to treatment and its effect on
overall survival. Not unlike with neoadjuvant therapy, the question is whether monitoring
patients with positive CTCs prior to treatment and an early change in treatment may
benefit those patients with persistent CTCs. However, before these ideas can be applied
to routine practice, the trial outcomes must be awaited so that this promising technology
does not give rise to false expectations or even endanger patients.
Table 2 Overall survival times for patients with and without CTC elimination during observation
and the corresponding hazard ratios (from [35 ]).
CTC status at treatment baseline/CTC status during the course of treatment
CTC+/
CTC+/CTC−
Overall population
median OS
17.87
32.2
HR
1
0.49 (95% CI: 0.44- 0.54)
HER2-positive
median OS
22.8
36.83
HR
1
0.54 (95% CI: 0.42 – 0.69)
HR-positive
median OS
20.45
36.58
HR
1
0.47 (95% CI: 0.41 – 0.54)
TNBC
median OS
9.38
20.47
HR
1
0.41 (95% CI: 0.32 – 0.52)
Breast Cancer Index and patient selection for extended adjuvant endocrine therapy
The aTTom trial (“Adjuvant Tamoxifen Treatment Offer More”) compared 5 years of adjuvant
tamoxifen therapy with 10 years of tamoxifen [36 ]. A retrospective analysis of this trial involving 1822 of 6956 patients employed
a multigene expression test, which had previously been validated as a strong prognostic
factor in several trials. The BCI test comprises two components, the H/I ratio (ratio
of the gene expression of HOXB13: IL17BR) and the Molecular Grade Index (MGI), which
maps tumour proliferation with 5 genes (BUB1B, CENPA, NEK2, RACGAP1, RRM2) [37 ], [38 ]. Moreover, different predictions can be made for the prognosis of patients who underwent
treatment with tamoxifen for 5 and 10 years, respectively.
It was analysed whether the H/I ratio (BCI[H/I]) could help to identify patients who
would benefit from extending endocrine therapy to 10 years. It was shown that the
predicted prognosis for patients treated with 5 years of tamoxifen treatment differed
significantly from patients treated with 10 years of tamoxifen (HR = 0.35; 95% CI
0.15 – 0.86; p = 0.014). Thus, the BCI(H/I) would be the first test capable of identifying
patients who would benefit from extended anti-hormone therapy. However, it must be
noted that since the aTTom trial had been conducted, far fewer patients have been
treated with adjuvant tamoxifen both in the premenopausal and especially in the postmenopausal
setting. The data from the MonarchE trial could also mean that in the future adjuvant
treatment could include other active substances. The possible significant predictive
value of the BCI(H/I) would then have to be explored again.
Progress in the treatment of metastatic HER2-positive breast cancer
Already in 2019 at the San Antonio Breast Cancer Congress (SABCS), trial results were
presented for two agents that still show impressive activity after prior treatment
of metastatic HER2-positive breast cancer with T-DM1: The HER2-specific tyrosine kinase
inhibitor tucatinib and the antibody-drug conjugate tastuzumab-deruxtecan (T-DXd).
In a prospective phase II trial, 612 patients with metastatic HER2+ breast cancer
and ≥ 2 prior treatments including T-DM1 were randomised 2 : 1 to capecitabine/trastuzumab/tucatinib
versus capecitabine/trastuzumab/placebo. 48% of the patients had brain metastases
[39 ]. The addition of tucatinib resulted in a significant benefit in both PFS and OS.
Of particular note is that in the subgroup of patients with cerebral metastasis, DFS
after one year was 24.9% in the tucantinib group and 0% in the control group. At the
last SABCS in December 2020, E. Hamilton for the HER2CLIMB trial group confirmed the
benefits for the combination with tucatinib in terms of DFS and OS, regardless of
hormone receptor status and also in patients with cerebral metastases. Adverse reactions
such as diarrhoea and hand-foot syndrome were more frequent in the experimental arm.
Approval of tucatinib in Germany is expected in the next few weeks and the drug is
currently available in Germany through a compassionate use programme.
In the single-arm phase II DestinyBreast01 trial the antibody-drug conjugate trastuzumab-deruxtecan
(T-DXd) displayed a good response of 60.9% and a PFS of 14.8 months in 184 patients
with metastatic HER2-positive breast cancer (13% of whom had stable brain metastases)
after prior T-DM1 treatment [28 ]. Apart from mild to moderate haematological and gastrointestinal side effects, interstitial
lung disease (ILD) was observed in 13.6% of all cases and ≥ 3rd degree in 3%. A 20.4-month
follow-up yielded a PFS benefit, which increased to 19.4 months in the last analysis.
The rate of pulmonary complications did not rise any further. Thus, ILD does not have
a cumulative effect, but it does require interdisciplinary management and good patient
education and selection. T-DXd approval in Germany depends on the outcome of the two
ongoing phase III trials (DestinyBreast06 trial, NCT0449442, and DestinyBreast03 trial,
NCT03529110).
Treatment Management and Patient Concerns
Treatment Management and Patient Concerns
Fertility following breast cancer
Women who develop breast cancer at a young age often face the question of pregnancy
after the disease with all its treatments (chemotherapy, radiotherapy, targeted therapy,
and endocrine therapy). An international working group has conducted a systematic
review with a meta-analysis. They were able to identify a total of 39 studies that
could be analysed for the chance of pregnancy, pregnancy complications and maternal
mortality.
48 513 breast cancer patients were compared with 3 289 113 healthy women regarding
the probability of pregnancy following breast cancer. The relative risk of pregnancy
was 0.40 (95% CI: 0.32 – 0.49). In other words, women who had developed breast cancer
were 60% less likely to become pregnant than women in the healthy comparison population.
The comparison with other types of cancer, shown in [Table 3 ]
[40 ], was interesting. Here it is noteworthy that only patients with cervical cancer
had a smaller chance of pregnancy after malignant disease than patients with breast
cancer. All other tumour entities had a better chance of pregnancy. With regard to
the rate of pregnancy complications, a comparison of 3240 breast cancer patients and
more than 4 800 000 women from healthy controls revealed that the risk of caesarean
section was increased with a relative risk of 1.14 (95% CI: 1.04 – 1.25), of low birth
weight
(RR: 1.50; 95% CI: 1.31 – 1.73) and of preterm birth (RR: 1.45; 95% CI: 1.11 – 1.88).
However, the risk of congenital anomalies had an RR of 1.68 (95% CI: 0.89 – 2.98).
Due to the small number of cases, though, this risk was probably not statistically
significant (p = 0.112). Further subgroup analyses revealed that the risk of low birth
weight was higher in the group of patients who had received chemotherapy for breast
cancer (RR: 1.662; 95% CI: 1.08 – 2.42) versus patients who did not undergo chemotherapy
(RR: 1.05; 95% CI: 0.77 – 1.43) [40 ].
Table 3 Relative risks of pregnancy after malignant disease [40 ].
Cancer
Relative risk
95% CI
bold = estimates for breast cancer
Cervix
0.33
0.31 – 0.35
Breast
0.4
0.32 – 0.49
Leukaemia
0.4
0.27 – 0.58
Kidney
0.42
0.18 – 0.99
CNS
0.52
0.39 – 0.69
Bone
0.56
0.37 – 0.86
Ovary
0.56
0.48 – 0.65
Hodgkin lymphoma
0.62
0.47 – 0.82
All types
0.65
0.55 – 0.77
Liver
0.65
0.19 – 2.26
Non-Hodgkin lymphoma
0.66
0.53 – 0.82
Colon
0.7
0.41 – 1.17
Thyroid
0.82
0.65 – 1.03
Skin
0.97
0.87 – 1.09
In terms of relapse-free survival/overall survival (OS) after breast cancer, 2003
(DFS)/3261 (OS) breast cancer patients with a pregnancy post disease were compared
with approximately 38 000 (PFS)/52 000 (OS) patients without pregnancy. In general,
pregnancy had protective effects on survival. The HR for DFS was 0.73 (95% CI: 0.56 – 0.94)
and 0.56 (0.46 – 0.67) for overall survival. Moreover, these effects were largely
independent of other disease parameters such as nodal status and chemotherapy.
Outlook
For some treatments with demonstrated definite efficacy, such as the CDK4/6 inhibitors,
the next stage will be to establish and understand any sequences with other treatment
regimens, as well as to possibly refine the treatment for other molecular subtypes
or treatment settings. With the ADC sacituzumab govitecan, another compound from this
drug class seems to be gaining a foothold. Tucatinib and trastuzumab-deruxtecan broaden
the therapeutic spectrum in metastatic HER2-positive breast cancer.
The insights into biomarkers are broadening our understanding of the mode of action
and the potential applications of ADCs in breast cancer. Some expectations regarding
Akt kinase inhibitors and HDAC inhibitors could not be confirmed in phase III trials.
Nevertheless, the development of new biomarkers and treatment regimens for patients
with advanced breast cancer is progressing rapidly, and the therapeutic options are
expected to evolve.
