Background: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited. Methods: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+). Results: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1–6) combined with 12 applications of regional hyperthermia (median 12, range 2–12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; p = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; p = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%). Conclusion: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR.

In triple-negative primary breast cancer (TNBC), which is characterized by absence of hormone receptor expression (estrogen ER–; progesterone PR–) and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), chemotherapy is able to induce high rates of tumor remission and also leads to a favorable long-term outcome [1]. When given as preoperative chemotherapy, standard regimes including taxane and anthracyclines result in a pathological complete response (pCR) in over 30% of patients at the time of surgery and an excellent long-term prognosis [2]. Mutations in BRCA 1 and BRCA 2 are more common in TNBC than in other molecular subtypes, with 11–17% of patients with TNBC carrying germ-line mutations [3]. Patients with TNBC and BRCA mutations are reported to have higher pCR rates than noncarriers in response to standard chemotherapies, with or without platinum agents [4]. In contrast, women in whom pCR is not achieved (non-pCR) are at high risk of recurrence and distant disease [5].

Regional hyperthermia is a noninvasive cancer treatment targeting heat (range 41–43°C) to the region of the localized tumor using electromagnetic antenna device with operating frequencies ranging from 100 to 220 MHz. The utility of combined modality therapy with hyperthermia rests on several hallmarks [6]. Hyperthermia can be directly cytotoxic and inhibits potentially lethal and sublethal damage repair. It also alters tumor blood flow and may improve tumor oxygenation, which in turn may result in delivery of a higher concentration of chemotherapeutic agents as well as enhance the effect of radiotherapy by decreasing the amount of hypoxia. In addition, preclinical results in vitro and in vivo by the use of animal systems show the potential of hyperthermia to induce innate and adaptive anti-tumor immune response [7].

There has been considerable interest in combining hyperthermia with radiotherapy for superficial chest wall recurrences of breast cancer [8]. Two prospective studies reported a statistically significant increase in the rate of radiographic CR when adding hyperthermia to radiotherapy versus radiotherapy alone [9, 10]. For the use of chemotherapy combined with hyperthermia, there are only a few phase 1/2 trials demonstrating feasibility and efficacy of this treatment strategy in locally advanced breast cancer [11, 12]. For patients with high-risk soft tissue sarcoma including chest wall tumors, a randomized phase III trial demonstrated that the addition of heat to neoadjuvant chemotherapy improved local control and survival [13, 14]. The benefit of adding regional hyperthermia was also seen in patients with previously resected (R0/R1) tumors [15].

As discovered more recently, the molecular mechanisms of hyperthermia action also include downregulation of BRCA1 und BRCA2, thereby inhibiting the homologous recombination repair machinery of DNA strand breaks induced by chemotherapeutic agents like platinum compounds [16].

In the metastatic setting, several studies have demonstrated the efficacy of cisplatin plus gemcitabine combination therapy in TNBC [17, 18].

The purpose of this analysis was to evaluate how adjuvant platinum-based chemotherapy in combination with regional hyperthermia given in a routine setting impacts outcome in a contemporary cohort of patients with TNBC and residual disease (non-pCR) after platinum-free preoperative chemotherapy.

Patient Selection

Between August 2012 and January 2019, additional adjuvant chemotherapy plus regional hyperthermia was offered to all high-risk TNBC patients with non-pCR as part of routine management. All patients had operable, unilateral, primary invasive noninflammatory early stage I-IIIB TNBC (ER and PR <1%, HER2 score: 0 or 1) and no pathological complete response after neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by a taxane (paclitaxel or docetaxel). All patients were 18 years or older in good performance status (0/1) and had adequate hematological, cardiac, renal, and hepatic function. Tumor size and lymph node involvement were classified according the UICC criteria. The pathological regression after preoperative chemotherapy was graded from 0 to 4 according to the response criteria of Sinn (0 = no effect, 1 = resorption and tumor sclerosis, 2 = minimal residual invasive tumor (<0.5 cm), 3 = residual noninvasive tumor only, 4 = no tumor detectable) [19]. Treatment was performed in the Medical Center for Hematology and Oncology MVZ, Munich, Germany, in cooperation with Red Cross Breast Center Munich, the Department of Medicine III and the Breast Center, Department of Gynecology of the University Hospital, LMU Munich and Breast Center, Department of Gynecology, Klinikum Dritter Orden. Treatment decisions were made by the Interdisciplinary Tumor Board. Written informed consent was obtained from every patient prior to adjuvant treatment, which was also carried out in collaboration with the health insurance (MDK Bayern).

Treatment Regimen

Patients were treated with postoperative, post-neoadjuvant chemotherapy consisting of gemcitabine (1,000 mg/m2) given on day 1 and cisplatin (25 mg/m2) given on days 2 and 4, every 2 weeks for 6 cycles. Regional hyperthermia (42°C for a 60-min period) was given concurrently with cisplatin on day 2 and day 4 of each cycle. Regional hyperthermia was performed according to the ESHO guidelines for quality and safety assurance [20]. The BSD-2000 hyperthermia system (Pyrexar, Salt Lake City, Utah, USA) was used with a single spiral applicator. The applicator is a circular-shaped, bolus applicator with a maximum heating pattern, depending on operating frequency, of 8–15 cm and a maximum applied power of 250 W. Skin temperature was permanently measured using nonmetallic sensors (Bowmann probes). Automatic temperature scanning along tumor bed was performed each 6–10 min to receive a time-temperature and length-temperature distribution along catheters on the skin surface. Treatment was stopped or omitted if severe adverse events occurred. If indicated, adjuvant standard radiotherapy of the breast/lymph nodes was administered when chemotherapy was completed.

Statistical Analysis

Patient and disease characteristics were analyzed using descriptive statistics. Quantitative variables were expressed as median and range. Survival was estimated by the Kaplan-Meier method and analyzed using the log-rank test. Disease-free survival (DFS) was defined as the time from the start of neoadjuvant chemotherapy to recurrence or death. Overall survival (OS) was defined as the time from start of neoadjuvant chemotherapy to death. Data for patients who did not have an event were censored at the date of the last follow-up. Data were analyzed using the statistical package SAS (V 9.2, SAS Inc., Cary, NC, USA). A p value below 0.05 was considered to indicate statistical significance. For the evaluation of toxicity, side effects that occurred within 6 months after start of the post-neoadjuvant chemotherapy were assessed and reported according to known adverse reactions to gemcitabine, cisplatin, and regional hyperthermia.

From August 2012 to January 2019, post-neoadjuvant chemotherapy plus hyperthermia was offered to 61 patients with TNBC and non-pCR after neoadjuvant therapy.

Of these 61 patients, we excluded 8 patients from this analysis because of early recurrence or metastatic disease prior start of planned treatment (n = 2) or because of having neoadjuvant chemotherapy without anthracycline and/or taxanes or including platinum compound (n = 6). A total of 53 patients fulfilled the criteria for this analysis. The characteristics of the patients are given in Table 1. The median age of the patients was 52 years (range 25–77 years); at baseline, 14 patients (26%) had cT1c, 36 patients (68%) had cT2–3, and 3 patients (6%) had cT4 tumors; 24 patients (45%) were clinically node positive as assessed by ultrasound. Thirty-nine patients (74%) had grade 3 tumors, and 14 patients (26%) had grade 2 tumors. BRCA1/2 mutation status was assessed in 44 patients (83%) and not done in 9 patients (17%). In 32 patients (60%), no BRCA1/2 mutation was found. Four patients (8%) were BRCA1 mutation carriers and another 8 patients (15%) had unclassified BRCA1 gene variants.

Table 1.

Clinical characteristics of patients

Clinical characteristics of patients
Clinical characteristics of patients

After neoadjuvant chemotherapy, all patients underwent surgical resection (37 patients breast conserving, 16 patients mastectomy). The majority of patients (77%) showed a regression grade 1 (Table 1). Postoperative tumor size was classified as ypT1a-ypT1c in 34 patients (64%), ypT2 in 12 patients (23%), and ypT3 or ypT4 in 5 patients (9%). Two patients (4%) revealed ypT0, ypN1a and were classified into non-pCR. The proliferation index Ki67 was median 50% (range 2–95%). After axillary surgery, residual lymph node involvement (ypN+) was detected in 19 patients (36%) whereas 34 patients (64%) were lymph node negative (ypN0).

The time period between start of neoadjuvant chemotherapy and start of post-neoadjuvant chemotherapy was median 8.1 months (range 4–11.1 months), including the time of surgery until start of post-neoadjuvant chemotherapy, which was a median of 1.6 months (range 0.9–4.9 months). Fifty patients underwent postoperative radiotherapy, 37 patients after breast conservative surgery (median 63 Gy, range 50–66.6 Gy), and 13 patients after mastectomy (median 50.4 Gy, range 50–58.8 Gy).

Toxicity

All patients who started the post-neoadjuvant treatment were analyzed. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1–6) combined with 12 applications of regional hyperthermia (median 12, range 2–12). Eighty-seven percent (46/53) of patients completed the allocated six treatment cycles. None of the patients showed progressive disease while on adjuvant treatment. Treatment was generally well tolerated. The most notable toxic grade 3/4 effects were leukopenia in 20 patients (38%), thrombocytopenia grade 3/4 in 2 patients (4%), grade 3/4 anemia in 2 patients (4%), and grade 3 elevation of transaminases (ALT/AST) in 3 patients (6%) without requirement of treatment modification. The common nonhematological adverse events grade 1/2 occurring in >20% of all patients were nausea (n = 35), polyneuropathy (n = 29), obstipation (n = 36), dyspnea (n = 26), mucositis (n = 24), and edema (n = 18). Table 2 summarizes all hematological and nonhematological toxicities occurring in 53 patients.

Table 2.

Toxicity (number per patient)

Toxicity (number per patient)
Toxicity (number per patient)

Outcome

The data cutoff for DFS analysis was March 30, 2019, with a total of 20 events and a median follow-up of 38 months. No relapse or death were recorded within the first 10 months.

For the entire group of 53 patients treated, DFS at 3 years was 57.5% (Fig. 1a). For the subgroup of 29 patients without (cN0) or 24 patients with (cN+) lymph node involvement (ultrasound assessment), DFS at 3 years was 80% (5 events) versus 31% (15 events), respectively (p = 0.001, Fig. 2a). Median DFS of cN+ and pN+ patients was 24 months, and for patients with cN0 and pN0, DFS was not reached. DFS at 3 years for BRCA 1 wild type (32 patients) and BRCA1 mutated or unclassified variants (12 patients) was 56% and did not differ from that of the entire group.

Fig. 1.

a Kaplan-Meier estimates of disease-free survival in all patients (n = 53). b Kaplan-Meier estimates of overall survival in all patients (n = 53).

Fig. 1.

a Kaplan-Meier estimates of disease-free survival in all patients (n = 53). b Kaplan-Meier estimates of overall survival in all patients (n = 53).

Close modal
Fig. 2.

a Kaplan-Meier estimates of disease-free survival according to lymph node (LN) involvement. Three-year survival: 80% (cN0) versus 31% (cN+). b Kaplan-Meier estimates of overall survival according to lymph node (LN) involvement. Three-year survival: 93% (cN0) versus 70.4% (cN+).

Fig. 2.

a Kaplan-Meier estimates of disease-free survival according to lymph node (LN) involvement. Three-year survival: 80% (cN0) versus 31% (cN+). b Kaplan-Meier estimates of overall survival according to lymph node (LN) involvement. Three-year survival: 93% (cN0) versus 70.4% (cN+).

Close modal

On March 30, 2019, 42 patients were alive, and 11 patients had died. For the entire group of 53 patients treated, OS at 3 years was 81.6% (95% CI: 70–93%) (Fig. 1b). For the subgroup of 29 patients without (cN0) or 24 patients with (cN+) lymph node involvement (ultrasound assessment), OS at 3 years was 93% (95% CI: 83–100%) (2 events) versus 70.4% (95% CI: 50.4–90.4%) (9 events), respectively (p = 0.02, Fig. 2b). Median OS of node-positive patients (cN+) was 54 months and was not reached for node-negative patients (cN0). OS at 3 years for BRCA 1 wild type (32 patients) was 82% (95% CI: 66–98%, 8 events) and 89% (95% CI: 68.4–100%, 1 event) for BRCA1 mutated or unclassified variants (12 patients).

Figure 3 shows univariate log-transformed hazard ratios (logHR) of DFS and OS between specific subgroups. A clear effect of the cN status can be seen for both survival times (DFS: logHR = 1.58, 95% CI [0.56; 2.60]; OS: logHR = 1.63 95% [0.09; 3.16]). This relationship is also true for ypN status which trends in the same direction as cN status (DFS: logHR = 0.84 95% CI [–0.12; 1.79]; OS: logHR = 0.97 95% CI [–0.39; 2.32]).

Fig. 3.

Forest plot analysis (univariate) of disease-free survival (a) and overall survival (b). Both figures show the log-transformed hazard ratio (log(HR)) between specific subgroups: age (<50 vs. >50 years); cN status (cN0 vs. cN+); menopause (premenopausal vs. postmenopausal); grade (grade 2 vs. grade 3); ypT status (ypT0/pN1a + ypT1a-c vs. ypT2–4); and ypN status (ypN0 vs. ypN1–3).

Fig. 3.

Forest plot analysis (univariate) of disease-free survival (a) and overall survival (b). Both figures show the log-transformed hazard ratio (log(HR)) between specific subgroups: age (<50 vs. >50 years); cN status (cN0 vs. cN+); menopause (premenopausal vs. postmenopausal); grade (grade 2 vs. grade 3); ypT status (ypT0/pN1a + ypT1a-c vs. ypT2–4); and ypN status (ypN0 vs. ypN1–3).

Close modal

Neoadjuvant chemotherapy has become the standard of care for most patients with TNBC, and the tumor response can be used as an in vivo chemosensitivity assay. Patients without pCR after surgery belong to a high-risk group and the best adjuvant treatment option remains an open question.

This analysis of a consecutive well-defined cohort of early TNBC patients performed for quality assurance purposes showed that gemcitabine and cisplatin combined with regional hyperthermia administered as postoperative post-neoadjuvant therapy in patients with residual invasive tumors or lymph node metastasis after neoadjuvant chemotherapy is feasible and constitutes an effective salvage treatment for this unfavorable subgroup. A similar chemotherapy regimen as first-line treatment without hyperthermia has been shown in a randomized trial to be noninferior and even superior to paclitaxel plus gemcitabine (CBCSG006), defining the significant role of platinum chemotherapy for previously untreated metastatic TNBC [17]. Moreover, in comparison with the toxicity of the regimen in combination with regional hyperthermia compared to the regimen alone in the randomized trial, we had less patients with adverse events and no increase by addition of hyperthermia. We registered grade 3 or 4 leucopenia in 20 patients (38%) and thrombocytopenia in 2 patients (4%), whereas in the randomized trial, more grade 3 or 4 adverse events occurred including nausea (7%), vomiting (11%) anemia (33%), and thrombocytopenia (32%). The safety in our cohort is quite remarkable because, in contrast to the randomized trial population, all of our patients had received neoadjuvant chemotherapy. At the time of starting our case series in 2012, there was no standard treatment for women with TNBC and non-pCR after neoadjuvant chemotherapy. It was known however, that response to preoperative chemotherapy predicts outcome in TNBC and that pCR correlates with excellent survival [21]. In the subgroup of patients with non-pCR, more than 30% will experience a relapse within 5 years, and overall, approximately half of patients with triple-negative disease will have a recurrence [22]. There is only one randomized trial published showing a survival benefit by additional systemic therapy in non-pCR patients. Adjuvant capecitabine in comparison to control in patients with non-pCR (CREATE-X protocol) was shown to be effective in prolonging disease-free and OS [23]. The study included patients with HER2-negative residual invasive breast cancer (no pathological complete response) after neoadjuvant therapy containing anthracyclines and/or taxanes. Among patients with TNBC representing one-third of the entire CREATE-X-population, the rate of DFS was 69.8% in the capecitabine group (139 patients), as compared with 56.1% in the control group (147 patients). The OS rate was 78.8 versus 70.3%, respectively. Unfortunately, the number of patients with positive lymph nodes at baseline was not reported for the TNBC subgroup. From our case series with TNBC patients without lymph node involvement (cN0), DFS at 3 years was 80%, and OS was 93%, and outcome was significantly better when compared to node-positive (cN+) patients in whom DFS was 31% and OS was 70.4%. Interestingly, the entire group of patients in the CREATE-X trial without lymph node involvement (cN0) did not benefit from addition of capecitabine regarding DFS [23]. Therefore, a comparison with our case series is limited and biased by the percentage of node-positive patients, which probably differs between both TNBC cohorts.

As a parallel treatment escalation effort to adding adjuvant treatment for non-pCR, more recent clinical trials, e.g. GeparSixto [24], CALGB 40603 Alliance [25], WSG-ADAPT-TN [26] have escalated neoadjuvant therapy. They were able to show that addition of platinum to an anthracycline or taxane backbone prior to surgery significantly improved pCR rates in TNBC. Yet, whether this pCR advantage translates into a survival advantage is still under discussion. Whereas GeparSixto [24] demonstrated a significantly improved DFS, CALGB 40603 did not [25]. Even though pCR rates with carboplatin were highest in BRCA mutation carriers, the additional benefit from carboplatin was most visible in non-BRCA mutation carriers [26]. In the WSG-ADAPT-TN randomized trial, TNBC patients who had received a neoadjuvant anthracycline-free regimen of nab-paclitaxel combined with carboplatin or gemcitabine, the pCR rate significantly favored the platinum combination [26]. Patients with non-pCR received adjuvant EC by protocol. DFS and OS rates at 3 years in cN0 patients were 78.9 and 88.5%, and 49.3 and 63.5% in cN+ patients, respectively [27]. The ADAPT TN survival rates are quite similar to the results in our cohort; yet, a direct comparison is difficult to make because of the reversed sequence of platinum-based chemotherapy prior surgery followed by postoperative EC.

Because of the heat-induced BRCAness, there is a strong rationale to add regional hyperthermia up front to platinum-based chemotherapy in order to increase the rate of pCR (defined as ypT0 ypN0) in wild-type BRCA patients with TNBC. In preclinical studies, cisplatin sensitization by hyperthermia has been shown both in wild-type cells and mutated cell lines deficient in DNA repair [28]. A previously performed comparison of hyperthermia cisplatin sensitization in human cell lines sensitive and resistant to cisplatin treatment had shown that the degree of thermal sensitization was not reduced in cis-platin-resistant cell lines [29]. Consistent with preclinical modelling, a clinical pilot study in platinum-resistant ovarian cancer suggested that hyperthermia at 41.5°C combined with carboplatin can overcome platinum resistance [30].

Furthermore, an advanced strategy might be the concept of heat-induced synthetic lethality by combining regional hyperthermia with poly (ADP-ribose) polymerase (PARP) inhibitors [31]. In the absence of PARP activity, unrepaired DNA single-strand breaks are converted to double-strand breaks that require homologous recombination for repair which can be blocked by hyperthermia [32]. The exciting results for PARP inhibitors in metastatic Her2-negative disease are limited to BRCA1/2 mutation carriers [33, 34]. Therefore, the potential synergistic benefit of adding hyperthermia to PARP inhibitors could be the rationale to investigate this heat-induced synthetic lethality concept also in BRCA wild-type TNBC.

After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of post-neoadjuvant gemcitabine plus cisplatin in combination with regional hyperthermia is safe and effective in primary TNBC patients with non-pCR. Given the intriguing data on induction of BRCAness by hyperthermia and its potential to reverse platinum resistance as well as the poor prognosis after non-pCR and limited clinical options, further evaluation of regional hyperthermia in the setting of non-pCR after neoadjuvant platin-based chemotherapy in high-risk primary TNBC seems to be warranted.

The authors thank the medical team of doctors and nurses of the Hyperthermia Unit at Red Cross Hospital and of Medical Center for Hematology and Oncology MVZ Munich and in particular A. Oswald-Petit, A. Hartmann, and I. Hitzenberger.

Each patient was presented to the Institutional Review Board. Informed consent was obtained, and treatment was performed according to the Declaration of Helsinki and registered for reimbursement before start of treatment.

O. Stoetzer and C. Salat received honoraria from MedTherm. D. Di Gioia received travel support from PharmaMar, Novartis, Merck, and Lilly. R. Issels received honoraria for invited lectures and reimbursement of travel expenses from PharmaMar, Bayer, Pyrexar, and MedTherm. S. Abdel-Rahman received travel support and honoraria from Dr. Sennewald Medizintechnik and MedTherm. L. Lindner received research and travel support from Dr. Sennewald Medizintechnik; travel support and honoraria from PharmaMar, Novartis, Lilly, Eisai, Bayer, Roche, and EL Medconsult. O. Gluz received advisory board and travel support from Celgene, Amgen, and Roche and honoraria from Genomic Health, Nanostring, Pfizer, Lilly, Novartis, Daiichi and Eisai. R. Würstlein received travel support, honoraria and consultancy from Celgene, Roche, MSD, Eisai, Pfizer, Astra Zeneca, Novartis, and Lilly. M. Braun received advisory board, honoraria and travel expenses from AstraZeneca, Celgene, Genomic Health, Medac, MSD, Novartis, Pfizer, Roche and Teva. All other authors declare no conflicts of interest.

The authors state that this work has not received any funding.

Conception and design: all authors. Development of methodology: O. Stoetzer, D. Di Gioia, L. Lindner, R. Issels, S. Abdel-Rahman, N. Harbeck, C. Salat. Acquisition of data: O. Stoetzer, D. Di Gioia, L. Lindner, R. Issels, S. Abdel-Rahman, C. Salat. Analysis and interpretation of data: all authors. Writing and/or review of the manuscript: all authors.

1.
Harbeck
N
,
Gluz
O
.
Neoadjuvant therapy for triple negative and HER2-positive early breast cancer
.
Breast
.
2017
Aug
;
34
Suppl 1
:
S99
103
.
[PubMed]
0960-9776
2.
von Minckwitz
G
,
Untch
M
,
Blohmer
JU
,
Costa
SD
,
Eidtmann
H
,
Fasching
PA
, et al
Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes
.
J Clin Oncol
.
2012
May
;
30
(
15
):
1796
804
.
[PubMed]
0732-183X
3.
Couch
FJ
,
Hart
SN
,
Sharma
P
,
Toland
AE
,
Wang
X
,
Miron
P
, et al
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer
.
J Clin Oncol
.
2015
Feb
;
33
(
4
):
304
11
.
[PubMed]
0732-183X
4.
Hahnen
E
,
Lederer
B
,
Hauke
J
,
Loibl
S
,
Kröber
S
,
Schneeweiss
A
, et al
Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial
.
JAMA Oncol
.
2017
Oct
;
3
(
10
):
1378
85
.
[PubMed]
2374-2437
5.
Kuroi
K
,
Toi
M
,
Ohno
S
,
Nakamura
S
,
Iwata
H
,
Masuda
N
, et al
Prognostic significance of subtype and pathologic response in operable breast cancer; a pooled analysis of prospective neoadjuvant studies of JBCRG
.
Breast Cancer
.
2015
Sep
;
22
(
5
):
486
95
.
[PubMed]
1340-6868
6.
Issels
R
,
Kampmann
E
,
Kanaar
R
,
Lindner
LH
.
Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology
.
North American Hyperthermia Group
.
2016
;
32
(
1
):
89
95
.
7.
Frey
B
,
Weiss
EM
,
Rubner
Y
,
Wunderlich
R
,
Ott
OJ
,
Sauer
R
, et al
Old and new facts about hyperthermia-induced modulations of the immune system. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology
.
North American Hyperthermia Group
.
2012
;
28
(
6
):
528
42
.
8.
Welz
S
,
Hehr
T
,
Lamprecht
U
,
Scheithauer
H
,
Budach
W
,
Bamberg
M
.
Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology
.
North American Hyperthermia Group
.
2005
;
21
(
2
):
159
67
.
9.
Vernon
CC
,
Hand
JW
,
Field
SB
,
Machin
D
,
Whaley
JB
,
van der Zee
J
, et al;
International Collaborative Hyperthermia Group
.
Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials
.
Int J Radiat Oncol Biol Phys
.
1996
Jul
;
35
(
4
):
731
44
.
[PubMed]
0360-3016
10.
Jones
EL
,
Oleson
JR
,
Prosnitz
LR
,
Samulski
TV
,
Vujaskovic
Z
,
Yu
D
, et al
Randomized trial of hyperthermia and radiation for superficial tumors
.
J Clin Oncol
.
2005
May
;
23
(
13
):
3079
85
.
[PubMed]
0732-183X
11.
Kouloulias
VE
,
Dardoufas
CE
,
Kouvaris
JR
,
Gennatas
CS
,
Polyzos
AK
,
Gogas
HJ
,
Sandilos
PH
,
Uzunoglu
NK
,
Malas
EG
,
Vlahos
LJ
: Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clinical cancer research : an official journal of the American Association for Cancer Research
2002
;8:374-382.
12.
Zagar
TM
,
Higgins
KA
,
Miles
EF
,
Vujaskovic
Z
,
Dewhirst
MW
,
Clough
RW
, et al
Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy
.
Radiother Oncol
.
2010
Dec
;
97
(
3
):
535
40
.
[PubMed]
0167-8140
13.
Issels
RD
,
Lindner
LH
,
Verweij
J
,
Wust
P
,
Reichardt
P
,
Schem
BC
, et al;
European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG)
;
European Society for Hyperthermic Oncology (ESHO)
.
Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study
.
Lancet Oncol
.
2010
Jun
;
11
(
6
):
561
70
.
[PubMed]
1470-2045
14.
Issels
RD
,
Lindner
LH
,
Verweij
J
,
Wessalowski
R
,
Reichardt
P
,
Wust
P
, et al;
European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology
.
Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial
.
JAMA Oncol
.
2018
Apr
;
4
(
4
):
483
92
.
[PubMed]
2374-2437
15.
Angele
MK
,
Albertsmeier
M
,
Prix
NJ
,
Hohenberger
P
,
Abdel-Rahman
S
,
Dieterle
N
, et al
Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study
.
Ann Surg
.
2014
Nov
;
260
(
5
):
749
54
.
[PubMed]
0003-4932
16.
Harnicek
D
,
Kampmann
E
,
Lauber
K
,
Hennel
R
,
Cardoso Martins
AS
,
Guo
Y
,
Belka
C
,
Mortl
S
,
Gallmeier
E
,
Kanaar
R
,
Mansmann
U
,
Hucl
T
,
Lindner
LH
,
Hiddemann
W
,
Issels
RD
:
Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair.
International journal of cancer Journal international du cancer
2016
;139:467-479.
17.
Hu
XC
,
Zhang
J
,
Xu
BH
,
Cai
L
,
Ragaz
J
,
Wang
ZH
, et al
Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial
.
Lancet Oncol
.
2015
Apr
;
16
(
4
):
436
46
.
[PubMed]
1470-2045
18.
Kim
JS
,
Park
IH
,
Lee
KS
,
Ro
J
.
Outcomes of palliative weekly low-dose gemcitabine-Cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients
.
J Breast Cancer
.
2014
Dec
;
17
(
4
):
339
43
.
[PubMed]
1738-6756
19.
Sinn
HP
,
Schmid
H
,
Junkermann
H
,
Huober
J
,
Leppien
G
,
Kaufmann
M
, et al
[Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy]
.
Geburtshilfe Frauenheilkd
.
1994
Oct
;
54
(
10
):
552
8
.
[PubMed]
0016-5751
20.
Trefna
HD
,
Crezee
H
,
Schmidt
M
,
Marder
D
,
Lamprecht
U
,
Ehmann
M
, et al
Quality assurance guidelines for superficial hyperthermia clinical trials: I. Clinical requirements. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology
.
North American Hyperthermia Group
;
2017
. pp.
1
12
.
21.
Liedtke
C
,
Mazouni
C
,
Hess
KR
,
André
F
,
Tordai
A
,
Mejia
JA
, et al
Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer
.
J Clin Oncol
.
2008
Mar
;
26
(
8
):
1275
81
.
[PubMed]
0732-183X
22.
Cortazar
P
,
Zhang
L
,
Untch
M
,
Mehta
K
,
Costantino
JP
,
Wolmark
N
, et al
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis
.
Lancet
.
2014
Jul
;
384
(
9938
):
164
72
.
[PubMed]
0140-6736
23.
Masuda
N
,
Lee
SJ
,
Ohtani
S
,
Im
YH
,
Lee
ES
,
Yokota
I
, et al
Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy
.
N Engl J Med
.
2017
Jun
;
376
(
22
):
2147
59
.
[PubMed]
0028-4793
24.
von Minckwitz
G
,
Schneeweiss
A
,
Loibl
S
,
Salat
C
,
Denkert
C
,
Rezai
M
, et al
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial
.
Lancet Oncol
.
2014
Jun
;
15
(
7
):
747
56
.
[PubMed]
1470-2045
25.
Sikov
WM
,
Berry
DA
,
Perou
CM
,
Singh
B
,
Cirrincione
CT
,
Tolaney
SM
, et al
Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance)
.
J Clin Oncol
.
2015
Jan
;
33
(
1
):
13
21
.
[PubMed]
0732-183X
26.
Gluz
O
,
Nitz
U
,
Liedtke
C
,
Christgen
M
,
Grischke
EM
,
Forstbauer
H
, et al
Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results
.
J Natl Cancer Inst
.
2018
Jun
;
110
(
6
):
628
37
.
[PubMed]
0027-8874
27.
Gluz O, Nitz U, Liedtke C, Prat A, Christgen M, Feuerhake F, et al. No survival benefit of chemotherapy escalation in patients with pCR and "high-immune" triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Cancer Res. 2019;79(4 Suppl):Abstract GS5-06.
28.
Raaphorst
GP
,
Li
LF
,
Yang
DP
,
LeBlanc
JM
.
Cisplatin sensitization by concurrent mild hyperthermia in parental and mutant cell lines deficient in homologous recombination and non-homologous endjoining repair
.
Oncol Rep
.
2005
Jul
;
14
(
1
):
281
5
.
[PubMed]
1021-335X
29.
Raaphorst
GP
,
Doja
S
,
Davis
L
,
Stewart
D
,
Ng
CE
.
A comparison of hyperthermia cisplatin sensitization in human ovarian carcinoma and glioma cell lines sensitive and resistant to cisplatin treatment
.
Cancer Chemother Pharmacol
.
1996
;
37
(
6
):
574
80
.
[PubMed]
0344-5704
30.
Westermann
AM
,
Grosen
EA
,
Katschinski
DM
,
Jäger
D
,
Rietbroek
R
,
Schink
JC
, et al
A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer
.
Eur J Cancer
.
2001
Jun
;
37
(
9
):
1111
7
.
[PubMed]
0959-8049
31.
Krawczyk
PM
,
Eppink
B
,
Essers
J
,
Stap
J
,
Rodermond
H
,
Odijk
H
, et al
Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition
.
Proc Natl Acad Sci USA
.
2011
Jun
;
108
(
24
):
9851
6
.
[PubMed]
0027-8424
32.
Eppink
B
,
Krawczyk
PM
,
Stap
J
,
Kanaar
R
.
Hyperthermia-induced DNA repair deficiency suggests novel therapeutic anti-cancer strategies. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology
.
North American Hyperthermia Group
.
2012
;
28
(
6
):
509
17
.
33.
Robson
M
,
Im
SA
,
Senkus
E
,
Xu
B
,
Domchek
SM
,
Masuda
N
, et al
Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation
.
N Engl J Med
.
2017
Aug
;
377
(
6
):
523
33
.
[PubMed]
0028-4793
34.
Litton
JK
,
Rugo
HS
,
Ettl
J
,
Hurvitz
SA
,
Gonçalves
A
,
Lee
KH
, et al
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation
.
N Engl J Med
.
2018
Aug
;
379
(
8
):
753
63
.
[PubMed]
0028-4793

O. Stoetzer and D. Di Gioia contributed equally to this work.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.