Triple negative breast cancer (TNBC) is the most aggressive subtype, including early BC. Neoadjuvant chemotherapy (NAC) has shown benefit in achieving more conservative surgeries, but also it is useful to determine therapeutic sensitivity, prognostic estimation, and consequent choice of an individualized adjuvant treatment. Traditionally, NAC was indicated in patients with cT2 (2 cm or more) TNBC. However, recent guidelines consider neoadjuvant treatment for cT1 TNBC patients. In this paper, we review the current evidence on neoadjuvant treatment in cT1 TNBC patients, including available signals on efficacy, choice of optimal regimen and identification of patients with the greatest potential benefit.
El cáncer de mama triple negativo (CMTN) es el subtipo más agresivo de CM, incluida la enfermedad precoz. La quimioterapia neoadyuvante (QTN) ha demostrado ser beneficiosa para lograr cirugías más conservadoras, pero también es útil para determinar la sensibilidad terapéutica, la estimación pronóstica y la consiguiente elección de un tratamiento adyuvante individualizado. Tradicionalmente, la QTN estaba indicada en pacientes con CMTN cT2 (2 cm o más). Sin embargo, las directrices recientes consideran el tratamiento neoadyuvante para las pacientes con CMTN cT1. En este artículo, revisamos la evidencia actual sobre el tratamiento neoadyuvante en pacientes con CMTN cT1N0, incluyendo los datos disponibles sobre eficacia, elección del régimen óptimo e identificación de las pacientes con mayor beneficio potencial.
Neoadjuvant chemotherapy (NAC) refers to the administration of cytotoxic treatment before tumor surgical removal. Initially aimed to convert inoperable BC into a surgically removable disease, the interest in NAC has significantly increased over the last decade.1,2 NAC increases the rate of conservative surgery, enables treatment response monitoring and provides unique opportunities for developing novel and individualized therapeutic strategies.3 Additionally, 2 more relevant observations contributed to the increase of NAC indications. First, pathological complete response (pCR) after NAC has been considered a robust predictor of disease-free survival (DFS), and overall survival (OS), especially for the most aggressive BC subtypes, such as triple negative BC (TNBC), a subtype in which both probability of reaching pCR after NAC and survival benefits from adjuvant chemotherapy are the highest.4 Second, recent randomized trials demonstrated that in those patients with TNBC and residual invasive disease after pre-operative systemic treatment, adjuvant capecitabine5 or olaparib (in carriers of BRCA1/2 mutations)6 significantly improves survival.
In TNBC, the most aggressive subtype of BC, systemic treatment is associated with improved survival and NAC is a standard of care in most of the patients with clinical stage II–III TN disease, even when initial breast conservation may be achieved by frontline surgery.7 With the aim of evaluating treatment efficacy by pathological response assessment, guiding risk stratification, reducing the extent of surgical need, and determining the adjuvant treatment plan, some authors have proposed to extend the traditional indication of NAC to cT1c stages. This is a frequent clinical scenario, which corresponds to around one third of stage I–III TNBC.8 The last version of ESMO Early Breast Cancer Clinical Practice Guidelines has also included cT1N0 TNBC as an indication for NAC [category IA].7
The aim of this narrative review is to determine whether neoadjuvant treatment is the preferred treatment in cT1N0 TNBC, and if that is the case, which treatment regimen should be used.
Basis of “traditional” treatment of triple negative cT1N0 breast cancer and potential limitations for neoadjuvant systemic treatmentPrevious guidelines from ESMO recommended primary surgery for cT1N0 TNBC, with NAC, which was reserved for tumors larger than 2 cm. This has been the classical strategy for tumors under 2 cm, based on the usually good results obtained with primary surgery followed by adjuvant chemotherapy. The rationale for surgery followed by adjuvant systemic treatment in patients with TNBC less than 2 cm (cT1N0) is varied.
Size-dependent benefit of adjuvant chemotherapy in small TNBCFirst, the benefit of adjuvant chemotherapy in TN tumors without axillary involvement is clearly dependent on tumor size, with virtually negligible gains in T1a tumors, limited in T1b tumors and clearly established and substantial in tumors larger than 1 cm.9–11 Most evidence on the benefit in these groups come from retrospective observational studies (Table 1).10–19 Clinical practice guidelines recommend adjuvant treatment with chemotherapy in pT1cN0M020,21 and even pT1bN0M0 stages directly [IA]7 or after individual discussion with the patient [IIIB],22 except in histological subtypes with a good prognosis (cystic adenoid, secretory). In tumor sizes close to 1 cm, therefore, inadequate estimation of tumor size could lead to overtreatment with chemotherapy.
Major studies evaluating chemotherapy results in T1N0 TNBC.
| Referencea | N | Type of series | pT1a benefit | pT1b benefit | pT1c benefit |
|---|---|---|---|---|---|
| Oladeru, JAMA Network Open 202012 | 16,180 | National registry (NCDB) | Deleterious effect OS (HR 1.46, 95%CI 1.17–1.82) | OS benefit (HR 0.74, 95%CI 0.63–0.87), higher in >50 yr | – |
| Carbajal-Ochoa, Breast Cancer Res Treat 202413 | 11,510 | SEER database (US) | – | No improvement in BCSS, but in OS (HR 0.52; 95%CI 0.41–0.68). | Yes (OS HR 0.54; 95%CI 0.47–0.62) |
| Tarantino, NPJ Breast Cancer 2024)14 | 8601 | Population-based (US) | No benefit in BCSS | No benefit in BCSS | Yes (BCSS, HR 0.64, 95%CI 0.48–0.85) |
| Stenbruggen, Eur J Cancer 202010 | 4366 | Population-based (Netherland) | No benefit (worse BCS for chemotherapy) | No benefit | Benefit (BCSS HR 0.60; 95%CI 0.43–0.82) |
| Shum, Med Oncol 202215 | 610 | Population-based (Canada) | No OS benefit pT1a-b (HR 0.40, 95%CI 0.02–2.5) | Yes (OS HR 0.40 95%CI 0.16–0.86) | |
| Nonneville, Eur J Cancer 201716 | 284 | Multicentric (France) | No benefit (DFS, HR 0.77, 95%CI 0.40–1.46; DRFS, HR 1, 95%CI 0.46–2.19) | – | |
| Wu, Gland Surg 202317 | 441 | Unicentric (China) | No benefit (5-yr BCFI, 93.6% vs 94.6%, p=.55) | Benefit (5-yr BCFI, 92.1% vs 79.5%, p=.03). No OS benefit | |
| Fasano, Breast Cancer Res Treat 202218 | 258 | Multicentric (US) | No (100% 5-yr OS both groups) | No (100% vs 95.8% 5-yr OS, p=.24) | Yes (5-yr OS, 93.2% vs 75.2%, p=.008) |
| Vaz-Luis, J Clin Oncol 201419 | 168 | Multicentric (US) | Higher numerical 5-yr DRFS (100% vs 93%, no formal comparison) | Higher numerical 5-yr DRFS 96% vs 90%, no formal comparisons | – |
| An, Cancer 202011 | 351 | Unicentric (China) | No benefit in RFS | No benefit in RFS (HR 0.64, 95%CI 0.05–7.74) | Yes (RFS, HR 0.107, 95%CI 0.047–0.244) |
| An, Cancer 202011 | 1525 | Meta-analysis (7 studies) | No benefit in risk of recurrence (RR 0.64, 95%CI 0.31–1.33) | Benefit (RR 0.62, 95%CI 0.42–0.92) | Benefit for whole T1N0 group (RR 0.58, 95%CI 0.43–0.78) |
BCS: breast cancer-specific survival; BCFI: breast cancer-free interval; DFS: disease-free survival; DRFS: distant relapse-free survival; OS: overall survival; RFS: relapse-free survival; RR: risk ratio.
Secondly, the results of the available series with initial surgery followed by adjuvant chemotherapy show, even in the cT1N0 tumor group, breast cancer-specific survival figures of around 94%,9 so that escalating treatment in this group does not seem fully justified by the results. Some biomarkers of good prognosis have been proposed from retrospective data, such as high tumor lymphocyte infiltration (TIL),23 which could probably justify omitting chemotherapy in some cT1N0 tumors. However, it is not clear if treatment escalation could improve results in groups with worse prognosis.
Under-representation of small TNBC in recent neoadjuvant trialsThirdly, recent modifications of neoadjuvant systemic treatment, particularly the introduction of immunotherapy, are based on studies that excluded the population of patients with cT1N0 tumors as most trials required the presence of at least one tumor larger than 2 cm for inclusion. This exclusion is especially notable for the KEYNOTE-522 study with pembrolizumab,24 which has established the indication for chemoimmunotherapy in the neoadjuvant and adjuvant setting, regardless of the levels of PD-L1 expression. Also, stage I patients were not included in the other neoadjuvant immunotherapy studies, such as IMpassion03125 or NeoTRIP trials.26 While it is biologically and clinically reasonable to consider that the results would be extrapolated to groups with a better prognosis, the absolute benefit of the new treatments will be lower in this lower risk group. Since the same toxicity is expected, the balance between benefit and toxicity is probably reduced in a group with a generally good prognosis. A similar issue occurs with the administration of dose-dense schedules, generally recommended in this population, but of uncertain efficacy in the N0 tumor group, which was underrepresented in the Oxford meta-analysis.27
Opportunities for chemotherapy downscaling in small TNBCIn contrast, there are data on the use of neoadjuvant carboplatin in cT1cN0 patients, which were included in the randomized phase II studies WSG-ADAPT,28 with 37% of cT1cN0 patients, and in the NeoSTOP trial,29 with 17% of cT1cN0 patients. In the former, a short regimen (4 cycles) with carboplatin and nabpaclitaxel achieved 44% pCR and showed the possibility of tailoring the sequential administration of anthracyclines to whether or not pCR was achieved. In the neoSTOP study, the results were virtually equal in terms of pCR rate (54%) and overall survival for sequential paclitaxel–carboplatin and anthracycline schedules and for the 6-cycle carboplatin and docetaxel schedule.29 Therefore, the administration of neoadjuvant carboplatin seems beneficial in these patients, improving pCR and survival rates,30 irrespective of the presence or absence of BRCA1/2 mutations.31
Finally, it is in the adjuvant setting of cT1N0 TNBC that shorter, anthracycline-free systemic treatment regimens (6 cycles of docetaxel and cyclophosphamide or carboplatin and taxane) have been most frequently proposed. The equivalence of docetaxel and cyclophosphamide regimens is more questionable, with mainly retrospective data,32 and these regimens should be restricted to patients with contraindications to anthracyclines, as the anthracycline–taxane sequence has generally shown better results in the pooled analysis of ABC trials, even in the N0 population.33 However, in the PATTERN trial, the weekly adjuvant paclitaxel–carboplatin regimen showed comparable results to 6 cycles of a sequential anthracycline–taxane regimen and was even better in the N0 tumor subgroup.34 Therefore, in cT1N0 tumors, such adjuvant schemes could be considered as an alternative to the use of anthracyclines, which is standard for NAC.
Potential overtreatment of small TNBCThe introduction of NAC in patients with cT1N0 tumors, therefore, poses the main problem of the risk of overtreatment due to imaging-based staging and the type of systemic treatment used.
The best approach to mitigate the risk of upstaging is to correctly assess tumor size through pre-treatment magnetic resonance imaging (MRI). Although MRI tend to overestimate tumor size, this seems to occur mostly in tumors larger than 2 cm.35 Regarding nodal staging, in most cases (around 85%–89%), cT1 tumors will be N0, so the risk of overstaging is low and the possibility of understaging is more relevant because of its therapeutic consequences.36 This risk can probably be reduced by half if correct axillary staging with ultrasound is performed.36 More recently, precisely to avoid this risk, pre-surgical sentinel lymph node biopsy has been proposed again for cT1N0 tumors in which primary surgery is being considered. However, the selection criteria for this approach remain unclear and might be especially applicable in cases with a high risk of axillary involvement (lymphovascular invasion or low lymphocyte infiltration).
Secondly, the introduction of NAC, if the same treatment regimens are used as in larger tumors, could overtreat a substantial group of patients without clear data of additional benefit. In stage T1N0, results are available from the randomized phase II study BT1902/ICBSG 61–20 Neo-N, which has shown a pCR rate of 54% after 12 weeks of carboplatin, paclitaxel, and nivolumab, but without comparison with a non-immunotherapy arm.37 Other non-comparative neoadjuvant immunotherapy studies that have included stage I patients have shown similar results, such as the NeoPACT trial, a phase II trial that included 18% of stage I patients larger than 1 cm and combined pembrolizumab with an anthracycline-free regimen (docetaxel and carboplatin), with a pCR rate of 58%.38 Therefore, in the absence of sufficient comparative data against chemotherapy, immunotherapy with pembrolizumab24 should not be used in these patients, as stated in the latest ESMO guidelines.7 As for the introduction of carboplatin, although the level of evidence is limited (2 randomized phase II in the neoadjuvant setting and only 1 phase III in the adjuvant setting),28,29,34 its use is probably reasonable and, especially in lower risk cases, carboplatin and taxane regimens could be considered as an alternative to the sequence of taxanes–carboplatin and anthracyclines.
Rationale for extending neoadjuvant treatment indication to cT1N0 triple negative breast cancerWhy, then, should we introduce NAC in tumors below 2 cm? First, in contrast to ESMO 2020 guidelines, ASCO guidelines excluded cT1a and cT1b of NAC indication, but they did not establish a clear recommendation for cT1c tumors.39 In fact, some authors had proposed a cut-point of 1.5 cm to decide whether NAC should be the preferred treatment.40 Thus, the use of NAC for smaller tumors is not new, and its clinical application has been evolving in the last years. The major rationale to extend NAC indication to cT1c TNBC is clearly based on the recent developments of NAC and in the value of pCR for prognostic stratification, which facilitates individualized tailoring of adjuvant treatment.
A second reason is the potential missed opportunities for offering better therapeutic strategies in those patients in which clinical staging underestimates the real extent of disease. In particular, some patients with cN0 tumors will be found to be pN1 after sentinel lymph node biopsy. This finding usually will not lead to a different surgical treatment, because high nodal burden leading to lymphadenectomy is infrequent in cN0 cases. On the contrary, if lymph node involvement is not clinically detected, neoadjuvant treatment would not include immunotherapy either, thereby limiting opportunities for the patient, as adjuvant immunotherapy alone41 has not demonstrated prognostic improvement, unlike neoadjuvant immunotherapy.
However, these patients will have lost the chance to upscale adjuvant treatment in the event of chemotherapy resistance. Specifically, patients with pathogenic BRCA1/2 variants would not have a clear indication for adjuvant olaparib unless the absence of pCR is demonstrated. The same would be applicable for adjuvant capecitabine, according to the CreateX trial results, which included a small group (around 5%) of stage I patients and might benefit those TNBC patients without pCR5 with better results and less toxicity than carboplatin.42 Thus, there are potentially missed opportunities for systemic therapy when surgical treatment is the first therapy. In addition, those patients with cN0/pN1 stage undergoing primary surgery will receive nodal adjuvant radiation therapy, while those cN0 patients with occult nodal disease treated with NAC and getting an axillary pCR will avoid radiation therapy according to the recently reported results of NR Oncology/NSABP B-51/RTOG 1304 trial.43
Finally, practical reasons may further justify the neoadjuvant approach to minimize delays between diagnosis and first treatment44 and to give some time for BRCA1/2 diagnosis, potentially leading to changes in BC surgery and adjuvant therapy.45
DiscussionThus, based on this rationale, the recent recommendation of NAC for cT1cN0 TNBC seems appropriate in the context of low risk of overestimation of tumor size, potential loss of additional therapeutic opportunities, and response-guided decisions for adjuvant systemic therapy in patients not achieving pCR after NAC. However, decisions in this group of patients should not be uncritically applied, and the cT1cN0 tumors should be considered as a heterogeneous and continuous spectrum in which some factors might refine the indication of NAC versus primary surgical treatment. We further discuss some of these factors.
The need for more precise radiological stagingA precise clinical and radiological initial staging is mandatory. MRI determination of tumor size and ultrasound assessment of nodal status may avoid overtreatment of patients with small size tumors. Since benefits of treatment are limited as we approach the 1 cm tumor size, in those cT1cN0 tumors with total diameters around 10 mm, special care should be taken to determine the final size of the invasive tumor and to avoid including DCIS or enhancement areas into the measurement. This issue will not be a concern in tumors around or larger than 1.5 cm, in which NAC poses less risk of overtreatment.
The need for a better prognostic stratificationSome patient characteristics, such as the presence of lymphatic and vascular invasion (associated with a higher frequency of axillary involvement)46 could increase the likelihood of occult nodal disease and therefore direct the decision towards NAC. Conversely, older age or greater comorbidity could tip the balance towards primary surgery given the greater difficulty and risk of NAC administration. The question of whether a pre-treatment sentinel lymph node biopsy should be performed in those cT1cN0 stages with risk factors for lymph node involvement has been discussed recently. This approach would prevent missed opportunities for immunotherapy in the cN0/pN+ group of patients and definitively establish the indication for neoadjuvant therapy. However, it would also raise additional questions about post-chemotherapy axillary evaluation and the surgical and radiotherapeutic management of the axilla.
Similarly, although not considered fully validated as biomarkers, the presence of high sTIL levels in a cT1N0 tumor could justify a primary surgical approach as the risk of distant relapse appears to be around 2% without chemotherapy.23 The use of high lymphocyte infiltration (equal to or greater than 50% in those over 40, greater than 75% in those under 40) to avoid adjuvant chemotherapy in triple-negative pT1abcN0 tumors will be evaluated in the OPTImaL study (EORTC 2257: Optimization of treatment for patients with low-stage TNBC with high sTIL). Other trials, such as NeoTRACT (NCT05645380), are also evaluating the use of sTIL to tailor neoadjuvant treatment intensity in early stages, a strategy supported by recent data showing that sTIL (with a 30% cut-off point) could improve prognostic stratification beyond pCR and stage, probably allowing de-escalation to anthracycline-free regimens.47 Other immune biomarkers could also be useful.
The choice of appropriate neoadjuvant regimens for small TNBCRegarding the NAC regimen and duration, the ESMO guidelines clearly states that immunotherapy should not be administered in the setting of cT1cN0 TNBC. However, the neoadjuvant strategy for cT1cN0 based on chemotherapy only addresses the problem of the lack of information provided by the pCR status but does not solve the problem of nodal understaging and missed opportunities for immunotherapy in this group of women. As previously discussed, further nodal staging, especially in high-risk patients, might be valuable in this setting. The chemotherapy schedule should include at least carboplatin and taxanes, and the regimens without anthracyclines might be used unless high-risk factors are present.
The duration of chemotherapy is usually between 6 and 8 cycles (depending on whether the NAC regime includes or not anthracyclines). Several de-escalation strategies aimed to reduce the duration of NAC are currently being pursued based on previous data showing similar results with 4 and 6 cycles of adjuvant chemotherapy in ER-negative disease48 and on the results of WSG-ADAPT trial,28 in which anthracyclines were administered in patients not achieving pCR after a 4-cycles course of nabpaclitaxel–carboplatin chemotherapy. Alternative strategies including early MRI49 or PET-TC50 evaluation of response have not been proved to be sufficiently reliable to predict pCR and reduce NAC duration.
Research challenges in small TNBCFinally, the neoadjuvant approach in stage I is also a suitable platform for the investigation of new de-escalation strategies, as demonstrated by its inclusion in recent studies aimed at the neoadjuvant use of iPARP in patients carrying BRCA1/2 mutations51,52 or ADC substitution for chemotherapy (NeoSTAR study with sacituzumab–govitecan),53 which achieve pCR rates of 40%–50% as single agents. Some ongoing or forthcoming studies, such as Olympia-N (NCT05498155), with olaparib, or ADAPT-TN-III (NCT06081244), which will compare an adaptive neoadjuvant design with sacituzumab–govitecan with or without pembrolizumab, are specifically targeting stage I TNBC patients.
ConclusionNeoadjuvant approach is the preferred option for cT1N0 TNBC, especially for patients with higher risk (tumors larger than 1.5 cm or with evidence of lymphovascular invasion). The chemotherapy schedule should include at least carboplatin and taxanes, and anthracyclines if high-risk factors are present. Further evidence about the role of immunotherapy in this subset of patients is necessary. A precise clinical and radiological initial staging (including MRI) may avoid either overtreatment or loss of therapeutic opportunities. The development of predictive biomarkers could decrease therapeutic uncertainty. An individualized approach is mandatory.
FundingThis research received no external funding.
Ethical disclosuresNot applicable.
