Early BC Research Articles

Political and cultural complexity in north-west China during the Western Zhou Period (1045–771 BC): new evidence from Yaoheyuan

During the early first millennium BC, having deposed the Shang dynasty, the Western Zhou exerted power over large parts of China. Archaeologically, however, the Western Zhou are less well known than their predecessors in terms of north-west China. The site of Yaoheyuan is one of the most important recent discoveries of the Western Zhou period in north-west China. Investigations have revealed a walled urban centre, with high-status cemeteries and sacrificial pits, a palace complex, a bronze-casting foundry, pottery workshops and inscribed oracle bones. These unparalleled finds provide significant new evidence with which to examine the political and cultural landscape of north-west China and, more broadly, to reassess the relationships between centres and peripheries during the Chinese late Bronze Age.

Risk of Subsequent Breast Cancer in Women with Early Stage HER2-Positive Breast Cancer in a Large Community Health Plan.

Clinical outcomes have improved for women with early stage, HER2-positive breast cancer following the FDA approval of adjuvant trastuzumab use in 2006. However, only limited information exists on such patients' outcomes in real-world settings outside of clinical trials. We examined the risk of subsequent breast cancer in women with HER-2 positive disease, and the impact of trastuzumab use, in a large California community-based health plan. A cohort of 3550 women with HER2-positive breast cancer (stages I-III) from 2009-2017 were followed through December 2018. We calculated subsequent breast cancer (SBC) rates overall and by trastuzumab use. Multivariable Cox proportional hazards modeling was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for SBC by trastuzumab use. Within the cohort diagnosed with HER2-positive disease, 81% received adjuvant trastuzumab. After 4.1 mean years follow-up (maximum 10 years), the risk of SBC was 22% lower with adjuvant trastuzumab use (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) compared with non-use. The cumulative incidence of SBC precipitously rose two years after diagnosis and by the 10th year, the cumulative incidence was 31% among those who had trastuzumab therapy versus 34% without this therapy. In community practice settings, the cumulative incidence of SBC in patients with early stage HER2-positive BC was 31% at 10 years in a cohort treated with adjuvant trastuzumab. Trastuzumab use was associated with a 22% reduced risk of developing SBC. This residual disease burden suggests breast cancer outcomes may be improved with further treatment given the advent of next-generation HER2-targeted therapies.

Investigating Colors and Techniques on the Wall Paintings of the ‘Tomb of the Philosophers’, an Early Hellenistic Macedonian Monumental Cist Tomb in Pella (Macedonia, Greece)

The ‘Tomb of the Philosophers’, owing its name to the iconographic theme depicted on the interior of its walls, offers a rare example of high-quality early Hellenistic painting, which enhances our knowledge on the use of painting materials and techniques in Greece during the late 4th–early 3rd century BC. The tomb was excavated in 2001 by the 17th Ephorate of Prehistoric and Classical Antiquities, in the area of the east cemetery of the ancient city of Pella and is among the largest built cist graves to have been found in the region to date. This article presents the results of a scientific investigation of the painting materials and techniques used in the tomb’s decoration by means of high-resolution visible- and raking-light imaging, broadband imaging (IRR, UIL, UVR, VIL), X-ray fluorescence spectroscopy and SEM-EDAX microanalysis on a representative number of samples. The examination of the paintings testifies to the application of elaborate painting techniques and to the use of a varied and rich chromatic ‘palette’ (iron oxides, Egyptian blue, malachite, conichalcite, cinnabar, lead white, carbon-based black, a purple organic colorant, yellow-orange arsenic and vanadium-based pigments). Furthermore, iconographic elements of the paintings were better visualized, allowing for a more accurate description and interpretation of the decorative program of the tomb.

Sounds from a Mountain. Acoustics at La Peña de los Enamorados (Antequera, Spain), a Neolithic sanctuary

La Peña de los Enamorados, a limestone massif located in Antequera, Spain, is a famous landmark since (at least) the Middle Ages on account of its marked anthropomorphic silhouette and geographic position right at the crossroads of Andalucía’s two main communication routes (connecting Málaga and Córdoba, in a South-North direction, and Sevilla and Granada in a West-East direction). In the last fifteen years, archaeological research has revealed substantial evidence of intense Late Neolithic, Copper Age and Early Bronze Age activity (spanning from the mid-4th to the early 2nd millennia BC) on its northern sector. This includes various loci of activity: (i) the Matacabras shelter, with schematic-style rock art, which is located at the foot of Tajo Colorado, a 100 m-high rocky wall that forms the mountain’s ‘chin’; (ii) the recently discovered Piedras Blancas megalithic grave; (iii) and several remains of activity, including Locus 4, on the steep glacis at the foot of Tajo Colorado. In this paper, we examine the acoustic behaviour of Tajo Colorado, Matacabras and Locus 4. Signals produced by means of a blank-shot pistol were recorded at each reception point by means of a high-quality audio recorder via a microphone condenser mic while controlling background noise levels. The study included impulse response analysis based on its temporal and frequency behaviour, through Schroeder decay curves, Envelop-Time Curves, spectrograms and spectrum curves. The results show good acoustic conditions, not unlike some ancient theatres, which reinforces the interpretation of the area as a major Neolithic open-air sanctuary.

Mobile craftspeople and orientalising transculturation in seventh-century BC Iberia

During the early first millennium BC, Phoenician peoples settled the Iberian coasts instigating cultural innovations known as the orientalising; indigenous communities of the interior have long been considered as passively dependent on, or isolated from, these developments. Recent excavations at the Early Iron Age village of Cerro de San Vicente in central Spain, however, have yielded domestic contexts that prompt reconsideration of this relationship. The authors use settlement layout, architecture and locally made tablewares to identify heterarchical organisation around virilocal and bilateral kinship and hybrid practices that attest to adoption of know-how and practices from distant places. Emphasis is placed on the role of embodied craftworking skills and female mobility in transculturation processes.

The Pre-Aksumite Period: indigenous origins and development in the Horn of Africa

ABSTRACT The Pre-Aksumite Period (mid-second to late first millennia BC) witnessed the rise of complex societies in the Horn of Africa. Archaeological survey and excavations in the Gulo Makeda region of Eastern Tigrai by the Eastern Tigrai Archaeological Project (ETAP) have produced new data and insights into this critical juncture in the cultural history of the region. Based on data from Mezber and other archaeological sites, we present a new Pre-Aksumite chronology and discuss the material culture, settlement, political organisation, economy, agricultural history and regional interactions of this period. We recommend the use of the term ‘Pre-Aksumite Period’ to encompass this time when the earliest polities developed in the region. Mezber provides us with a glimpse into the lifeways of indigenous peoples inhabiting the northern Horn of Africa who encountered South Arabian visitors to the region during the early first millennium BC. Data from Mezber shift our focus from external influences to considering the culture and development of autochthonous peoples of the Ethiopian/Eritrean highlands who had an active role in negotiating cultural contacts. This perspective constitutes a missing piece of the puzzle needed to better understand the broader socio-economic, political and cultural dynamics of the Pre-Aksumite Period.

THREE TYPES OF INDUSTRY IN THE STONE AGE OF GOBUSTAN

In the east of the Republic of Azerbaijan, in Gobustan district, there are numerous Stone Age sites with preserved culture-bearing deposits. Interest in the richest rock art sites concentrated there overshadowed studying the stone inventory of the region’s earliest sites relegating them to the background. In this work, the author proposes a general systematization of the materials of the Gobustan Stone Age. The paper contains detailed typological lists of key sites; suggests the criteria for dividing the material into three cultural and chronological groups; and substantiates a new view on the chronology and local peculiarities of these groups that is different from previously held ones in many respects. For the sites of the Upper Palaeolithic of Gobustan, an estimated age is proposed corresponding to the period prior to maximum of the Würm glaciation (i.e., no later than approximately 25–20 thousand years ago). The lower date of the Mesolithic layers correlates roughly with the end of the Allerød and the Younger Dryas (approximately 14–12 thousand years ago). The emergence of the local Neolithic is attributed approximately to the early 6th millennium BC.

Dorstone Hill: a Neolithic timescape

Studies of early fourth-millennium BC Britain have typically focused on the Early Neolithic sites of Wessex and Orkney; what can the investigation of sites located in areas beyond these core regions add? The authors report on excavations (2011–2019) at Dorstone Hill in Herefordshire, which have revealed a remarkable complex of Early Neolithic monuments: three long barrows constructed on the footprints of three timber buildings that had been deliberately burned, plus a nearby causewayed enclosure. A Bayesian chronological model demonstrates the precocious character of many of the site's elements and strengthens the evidence for the role of tombs and houses/halls in the creation and commemoration of foundational social groups in Neolithic Britain.

TWO BRONZE AGE MINIATURE WAGON AND WHEEL BURIALS IN ENCS (NORTH‐EASTERN HUNGARY)

SummaryDuring an excavation of a Bronze Age, Füzesabony‐culture cemetery at Encs (north‐eastern Hungary), a clay wagon model with spoked wheels (grave 1290) and three miniature solid clay wheels were found (grave 1389). Miniature wagon and wheel models in burials began to appear in the Late Copper Age and lasted until the Iron Age in Central Europe. Their presence allows of several interpretations. These spoked wheels of grave 1290 provide early evidence about the appearance of such in the Carpathian Basin. Focussing on the two graves from Encs, this article reports AMS radiocarbon dates that suggest the spoked wheels belong to the early second millennium BC. The implications of these finds are interpreted though a comparative review of both wagon models from the Füzesabony culture and the evidence for early spoked wheels in the Carpathian Basin.

Milk and meat exploitation, autumn lambing and use of forest resources in Neolithic Corsican sheep farming systems (fifth to third millennia cal BC)

Corsica has been inhabited since the ninth millennium BC, but it is only from the sixth millennium BC onwards, that Neolithic societies originating from Italy settled mostly along coastal areas but also inland, in high mountainous areas. By then, Corsica was already experiencing some Mediterranean climate trends and was covered with dense forests. In order to assess how these Neolithic societies sustainably occupied this new insular territory, we need to understand how the local environment and resources were incorporated in the pastoral system. Osteological and isotopic analyses on remains from the sites of Araguina Sennola (late fifth – early third millennia cal BC) and Montlaur (4100–3600 cal BC) investigated the key parameters of these husbandry systems. Sheep mortality profiles from dental remains suggest mixed meat and milk exploitation. Modelled intra-tooth variations of oxygen isotope ratios (δ18O) revealed extended birth season, including autumnal lambing. Carbon isotope ratios (δ13C) showed high seasonal variation, involving forest resources in winter, as well as high-δ13C summer plant resources, possibly C4 plants from coastal salt marshes. This raises the question of the seasonal mobility of herds. Great inter-individual variability in δ13C values reflects variable degrees and patterns of mobility, suggesting that herders adapted to the conditions of the contrasted Mediterranean landscape.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial.

LBA500 Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented. Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and premenopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy. Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals. Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease. Clinical trial information: NCT03701334 .

Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer undergoing neoadjuvant chemotherapy: A comparison between patients with triple negative breast cancer (TNBC) and non-TNBC.

e14546 Background: Checkpoint proteins regulate the immune system. Breast cancer is associated with up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (sICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) and compare the biological behaviour of these sICMs between TNBC and non-TNBC patients. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data were prospectively obtained and levels were compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in the activation of CD8+ cytotoxic T cells, were significantly increased (p < 0.04-p < 0.00001). Four of the soluble co-inhibitory checkpoints (LAG-3, PDL1, TIM-3 and HVEM) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p < 0.03 and p < 0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints seemingly indicates a reversal of systemic immune dysregulation following the administration of NAC in early BC. In contrast, recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. No significant differences were detected between the changes of 16 sICMs levels at pre-NAC, post-NAC and post-surgery when comparing the TNBC and non-TNBC patients. Conclusions: This study demonstrates low levels of co-stimulatory and co-inhibitory sICMs in newly-diagnosed, non-metastatic BC pts. Following treatment with NAC, the sICMs levels increase substantially, except CTLA-4. In the case of co-stimulatory sICMs, these novel findings are indicative of an immune-restorative mechanism. The pattern of co-inhibitory sICMs (elevated levels of PD-L1, LAG-3, TIM-3 and HVEM), might be indicative of immune-therapeutic resistance, underscoring the augmentative immune-therapeutic promise of targeting these molecules, either individually or in combination, to improve the outcome of pts with early BC. These differences were not significant between TNBC and non-TNBC patients.

Меотские сероглиняные кружки IV–III вв. до н.э.

The article is devoted to the typology and chronology of gray clay cups from the Maeotian burial grounds on the right bank of the Kuban river. Type 1 refers to biconical cups with a high, narrow neck widening upwards (30 items). A little over half of the studied vessels come from assemblages with a wide chronological range dating back to the 4th and early 3rd centuries BC, where they are accompanied by swords of the Sindian-Maeotian type or sets of pottery characteristic of this period. The remaining burials with cups can be dated more precisely by the finds of container amphorae from different centers (Heraclea, Thasos, Ikos, Mende, Sinope, etc.). The wide chronological framework of the existence of type 1 cups among the Maeotians can be determined within the first half of the 4th century BC, but their narrow chronology is limited to the second quarter of this century. Two versions of the origin of cups of this shape are put forward: the first one is from imported red clay vessels; the second one is from hand-made cups of the 6th–5th centuries BC. Type 2 is truncated conical cups widening upwards (13 items). There are not enough strong chronological references for a narrow dating of this type of cups. Furthermore, apart from the cups, imported vessels were found in the three assemblages including amphorae of Rhodes, a black glazed plate and a fish plate. As the analysis of the assemblages shows, type 2 cups existed among the Maeotians for a rather limited period from the late 3rd century BC up until the beginning of the next century.

TOWARDS A RADIOCARBON-BASED CHRONOLOGY OF URBAN NORTHERN MESOPOTAMIA IN THE EARLY TO MID-SECOND MILLENNIUM BC: INITIAL RESULTS FROM KURD QABURSTAN

ABSTRACTRadiocarbon (14C) data for 2nd millennium BC urban sites in northern Mesopotamia have been lacking until recently. This article presents a preliminary dataset and Bayesian model addressing the Middle and early Late Bronze Age (Old Babylonian and pre/early Mittani) strata of Kurd Qaburstan—one of the largest archaeological sites on the Erbil plain of Iraqi Kurdistan. The results place the large, densely occupied and fortified Middle Bronze Age city in the first part of the 18th century BC, an outcome consistent with the site’s tentative identification as ancient Qabra. A long occupation gap (up to two centuries) probably ensued, before a smaller town confined to the high mound and part of the northeastern lower town resumed in the late 16th and early 15th centuries BC, possibly before this region became part of the Late Bronze Age kingdom of Mittani.

INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–) PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC).

TPS1123 Background: Standard-of-care (SoC) endocrine therapy (ET) for pts with HR+, HER2– LA/mBC was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. ALP (a selective PI3Kα inhibitor; PI3Kαi) + FUL is approved for pts with HR+, HER2–, PIK3CAmut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. INAVO is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CAmut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. Methods: INAVO121 (NCT05646862) is a Phase III, randomized, open-label study evaluating INAVO + FUL vs. ALP + FUL in pts with HR+, HER2–, PIK3CAmut LA/mBC (confirmed by circulating-tumor DNA or tumor tissue), who progressed during or after a CDK4/6i-based regimen with adequate hematologic and organ function. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy are allowed. Pts are randomized 1:1 to receive INAVO (9 mg oral daily; PO QD) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle [C] 1, then D1 of subsequent cycles), or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs. no) and prior CDK4/6i therapy (adjuvant vs. metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. The study is open for enrollment, targeting 400 pts at ~200 sites globally. A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. Clinical trial information: NCT05646862 .

Efficacy analysis of CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) treatment in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (aBC): Biomarker analysis including chemoendocrine score (CES) by CDKi type in SOLTI-1801_CDK-PREDICT study.

1065 Background: CDKi + ET improved progression-free survival (PFS) and ribociclib also overall survival (OS) in HR+/HER2- aBC first-line setting. Intrinsic subtypes (IS) are prognostic and predict benefit from CDKi + ET (Finn. SABCS 2017, Prat. JCO 2021, Tolosa. SABCS 2022). We previously reported a PAM50-based CES in HR+/HER2-negative early BC (Prat et al. CCR 2016). Here, we evaluated the association of CES with PFS following CDKi therapy in aBC. Methods: CDK-PREDICT prospectively evaluated 113 HR+/HER2- aBC patients (pts) treated in the first-line setting with CDKi + ET. RNA from FFPE metastatic tumors was analyzed at the nCounter (Nanostring Technologies) using a 72 custom gene panel including the PAM50 genes. CES was evaluated as a continuous variable, and categorically (CES-E[endocrine-sensitive], CES-I[intermediate] and CES-C[chemo-sensitive]) using the previously reported cut-offs. Multivariable analyses were used to test CES association with PFS. Results: The median follow-up for PFS was 18.5 m. PAM50 IS and CES distribution are shown. No statistically significant difference in mPFS by CDKi. CES (as a continuous variable or as group categories) was found significantly associated with mPFS. mPFS for CES-E pts was NR (95% CI: 26.0 - NR), 20.7m for CES-I (95% CI: 14.2 – 31.7m; HR= 1.98, p<0.05) and 11.7m for CES-C (CI 95%: 7.0 - 18.8; HR= 3.72, p<0.05). CES-C was associated with lower PFS compared to CES-I (aHR= 0.55, p=0.10) and CES-E (aHR= 0.29, p<0.05) independent of CDKi, ET, intrinsic subtype (Luminal versus not), endocrine sensitivity, onset metastatic and visceral disease. CES-C was significantly associated with higher expression of, MIA and lower expression of CCND1, CCNE1, FOXA1, MLPH and UBE2T compared with CES-E (p< 0.05). In CES-E pts mPFS for palbociclib was NR (IC95:22.9-NR) compare with 43.8 m for ribociclib (IC95: 12.0-NR); aHR=1.17 p=0.546), in CES-I pts mPFS for palbociclib was 18.9 m (IC95: 5.8-27.3) compare with 31.7 m for ribociclib (IC95: 12.2-NR); aHR=0.50 p=0.294), and in CES-C pts mPFS for palbociclib was 11.6 m (CI95: 2.7-15-7) compare with 10.0 m for ribociclib (CI95: 2.1-NR; aHR=0.48 p=0.102). Abemaciclib not reported due to low numbers (n=16). Conclusions: We confirmed independent prognostic value of CES in first-line setting, suggesting a not statistically significant benefit with ribociclib vs palbociclib in CES-I. [Table: see text]

HER2CLIMB-05: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer.

TPS1115 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .

Real de-escalation or escalation in disguise?

The past two decades have seen an unprecedented trend towards de-escalation of surgical therapy in the setting of early BC, the most prominent examples being the reduction of re-excision rates for close surgical margins after breast-conserving surgery and replacing axillary lymph node dissection by less radical procedures such as sentinel lymph node biopsy (SLNB). Numerous studies confirmed that reducing the extent of surgery in the upfront surgery setting does not impact locoregional recurrences and overall outcome. In the setting of primary systemic treatment, there is an increased use of less invasive staging strategies reaching from SLNB and targeted lymph node biopsy (TLNB) to targeted axillary dissection (TAD). Omission of any axillary surgery in the presence of pathological complete response in the breast is currently being investigated in clinical trials. On the other hand, concerns have been raised that surgical de-escalation might induce an escalation of other treatment modalities such as radiation therapy. Since most trials on surgical de-escalation did not include standardized protocols for adjuvant radiotherapy, it remains unclear, whether the effect of surgical de-escalation was valid in itself or if radiotherapy compensated for the decreased surgical extent. Uncertainties in scientific evidence may therefore lead to escalation of radiotherapy in some settings of surgical de-escalation. Further, the increasing rate of mastectomies including contralateral procedures in patients without genetic risk is alarming. Future studies of locoregional treatment strategies need to include an interdisciplinary approach to integrate de-escalation approaches combining surgery and radiotherapy in a way that promotes optimal quality of life and shared decision-making.

Selective avoidance of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with HER-2 positive/triple negative breast cancer: Prospective, multi-center, single-arm study (ASLAN).

TPS624 Background: According to advanced neoadjuvant chemotherapy (NACT), which dual HER2 blockage in HER2+ BC and adding carboplatin or immunotherapy in triple-negative breast cancer (TNBC) increased pathologic complete response (ypCR) rates up to 68% and 80%. Because ypCR patients showed better survival, the indications for NACT have expanded to early BC and the expected ypCR rate has increased. Therefore, it may be reasonable to consider omitting surgery in cases with excellent responses to NACT. Several recent retrospective studies and pilot prospective studies have reported axillary pathologic complete response (ApCR) is highly correlated with breast pathologic complete response (BpCR) in HER2+ or TNBC after NACT. The current report describes the design of omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+ or TNBC patients with excellent response. Similarly, EUBREAST-01 (NCT04101851) study is ongoing omission of sentinel lymph node biopsy (SLNB) after NACT in HER2+/TNBC with radiologic complete remission and a BpCR. Methods: The ASLAN trial is a prospective, multicenter, single-arm, clinical study. Five tertiary care hospitals in South Korea are participating. Inclusion criteria: women aged 20-69; cT1-3N0-1M0; HER2+ or TNBC (defined by ER-negative (< 10% positive cells in IHC) and PgR-negative (< 10% positive cells in IHC)); expected complete remission at physical examination and radiological expected Tumor size ≤ 2cm or non-mass enhancement ≤ 4cm at breast MRI after standard NACT; planned breast conserving surgery (BCS) with whole-breast irradiation; ECOG performance status 0-1. Exclusion criteria: SLNB before NACT; previous axillary surgery; bilateral BC. Patients who are eligible proceed BCS. After BCS, patients who showed BpCR are enrolled with omission of SLNB. Patients with no BpCR proceed with routine axillary surgery. The assumption for acceptable 5-year RFS ≥84% is based on previous study findings. The calculated total case number for per- protocol analysis is N=178. Primary endpoint: 5-year recurrence free survival. Secondary endpoint: local recurrence free survival, breast cancer specific survival, overall survival, ipsilateral axillary recurrence interval, distant metastasis free survival, contralateral breast free survival, re-operation rate according to breast biopsy after NACT, adverse event, and quality of life. The first patient was enrolled on September 2021. Among 147 patients who screened, 106 patients have been enrolled in January 2022. We plan to complete the target accrual by December 2025. Clinical trial information: NCT04993625 .

West Semitic Lexicon in Sumerian

Sumer’s conquest by Semitic-speaking peoples from the west is symbolized by the history of Sargon of Akkad. Assyrian sources report that he was the son of an unknown father, associated with hilly regions, born in the west on the banks of the Euphrates, and defeated Lugalzagesi of Uruk (Liverani, 2013). This narrative has influenced both historical reconstructions and the perception of cultural and linguistic contact between the Semitic and Sumerian worlds. Indeed, while the absorption of syntactic, morphological, and lexical features from Sumerian into Akkadian and West Semitic languages has been studied extensively (Zólyomi, 2012), little has been said about Semitic influences in Sumerian, especially West Semitic. Certainly, until the early second millennium BC, Sumerian remained an evolving linguistic system rather than a frozen substrate, acquiring Semitic features (Streck, 1998). Yet before the Akkadian empire’s foundation, West Semitic lexicon seems to have penetrated Sumerian, already in its formative period.