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Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and high relapse rates. The incorporation of immune checkpoint inhibitors (ICIs), particularly anti–PD-1/PD-L1 agents, into neoadjuvant chemotherapy (NAC) has improved outcomes for some patients. However, not all individuals benefit, and the risk of immune-related adverse events (irAEs) necessitates robust predictive biomarkers to guide treatment selection.

Less than 10% of patients experience meaningful benefit from the addition of ICIs to NAC. Hence, identifying biomarkers predictive of immunotherapy response remains an urgent priority.

Rationale for Tumor-Specific MHC-II (tsMHC-II)

Tumor-specific MHC class II expression has emerged as a promising immunotherapy biomarker in melanoma, bladder cancer, and now breast cancer. While MHC-II is traditionally associated with antigen-presenting cells, it can also be expressed on epithelial tumors, including breast cancers.

MHC-II molecules (e.g., HLA-DR) present exogenous antigens to CD4⁺ T cells, potentially activating adaptive immunity within the tumor microenvironment. The expression of these molecules on tumor cells (tsMHC-II) may signal an inflamed, immune-responsive tumor phenotype, making them especially relevant in the context of PD-L1 blockade.

 

NeoTRIPaPDL1 Trial design

The NeoTRIPaPDL1 trial was a phase III, multicenter, randomized, open-label study designed to test whether adding the PD-L1 inhibitor atezolizumab to neoadjuvant chemotherapy improves outcomes in high-risk early-stage triple-negative breast cancer. About 280 patients were assigned to receive eight cycles of carboplatin plus nab-paclitaxel, either alone or in combination with atezolizumab, followed by surgery and optional anthracycline chemotherapy.

The primary endpoint was event-free survival, with pathological complete response as a key secondary endpoint. To support translational research, baseline and on-treatment biopsies were collected and analyzed using advanced methods such as imaging mass cytometry, focusing on biomarkers like tumor-specific MHC-II. Conducted across multiple centers in Europe, Russia, and Asia, the trial combined rigorous clinical evaluation with biomarker discovery, aiming to refine patient selection for chemo-immunotherapy in triple-negative breast cancer.

NeoTRIPaPDL1 Trial Results

In the NeoTRIPaPDL1 trial, tumor-specific MHC-II expression was found in a substantial proportion of patients. Using the predefined 5% cutoff, 41% of triple-negative breast cancers were considered tsMHC-II positive, while application of a stricter exploratory cutoff identified positivity in about 20% of cases. The predictive value of this biomarker was most apparent in the chemo-immunotherapy arm. At the 5% cutoff, tsMHC-II positivity was associated with significantly higher pathological complete response rates, with an odds ratio of 2.58 and a p-value of 0.016. When the exploratory 80th percentile cutoff was applied, the association was even stronger, yielding an odds ratio of 4.19 and a p-value of 0.006.

In contrast, in the chemotherapy-only arm, tsMHC-II expression was not predictive of response. The odds ratio was 1.37 with a p-value of 0.34 at the 5% cutoff, and 1.03 with a p-value of 0.956 at the 80th percentile cutoff, indicating no meaningful relationship. Importantly, when tsMHC-II expression was evaluated as a continuous variable, a statistically significant interaction between biomarker status and treatment effect was observed, with a p-value of 0.006. Supporting these findings, receiver-operator characteristic analysis demonstrated improved predictive accuracy for pCR in the chemo-immunotherapy group compared to chemotherapy alone.

Together, these results underline the potential of tsMHC-II as a clinically relevant biomarker to identify patients most likely to benefit from the addition of atezolizumab to neoadjuvant chemotherapy in early-stage triple-negative breast cancer.

Insights and Discussion

• TsMHC-II consistently emerged as a predictive biomarker of ICI benefit in TNBC, unlike stromal TILs and PD-L1, which are largely prognostic or predictive of chemotherapy response.
• IMC provided greater sensitivity than traditional IHC or protein arrays, necessitating alternative cutoffs but confirming validity across methods.
• While the NeoTRIP regimen (atezolizumab + carboplatin/nab-paclitaxel) differs from the currently approved pembrolizumab-based NAC regimen, findings support tsMHC-II as a robust biomarker candidate.
• Limitations include lack of event-free survival (EFS) data and protocol-defined biomarker validation, making this an exploratory correlative analysis.

Key Takeaway Messages

• Tumor-specific MHC-II expression predicts pathological complete response specifically to chemo-immunotherapy, not chemotherapy alone, in early-stage TNBC.
• TsMHC-II outperforms PD-L1 and TILs as a predictive biomarker for immunotherapy benefit.
  Ongoing Phase III trials (e.g., S1418, S2206) will further evaluate tsMHC-II in early breast cancer, with assay harmonization efforts underway.
• If validated prospectively, tsMHC-II could enable personalized immunotherapy selection, sparing non-responders from unnecessary toxicity.

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(Bloomberg) — The dollar gained and global equities held near record highs as the election of a pro-stimulus leader in Japan added momentum to gains in Asia.

The greenback rose against all Group-of-10 peers, while gold backtracked from an earlier 0.4% gain which set another record as political crises around the world lifted demand for the haven asset. The MSCI Asia Pacific Index pared an advance of as much as 0.4% that had taken it to a new intraday peak with chips and technology stocks leading. European and US equity-index futures were flat.

Japanese shares extended their rally after Sanae Takaichi’s near-certain ascent to become the country’s next prime minister had sent the yen sliding and drove up yields on long-tenor bonds. Japanese bond futures pared their losses after an auction of 30-year government bonds drew firm demand.

While equities worldwide have surged to successive record highs, worries over the US government shutdown and a political crisis in France have driven investors toward alternative assets such as gold and Bitcoin, sending both to new peaks. At the same time, a flurry of AI-related deals among chipmakers has propelled shares higher and fueled some concerns of a speculative bubble reminiscent of the late-1990s dot-com era.

“Semiconductors are ‘on fire,’” said Louis Navellier at Navellier & Associates. “The AI narrative continues to gain momentum.”

Technology stocks have been powering a global equity rally, with Monday’s AMD deal being the latest big-budget data center agreement this year.

It follows last month’s announcement that Nvidia Corp. was planning to invest as much as $100 billion in OpenAI amid demand for tools like ChatGPT and the computing power needed to make them run.

Tech firms are spending hundreds of billions of dollars on advanced chips and data centers, and the final bill may run into the trillions. The financing is coming from venture capital, debt and, lately, some more unconventional arrangements that have raised eyebrows on Wall Street.

Meantime, Chinese and Hong Kong markets were closed Tuesday.

Takaichi’s election shook up global markets Monday with stocks surging on prospects for more spending, while currencies and bonds weakened. The yen held its losses, hovering around the highly watched 150-a-dollar level.

“I think there’s definitely some more room to sell off, but at the same time I think this might be an overreaction,” said Tracy Chen, a portfolio manager at Brandywine Global, on Bloomberg TV.

Options traders are the least bullish on the yen in more than three years now that Takaichi appears in line to become the next prime minister.

Volatility in Japan’s longer-dated government bonds is on the rise following Takaichi’s win, and the moves may spill over to markets as far away as the US and UK, according to Goldman Sachs Group Inc.

What Bloomberg strategists say…

“Japan’s 30-year auction went off smoothly with a higher bid-to-cover ratio than the previous sale, which will be a relief for investors across G-10 long-term debt. A solid auction, but investors won’t get too excited about JGBs until they are certain whether Takaichi will be confirmed as prime minister.”

— Mark Cranfield, MLIV strategist.

Meanwhile, Goldman Sachs Group Inc. raised its gold forecast for December 2026 to $4,900 an ounce, up from $4,300, citing ETF inflows and central-bank buying. According to the latest data, the People’s Bank of China added to its gold holdings in September for an 11th consecutive month.

Such frenzied buying amid a broad decline in the dollar has lifted gold’s gains this year to more than 50%, putting the metal on track for its strongest annual advance since 1979. Investors starting to view gold as a safer asset than the dollar is “really concerning,” said Citadel’s billionaire investor Ken Griffin.

This year, traders have been betting more on gold, silver and Bitcoin, in what’s been called the “debasement trade.” The sudden push to a fresh all-time high in Bitcoin over the weekend has options traders adding to bets that the largest cryptocurrency will rally to $140,000.

Corporate News:

LG Electronics Inc.’s Indian unit is set to start taking orders for its $1.3 billion initial public offering, joining Tata Capital Ltd. to launch deals in what could be a record month for new listings in the country. A devastating fire at a major supplier for Ford Motor Co. is set to disrupt business for months, the Wall Street Journal reported. Elliott Investment Management has approached several Japanese companies about buying their shares in Sumitomo Realty & Development Co., according to people familiar with the matter. Some of the main moves in markets:

Stocks

S&P 500 futures were little changed as of 6:52 a.m. London time Nasdaq 100 futures were little changed Futures on the Dow Jones Industrial Average fell 0.2% The MSCI Asia Pacific Index was little changed The MSCI Emerging Markets Index rose 0.3% Japan’s Topix was little changed Euro Stoxx 50 futures were little changed Currencies

The Bloomberg Dollar Spot Index was little changed The euro fell 0.2% to $1.1693 The Japanese yen was little changed at 150.48 per dollar The offshore yuan was little changed at 7.1387 per dollar The British pound fell 0.2% to $1.3458 Cryptocurrencies

Bitcoin fell 0.7% to $124,399.81 Ether rose 0.5% to $4,715.51 Bonds

The yield on 10-year Treasuries was little changed at 4.15% Germany’s 10-year yield advanced two basis points to 2.72% Britain’s 10-year yield advanced five basis points to 4.74% Japan’s 10-year yield declined one basis point to 1.670% Australia’s 10-year yield advanced five basis points to 4.39% Commodities

Spot gold was little changed West Texas Intermediate crude rose 0.3% to $61.89 a barrel This story was produced with the assistance of Bloomberg Automation.

–With assistance from John Cheng and Joanne Wong.

©2025 Bloomberg L.P.