Watanabe Hideki, Nakagomi Hiroshi, Hirotsu Yosuke, Amemiya Kenji, Mochizuki Hitoshi, Inoue Masayuki, Kimura Ayako, Omata Masao
Department of Surgery, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
Genome Analysis Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.
Breast Cancer Res Treat. 2022 Nov;196(2):255-266. doi: 10.1007/s10549-022-06731-z. Epub 2022 Sep 10.
The prognosis of HER2-positive breast cancer has improved with the development of anti-HER2 therapies. In order to further improve the prognosis of HER2-positive breast cancer, it is essential to elucidate the cells that survive during the therapy (drug-tolerant persister DTP).
Of the 2022 breast cancer patients operated at our institution during 2004-2018, 240 (12%) had HER2-positive breast cancer. Neo-adjuvant chemotherapy including trastuzumab (Tr-NAC) was administered to 94 of them. Forty-six of them were complete remission (CR), and 48 were non-CR. After 6.9 ± 3.7 years of follow-up, all 46 CR cases showed no recurrence (Cohort A), and 48 non-CR cases were divided into 31 cases with no recurrence (Cohort B) and 17 cases with recurrence (Cohort C). In addition to clinical backgrounds, we compared genomic profiles for 27 patients (Cohort A; 15/48, B; 7/31, and C; 5/17) who consented to genomic analysis.
Genomic abnormalities of TP53 and PIK3CA were frequently observed in biopsy samples pre Tr-NAC, but we found no differences between CR (Cohort A) and non-CR (Cohorts B + C). Then, we examined both of pre and post Tr-NAC samples of Cohort B (7) and C (5) to see the relationship between recurrence and genomic abnormalities. TP53 mutations were significantly more prevalent in Cohort C (5/5, 100%) than cohort B (3/7, 43%) in the surgical sample after treatment (p = 0.04). PyClone analysis of TP53 mutations showed that the cellular frequency of TP53 clones increased in 4 of 5 patients in Cohort C and none of B. On the other hand, we found no enhancement of PIK3CA mutant clones in Cohort C.
The DTP after Tr-NAC associated with subsequent relapse had TP53 mutations, suggesting that overcoming DTP with TP53 mutations is the most important clinical challenge.
Not applicable.
随着抗HER2疗法的发展，HER2阳性乳腺癌的预后有所改善。为了进一步改善HER2阳性乳腺癌的预后，阐明治疗期间存活的细胞（耐药持久性细胞，DTP）至关重要。
在2004年至2018年期间于我院接受手术的2022例乳腺癌患者中，240例（12%）为HER2阳性乳腺癌。其中94例接受了包括曲妥珠单抗在内的新辅助化疗（Tr-NAC）。其中46例达到完全缓解（CR），48例未达到CR。经过6.9±3.7年的随访，所有46例CR病例均无复发（队列A），48例未达到CR的病例分为31例无复发（队列B）和17例复发（队列C）。除临床背景外，我们还比较了27例同意进行基因组分析的患者（队列A；15/48，B；7/31，C；5/17）的基因组图谱。
在Tr-NAC前的活检样本中经常观察到TP53和PIK3CA的基因组异常，但我们发现CR组（队列A）和未达到CR组（队列B + C）之间没有差异。然后，我们检查了队列B（7例）和C（5例）的Tr-NAC前后样本，以观察复发与基因组异常之间的关系。治疗后的手术样本中，队列C（5/5，100%）的TP53突变明显比队列B（3/7，43%）更普遍（p = 0.04）。对TP53突变的PyClone分析表明，队列C的5例患者中有4例TP53克隆的细胞频率增加，而队列B中无一例增加。另一方面，我们在队列C中未发现PIK3CA突变克隆的增加。
Tr-NAC后与后续复发相关的DTP具有TP53突变，这表明克服具有TP53突变的DTP是最重要的临床挑战。
不适用。
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