쉐도잉 연습: PARP Inhibitors: 2023 Updates - 영상으로 영어 말하기 배우기

연습 모드 선택

각 모드는 전체 화면 연습실로 열립니다.

179 문장

문장이 너무 짧거나 길면 Edit를 눌러 조정하세요.

Thank you for joining us for this session on PARP inhibitors.

PARP inhibitors have been one of the most exciting advancements in the treatment of ovarian cancer in years,

but recently have come under increasing scrutiny from the Food and Drug Administration.

Dr. Ginny Fleming from the University of Chicago will update us on the latest.

Dr. Fleming is Professor of Medicine and Director of the Medical Gynecologic Oncology program at the University of Chicago,

and we're thrilled to have her join us for this session.

Hello, it's a pleasure to be here with you to discuss

some of the changing indications for PARP inhibitors in the treatment of ovarian cancer.

Here are the topics I'm going to try to cover.

First, what is HRD?

Second, in brief, how do PARP inhibitors work?

Third, which ones are currently FDA -approved and for what ovarian cancer indications?

And finally, what has been a whirlwind of changes,

what are the recent changes in the FDA -approved settings for PARP inhibitor use for women with ovarian cancer?

And what has motivated these changes.

First, homologous DNA repair, sometimes abbreviated HR for homologous repair.

DNA is what carries the messages for all the proteins and enzymes in our body.

It's the mat for everything.

DNA is usually wound together in double strands, and there can occur from many various reasons,

ultraviolet light, many other things, breaks in the DNA.

And these are primarily repaired by what we call the homologous recombination repair pathway, the HR repair pathway.

The BRCA gene is involved in homologous repair.

A mutated BRCA gene does not do its job, So cells with BRCA deficiency lack HR repair,

and they're referred to as HR deficient or HRD.

Ovarian cancers may also harbor many other alterations which lead to deficiency in the HR pathway,

and these tumors are also referred to as HRD.

About half of ovarian cancers are HRD, including those with germline or tumor BRCA alterations.

Homologous recombination deficiency leads to increased sensitivity of cancers to both platinum therapy and PARP inhibitor therapy.

Tests for HRD are generally done on the tumor, and there's a variety of approved companies that do these tests

and you are probably familiar with their use as physicians consider whether

or not PARP inhibitor maintenance should be used in a particular situation.

So PARP inhibitors, as you can see here, are also involved in the repair of DNA breaks.

That's a double -strand DNA diagram there and the PARP inhibitors help repair a single -strand break.

Single -strand breaks occur all the time, and PARP helps detect and repair them.

However, during the replication process, they convert single -strand breaks into double -strand breaks.

Normal cells then repair these by homologous recombination, but cells that are HRD do not have an effective repair pathway, and this leads to cell death.

So these are the cells, the HR -deficient cells, that are particularly sensitive to PARP inhibitors.

PARP inhibitors can clearly shrink ovarian cancer.

What is not so clear is in what situations they are better than other options

when they are used in trials of treatment.

The very first, I'm going to give some examples here of use in what we're calling treatment,

which is when it's used in the setting of measurable disease, usually not just as maintenance after chemotherapy.

So Rocaprib, one of the three PARP inhibitors approved for ovarian cancer,

was initially approved based on two actually quite small studies for

the total of 106 patients with high -grade ovarian cancer whose disease had progressed after two or more prior therapies.

All the women in this study had either a germline mutation or their tumor had a somatic mutation.

So a germline mutation is when the mutation is inherited and can be passed on to your children.

And it's found in all the cells of your body, blood cells, cells from a cheap swab.

But ovarian cancers can also have what we call somatic mutations.

And those are mutations that are only in the tumor and not passed on from, you know, parent to child.

Either one of these confers sensitivity to platinum or PARP inhibitor therapy.

The primary endpoint of the study, meaning how was the study designed, what was it designed to find, was response rates or rate of tumor shrinkage.

And in these two studies, the rate of tumor shrinkage was over 50%,

and these shrinkages lasted for a median or an average of 9 .2 months.

So that's if it shrank, how long did it stay shrink?

similarly another one of the PARP inhibitors used for ovarian cancer

olaparib was in an early study tested again in women all of whom had a germline BRCA1

or 2 mutation and who had more than three lines of prior chemotherapy

and was found to have a response rate of 34 percent where these responses lasted an average of eight months.

However, notice below

that you can see on this table divides the tumors treated

on this admittedly small group of patients into tumors in the situation that were expected to be platinum sensitive,

generally more than six months from prior platinum therapy and shrank with the prior platinum therapy, platinum resistant, so recurrence less than six months,

and platinum refractory progressed on platinum.

And you can see that the rate of tumor shrinkage was clearly highest in tumors that were platinum -sensitive,

and only two patients responded who had platinum refractory disease.

So clearly there is, as we say, non -cross -resistance between platinum and a PARP inhibitor.

Tumors that are resistant to platinum are much more likely to be resistant to PARP inhibitors as well.

And this will become important when we discuss why there have been some changes in indications for PARP inhibitors.

That is to say, they are no longer indicated.

The FDA no longer approves them for use as so -called treatment.

All the current approvals are only as maintenance.

So one very early trial, again, many years ago, one of the first PARP inhibitor trials, they compared PARP to liposomal doxorubicin in women,

all of whom had a germline BRCA mutation and had recurrence within 12 months of prior platinum therapy.

These women were only about 100 in total,

and they were randomized to one of two different doses of Olaprib versus liposomal doxorubicin,

and patients were permitted to cross over at the time of progression.

So a woman who was on doxyl could cross over at the time of progression to a PARP inhibitor and vice versa.

And here you see the schema of the trial, low -dose olaparib, higher -dose olaparib, and liposomal doxorubicin.

And here are the response rates and the progression -free survival.

So the progression -free survival was slightly higher in the high -dose olaparib than it was in liposomal doxorubicin,

but these results, all of them, were no different than what was expected to be with chance.

So here was an early trial that began to raise questions about, although PARP inhibitors clearly have activity, are they better than something else?

And a lot of the trials

that were used to try to gain FDA approval were trying to show

that PARP inhibitors were better than something else in some way.

So again, the terminology I'm using, when I say we're using it as treatment,

it's used to treat a cancer that would generally have progressed or recurred after some other therapy, although you could use it for first -line treatment.

But none of the PARP inhibitors are approved as first -line treatment.

Whereas maintenance, the drug is used to treat a cancer after chemotherapy has already decreased the size of the tumor

or made it disappear entirely.

And the idea is to maintain that response, hence maintenance therapy. So back in 2014,

Olaparib was approved by the FDA for use as treatment in patients who had BRCA -mutated ovarian cancer

and at least three or more rounds of prior treatment.

However, and by 2018, Rucaparib and Naraparib were also approved, and in 2022, the FDA began issuing withdrawals.

Currently, there are no more treatment approvals.

The approvals are for olaparib for maintenance,

niraparib as maintenance, and rucaparib as maintenance.

And the exact indications, whether for BRCA or for any platinum -sensitive disease, have varied by drug.

100

probably more due to details of trial design than because the different PARP inhibitors are so different.

101

However, we are expecting a withdrawal, the first withdrawal of maintenance of Rucaparib,

102

or may have already happened for platinum -sensitive disease.

103

What has been withdrawn, which indications are no longer FDA approved?

104

All the treatment indications.

105

So all the uses of PARP inhibitors other than as maintenance have been withdrawn by the companies in response to FDA communications.

106

And niraparib has been withdrawn for maintenance in platinum -sensitive recurrent disease for women and tumors that don't have BRCA mutations. So what happened?

107

Why would they approve all these things and then change it?

108

In general, of PARP inhibitors were initially approved based on information regarding progression -free survival,

109

how long the treatment could continue before the cancer grows, or response rate,

110

where response rate is generally in trials defined as percentage of subjects whose tumors shrink by 30 % or more.

111

But later data began suggesting that overall survival was not as positively affected as progression -free survival.

112

And in some trials, it appeared that the subjects getting PARP inhibitor therapy might even have decreased survival compared to controls.

113

In many, it wasn't statistically significant, but it was alarming.

114

There are a lot of arguments, as you can imagine, that have been flying about the validity of these different endpoints

115

that are used to try to justify FDA approval.

116

Again, the withdrawals are based on new overall survival information, which as you can imagine takes a lot longer to come by than tumor shrinkage.

117

Tumor shrinkage is the first thing that you get out of a clinical trial.

118

The time till the cancer grows takes longer and overall survival takes longer yet.

119

So it's years before we have an adequate data set to really assess overall survival.

120

Many of the trials were designed for progression -free survival, not overall survival.

121

So their size and design may not have been adequate for an accurate assessment of overall survival.

122

Crossover, as we discussed, is people who were, for example, randomized to placebo,

123

but then after progression, maybe broke the blind and then took a PARP inhibitor.

124

That's referred to as crossover.

125

And that might affect overall survival.

126

However, the hypothesis of people who are concerned about the decreased overall survival

127

that is numerically shown in some studies is since tumors that are resistant to PARP inhibitors are more resistant to platinum,

128

then taking PARP inhibitors may make subsequent treatment work less well.

129

As we showed, people with tumors who's resistant to carboplatin will not have as good a response to PARP inhibitors.

130

The converse is also true.

131

And again, to review the terminology, progression -free survival in a clinical trial is the time from

132

when drug therapy is started until the tumor grows or death of disease, if that happens first.

133

Overall survival, obviously, is the time from when drug therapy is started on the study until death of the patient from any cause.

134

I'm going to review for you one representative example.

135

There are too many to go over, but what a specific example of concern that is caused for a withdrawal of indication.

136

And I think that you'll find that if you look at all of them in detail, it's similar.

137

So the representative example I'm going to use is the trial is called the NOVA trial.

138

It was for niraparib, and it's in the setting of recurrent platinum -sensitive maintenance.

139

So this is the design of the NOVA trial.

140

Women who were on the trial had platinum -sensitive ovarian cancer.

141

with at least two prior platinum treatments.

142

So typically, they got platinum, maybe the cancer came back a year or two later, they got platinum again, and the tumor shrank.

143

And then at that point, they were randomized to either noreparib or to placebo.

144

So this was planned to be almost 500 patients participating,

145

and all of them had to have high -grade serous tumors.

146

And they had to be in complete or partial response to their most recent platinum therapy.

147

And then they were randomized to one of these two regimens, placebo or noreparib, to try to maintain that response, hence the term maintenance therapy.

148

So initial publication was in the New England Journal in 2016.

149

And you can see that if we look at the group of women who had noreparib maintenance compared to those with placebo.

150

they did better in all categories.

151

Those that got the most benefit were those that had a germline BRCA mutation.

152

And here you can see the time to progression was hugely improved, 21 months versus five months.

153

In women who are not germline BRCA mutated, the progression was also improved, although it was shorter overall, nine months versus about four months,

154

and so on and so forth for each of the subgroups.

155

Again, benefits seen in all subgroups and most dramatic for the germline BRCA mutated.

156

But when the later results then more recently came out, presented at 2023, again, overall survival takes years until we have the results,

157

you can see that there was not any real difference, even in the patients with the germline BRCA mutation,

158

that is 40 months, That's 40 .9 versus 38 .1, which, you know, is a little bit better.

159

But when these confidence intervals, that's what we call the numbers in the brackets here, 0 .61 to 1 .2.

160

When one is included in that, it's generally considered that it could have happened by chance.

161

And then numerically, in the patients who did not have a germline BRC mutation,

162

there was numerically worse survival in those who got niraparib, 31 months versus almost 35 in placebo.

163

Again, you can see that one is included in the confidence interval.

164

So none of these differences here are statistically significant.

165

They're all could be the same, and the differences seen between the two groups could be chance.

166

But again, there was concern that no survival benefit was seen.

167

And even if patients did cross over and take olaparib subsequently, it's hard to understand how that would make them have a shorter survival.

168

So the indication, again, for niraparib in the non -germline BRCA mutation was withdrawn as maintenance in the second -line setting.

169

Now, in the frontline setting, we don't have overall survival in most of the trials yet.

170

The one we do have is the SOLO1 frontline maintenance BRCA mutation carriers.

171

And here, there still seems to be an overall survival benefit,

172

although for technical reasons, it wasn't quite statistically significant in frontline.

173

And I think at this point, the frontline indications are still in place.

174

And this is probably where patients are going to get the most benefit.

175

And there's also appears to be the lowest risk of secondary myelodysplastic syndrome or leukemia, which is a concern.

176

So in conclusion, newer long -term trial results with overall survival continue to gradually come available.

177

There is clear benefit for BRCA mutation cares when PARP inhibitors are used in frontline maintenance, and I think focusing on frontline use,

178

where the benefit at this point still appears to be very strong is important.

179

Thank you.

앱 다운로드

유창하게 말하는 데 필요한 모든 것

AI 발음 평가문장마다 점수 확인

IPA 발음 연습모든 소리 마스터

단어 학습나만의 단어장 만들기

단어 게임놀면서 외우기

QR 스캔

Download on theApp Store Get it onGoogle Play

FOR YOU

이 레슨의 어휘와 말하기 포인트

이 말하기 레슨은 영상 “PARP Inhibitors: 2023 Updates”을(를) 바탕으로 합니다. 가장 자주 반복되는 단어는 다음과 같습니다: Parp, inhibitor, platinum, survival, tumor. 이 영상에는 섀도잉할 문장 179개와 단어 2557개가 있습니다. 말하는 구간의 길이는 18:18입니다. 화자는 분당 약 140단어의 일정한 속도로 말해서 섀도잉하기에 편한 속도입니다. 영어에서 가장 많이 쓰이는 3,000단어에 속하는 단어가 78%뿐이라 어휘가 어려운 편입니다.

이 영상의 핵심 어휘

영상에 나오는 익혀 둘 만한 단어 15개를 발음, 뜻과 함께 정리했습니다.

단어	발음	뜻
survival 명사	/sɚˈvaɪ.vəl/	생존
platinum 명사	/ˈplæt.ɪn.əm/	백금, 플래티나
tumor 명사	/tuː.məɹ/	종양
mutation 명사	/mjuˈteɪʃən/	변형, 변이
repair 동사	/ˈɹiːpɛɚ/	고치다, 수리하다
approve 동사	/əˈpɹuːv/	승인하다, 찬성하다
indication 명사	/ɪndɪˈkeɪʃən/	부호
sensitive 형용사	/ˈsɛn.sɪt.ɪv/	민감하다
versus	/ˈvɝsəs/	대
withdrawal 명사	/wɪðˈdɹɔ(ə)l/	인출, 출금
dose 명사	/ˈdəʊ̯s/	복용량
withdraw 동사	/wɪðˈdɹɔ/	후퇴하다, 취소하다
refer 동사	/ɹɪˈfɜː/	언급하다
occur 동사	/əˈkɜː/	일어나다, 발생하다
gene 명사	/d͡ʒiːn/	유전자

영상에 나오는 구동사

단어	발음	뜻
come back 동사		돌아오다
come out 동사	/ˌkʌm ˈaʊt/	나오다

이 영상의 문법

화자가 가장 많이 쓰는 문형을 영상 속 실제 표현과 함께 정리했습니다.

문형	영상 속 표현
현재완료 have/has + 과거분사 — 과거의 일이 지금도 관련이 있을 때	have been · have come · has been
수동태 be + 과거분사 — 누가 하는지보다 무슨 일이 일어나는지에 초점	is usually wound · are primarily repaired · is involved
관계절 who / which + 절 — 사람이나 사물에 대한 추가 정보	woman who was · people who were · people who are

주의할 발음

화자는 I'm, we're, don't 같은 축약형과 약화된 형태를 15번 사용합니다. 들리는 대로 짧게 발음하세요.

“th” 소리: withdrawal /wɪðˈdɹɔ(ə)l/, withdraw /wɪðˈdɹɔ/, pathway /ˈpæθˌweɪ/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, hypothesis /haɪˈpɒθɪsɪs/
“sh”와 “zh” 소리: mutation /mjuˈteɪʃən/, progression /pɹəˈɡɹɛʃən/, indication /ɪndɪˈkeɪʃən/, deficiency /dɪˈfɪʃənsi/, publication /ˌpʌblɪˈkeɪʃ(ə)n/
긴 단어 — 강세 위치에 주의: indication /ɪndɪˈkeɪʃən/, statistically /stəˈtɪs.tɪ.kə.li/, deficiency /dɪˈfɪʃənsi/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/

한국어 화자가 어려워하는 소리:

/f/ — ㅍ(/p/)으로 바꾸지 말고 윗니를 아랫입술에 대기: refer /ɹɪˈfɜː/, deficiency /dɪˈfɪʃənsi/, define /dɪˈfaɪn/, physician /fəˈzɪʃən/, justify /ˈd͡ʒʌstɪfaɪ/
/v/ — ㅂ(/b/)과 구별하기: survival /sɚˈvaɪ.vəl/, approve /əˈpɹuːv/, sensitive /ˈsɛn.sɪt.ɪv/, versus /ˈvɝsəs/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/
/z/ — ㅈ이 아니라 성대를 울리는 /s/: resistant /ɹəˈzɪstənt/, whereas /(h)wɛɹˈæz/, physician /fəˈzɪʃən/, positively /ˈpɑ.zɪ.tɪv.li/, enzyme /ˈɛn.zaɪm/

이 영상으로 연습하는 방법

먼저 말하지 않고 영상을 끝까지 듣고 모르는 단어를 적어 둡니다.
보통 속도로 한 문장씩 섀도잉하고, 화자의 리듬과 맞을 때까지 반복합니다.
자신의 목소리를 녹음해 원본과 비교하고, survival, platinum, tumor 같은 단어에 특히 주의합니다.

쉐도잉이란? 영어 실력을 빠르게 키우는 과학적 방법

쉐도잉(Shadowing)은 원래 전문 통역사 훈련을 위해 개발된 언어 학습 기법으로, 다언어 학자인 Dr. Alexander Arguelles에 의해 대중화된 방법입니다. 핵심 원리는 간단하지만 매우 강력합니다: 원어민의 영어를 들으면서 1~2초의 짧은 지연으로 즉시 소리 내어 따라 말하는 것——마치 '그림자(shadow)'처럼 화자를 따라가는 것입니다. 문법 공부나 수동적인 청취와 달리, 쉐도잉은 뇌와 입 근육이 동시에 실시간으로 영어를 처리하고 재현하도록 훈련합니다. 연구에 따르면 이 방법은 발음 정확도, 억양, 리듬, 연음, 청취력, 말하기 유창성을 크게 향상시킵니다. IELTS 스피킹 준비와 자연스러운 영어 소통을 원하는 분들에게 특히 효과적입니다.

섀도잉 방법: 단계별 전체 가이드 읽기 →

쉐도잉 연습: PARP Inhibitors: 2023 Updates - 영상으로 영어 말하기 배우기

연습 모드 선택

앱 다운로드

추천 영상

Dr. Isabelle Ray-Coquard | What Has Changed in Clinical Practice for ovarian Cancer in 2025?

PCR (Polymerase Chain Reaction)

Hypertrophic Cardiomyopathy - Patient’s Guide for Better Understanding

Sec Growth DataScience staff meeting Sep 14 2022

The Science of Obesity: Regeneron’s Research on Genetics, GLP-1s, and Quality Weight Loss

CNV analysis with Daniel Howrigan

What is AL amyloidosis?

Human Immortality 4K | Can Science Defeat Aging?

Sequential, Multiple Assignment, Randomized Trial Designs With Dr Kidwell

Interview with Dr. Peter Schwartz | SADS Live Episode 23 | July 31, 2020

Children’s Cancer Institute speeds genomic analysis with Azure, giving kids with cancer hope

SOFI: Sequence-based, cross-sectoral, One-health surveillance of food-borne infections | IMMEM XIV